10192393|t|A common human skin tumour is caused by activating mutations in beta-catenin.
10192393|a|WNT signalling orchestrates a number of developmental programs. In response to this stimulus, cytoplasmic beta-catenin (encoded by CTNNB1) is stabilized, enabling downstream transcriptional activation by members of the LEF/TCF family. One of the target genes for beta-catenin/TCF encodes c-MYC, explaining why constitutive activation of the WNT pathway can lead to cancer, particularly in the colon. Most colon cancers arise from mutations in the gene encoding adenomatous polyposis coli (APC), a protein required for ubiquitin-mediated degradation of beta-catenin, but a small percentage of colon and some other cancers harbour beta-catenin-stabilizing mutations. Recently, we discovered that transgenic mice expressing an activated beta-catenin are predisposed to developing skin tumours resembling pilomatricomas. Given that the skin of these adult mice also exhibits signs of de novo hair-follicle morphogenesis, we wondered whether human pilomatricomas might originate from hair matrix cells and whether they might possess beta-catenin-stabilizing mutations. Here, we explore the cell origin and aetiology of this common human skin tumour. We found nuclear LEF-1 in the dividing tumour cells, providing biochemical evidence that pilomatricomas are derived from hair matrix cells. At least 75% of these tumours possess mutations affecting the amino-terminal segment, normally involved in phosphorylation-dependent, ubiquitin-mediated degradation of the protein. This percentage of CTNNB1 mutations is greater than in all other human tumours examined thus far, and directly implicates beta-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans.. 
10192393	15	26	skin tumour	DiseaseClass	D012878
10192393	443	449	cancer	DiseaseClass	D009369
10192393	483	496	colon cancers	DiseaseClass	D003110
10192393	539	565	adenomatous polyposis coli	SpecificDisease	D011125
10192393	567	570	APC	SpecificDisease	D011125
10192393	670	698	colon and some other cancers	CompositeMention	D003110|D009369
10192393	855	867	skin tumours	DiseaseClass	D012878
10192393	879	893	pilomatricomas	SpecificDisease	D018296
10192393	1021	1035	pilomatricomas	SpecificDisease	D018296
10192393	1210	1221	skin tumour	DiseaseClass	D012878
10192393	1262	1268	tumour	Modifier	D009369
10192393	1312	1326	pilomatricomas	SpecificDisease	D018296
10192393	1385	1392	tumours	DiseaseClass	D009369
10192393	1615	1622	tumours	DiseaseClass	D009369

10194428|t|HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis.
10194428|a|Hereditary hemochromatosis (HH) is a common autosomal recessive genetic disorder of iron metabolism. The HFE candidate gene encoding an HLA class I-like protein involved in HH was identified in 1996. Two missense mutations have been described  C282Y, accounting for 80% to 90% of HH chromosomes, and H63D, which is associated with a milder form of the disease representing 40% to 70% of non-C282Y HH chromosomes. We report here on the analysis of C282Y, H63D, and the 193A-- > T substitution leading to the S65C missense substitution in a large series of probands and controls. The results confirm that the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, our screening showed that the S65C substitution was significantly enriched in probands with at least one chromosome without an assigned mutation. This substitution accounted for 7. 8% of HH chromosomes that were neither C282Y nor H63D. This enrichment of S65C among HH chromosomes suggests that the S65C substitution is associated with the mild form of hemochromatosis. 
10194428	30	45	hemochromatosis	Modifier	D016399
10194428	102	117	hemochromatosis	SpecificDisease	D006432
10194428	119	145	Hereditary hemochromatosis	SpecificDisease	D006432
10194428	147	149	HH	SpecificDisease	D006432
10194428	163	199	autosomal recessive genetic disorder	DiseaseClass	D030342
10194428	292	294	HH	SpecificDisease	D006432
10194428	399	401	HH	Modifier	D006432
10194428	516	518	HH	Modifier	D006432
10194428	779	794	hemochromatosis	SpecificDisease	D006432
10194428	892	894	HH	Modifier	D006432
10194428	1146	1148	HH	Modifier	D006432
10194428	1225	1227	HH	Modifier	D006432
10194428	1312	1327	hemochromatosis	SpecificDisease	D006432

10196379|t|Germline BRCA1 alterations in a population-based series of ovarian cancer cases.
10196379|a|The objective of this study was to provide more accurate frequency estimates of breast cancer susceptibility gene 1 (BRCA1) germline alterations in the ovarian cancer population. To achieve this, we determined the prevalence of BRCA1 alterations in a population-based series of consecutive ovarian cancer cases. This is the first population-based ovarian cancer study reporting BRCA1 alterations derived from a comprehensive screen of the entire coding region. One hundred and seven ovarian cancer cases were analyzed for BRCA1 alterations using the RNase mismatch cleavage assay followed by direct sequencing. Two truncating mutations, 962del4 and 3600del11, were identified. Both patients had a family history of breast or ovarian cancer. Several novel as well as previously reported uncharacterized variants were also identified, some of which were associated with a family history of cancer. The frequency distribution of common polymorphisms was determined in the 91 Caucasian cancer cases in this series and 24 sister controls using allele-specific amplification. The rare form of the Q356R polymorphism was significantly (P = 0. 03) associated with a family history of ovarian cancer, suggesting that this polymorphism may influence ovarian cancer risk. In summary, our data suggest a role for some uncharacterized variants and rare forms of polymorphisms in determining ovarian cancer risk, and highlight the necessity to screen for missense alterations as well as truncating mutations in this population. 
10196379	59	73	ovarian cancer	Modifier	D010051
10196379	161	174	breast cancer	Modifier	D001943
10196379	233	247	ovarian cancer	Modifier	D010051
10196379	371	385	ovarian cancer	Modifier	D010051
10196379	428	442	ovarian cancer	Modifier	D010051
10196379	564	578	ovarian cancer	Modifier	D010051
10196379	796	820	breast or ovarian cancer	CompositeMention	D001943|D010051
10196379	969	975	cancer	DiseaseClass	D009369
10196379	1063	1069	cancer	Modifier	D009369
10196379	1257	1271	ovarian cancer	SpecificDisease	D010051
10196379	1321	1335	ovarian cancer	Modifier	D010051
10196379	1459	1473	ovarian cancer	Modifier	D010051

10021369|t|Identification of APC2, a homologue of the adenomatous polyposis coli tumour suppressor.
10021369|a|The adenomatous polyposis coli (APC) tumour-suppressor protein controls the Wnt signalling pathway by forming a complex with glycogen synthase kinase 3beta (GSK-3beta), axin/conductin and betacatenin. Complex formation induces the rapid degradation of betacatenin. In colon carcinoma cells, loss of APC leads to the accumulation of betacatenin in the nucleus, where it binds to and activates the Tcf-4 transcription factor (reviewed in [1] [2]). Here, we report the identification and genomic structure of APC homologues. Mammalian APC2, which closely resembles APC in overall domain structure, was functionally analyzed and shown to contain two SAMP domains, both of which are required for binding to conductin. Like APC, APC2 regulates the formation of active betacatenin-Tcf complexes, as demonstrated using transient transcriptional activation assays in APC -/- colon carcinoma cells. Human APC2 maps to chromosome 19p13. 3. APC and APC2 may therefore have comparable functions in development and cancer.
10021369	43	76	adenomatous polyposis coli tumour	Modifier	D011125
10021369	93	132	adenomatous polyposis coli (APC) tumour	Modifier	D011125
10021369	357	372	colon carcinoma	Modifier	D003110
10021369	955	970	colon carcinoma	Modifier	D003110
10021369	1090	1096	cancer	SpecificDisease	D009369

100562|t|Familial deficiency of the seventh component of complement associated with recurrent bacteremic infections due to Neisseria.
100562|a|The serum of a 29-year old woman with a recent episode of disseminated gonococcal infection and a history of meningococcal meningitis and arthritis as a child was found to lack serum hemolytic complement activity. The seventh component of complement (C7) was not detected by functional or immunochemical assays, whereas other components were normal by hemolytic and immunochemical assessment. Her fresh serum lacked complement-mediated bactericidal activity against Neisseria gonorrhoeae, but the addition of fresh normal serum or purified C7 restored bactericidal activity as well as hemolytic activity. The absence of functional C7 activity could not be accounted for on the basis of an inhibitor. Opsonization and generation of chemotactic activity functioned normally. Complete absence of C7 was also found in one sibling who had the clinical syndrome of meningococcal meningitis and arthritis  as a child and in this siblings clinically well eight-year-old son. HLA histocompatibility typing of the family members did not demonstrate evidence for genetic linkage of C7 deficiency with the major histocompatibility loci. This report represents the first cases of C7 deficiency associated with infectious complications and suggests that bactericidal activity may be important in host defense against bacteremic neisseria infections.
100562	0	58	Familial deficiency of the seventh component of complement	SpecificDisease	OMIM:610102
100562	85	123	bacteremic infections due to Neisseria	DiseaseClass	D016870
100562	183	216	disseminated gonococcal infection	SpecificDisease	D004673
100562	234	258	meningococcal meningitis	SpecificDisease	D008585
100562	263	272	arthritis	DiseaseClass	D001168
100562	734	758	absence of functional C7	Modifier	OMIM:610102
100562	898	920	Complete absence of C7	SpecificDisease	OMIM:610102
100562	984	1008	meningococcal meningitis	SpecificDisease	D008585
100562	1013	1022	arthritis	DiseaseClass	D001168
100562	1196	1209	C7 deficiency	SpecificDisease	OMIM:610102
100562	1292	1305	C7 deficiency	SpecificDisease	OMIM:610102
100562	1428	1459	bacteremic neisseria infections	SpecificDisease	D016870

10078749|t|GCH1 mutation in a patient with adult-onset oromandibular dystonia.
10078749|a|The authors report a mutation in exon 5 of GCH1 in a patient with adult-onset oromandibular dystonia and no obvious family history of dystonia. The patient responded positively to treatment with L-dopa. These findings demonstrate that GCH1 mutations must be considered even in patients with dystonic symptoms not typical of dopa-responsive dystonia.
10078749	44	66	oromandibular dystonia	SpecificDisease	D008538
10078749	146	168	oromandibular dystonia	SpecificDisease	D008538
10078749	202	210	dystonia	DiseaseClass	D004421
10078749	359	367	dystonic	Modifier	D004421
10078749	392	416	dopa-responsive dystonia	SpecificDisease	C538007

10085150|t|The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells.
10085150|a|HFE is the protein product of the gene mutated in the autosomal recessive disease hereditary hemochromatosis (Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R. J., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., Kimmel, B. E., Kronmal, G. S., Lauer, P., Lee, V. K., Loeb, D. B., Mapa, F. A., McClelland, E., Meyer, N. C., Mintier, G. A., Moeller, N., Moore, T., Morikang, E., Prasss, C. E ., Quintana, L., Starnes, S. M ., Schatzman, R. C ., Brunke, K. J ., Drayna, D. T., Risch, N. J ., Bacon, B. R ., and Wolff, R. R . (1996) Nat. Genet. 13, 399-408). At the cell surface, HFE complexes with transferrin receptor (TfR), increasing the dissociation constant of transferrin (Tf) for its receptor 10-fold (Gross, C. N ., Irrinki, A., Feder, J. N ., and Enns, C. A . (1998) J. Biol. Chem. 273, 22068-22074; Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl . Acad. Sci. U S A 95, 1472-1477). HFE does not remain at the cell surface, but traffics with TfR to Tf-positive internal compartments (Gross et al., 1998). Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, we show that the expression of HFE reduces 55Fe uptake from Tf by 33% but does not affect the endocytic or exocytic rates of TfR cycling. Therefore, HFE appears to reduce cellular acquisition of iron from Tf within endocytic compartments. HFE specifically reduces iron uptake from Tf, as non-Tf-mediated iron uptake from Fe-nitrilotriacetic acid is not altered. These results explain the decreased ferritin levels seen in our HeLa cell system and demonstrate the specific control of HFE over the Tf-mediated pathway of iron uptake. These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in hereditary hemochromatotic individuals lacking functional HFE.
10085150	4	30	hereditary hemochromatosis	Modifier	D006432
10085150	170	197	autosomal recessive disease	DiseaseClass	D030342
10085150	198	224	hereditary hemochromatosis	SpecificDisease	D006432
10085150	2094	2120	hereditary hemochromatotic	Modifier	D006432

10090880|t|Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.
10090880|a|Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was cloned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3. Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF. The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region.
10090880	34	62	familial Mediterranean fever	SpecificDisease	D010505
10090880	200	228	Familial Mediterranean fever	SpecificDisease	D010505
10090880	230	233	FMF	SpecificDisease	D010505
10090880	240	258	recessive disorder	DiseaseClass	D030342
10090880	299	308	serositis	DiseaseClass	D012700
10090880	312	321	synovitis	DiseaseClass	D013585
10090880	327	330	FMF	Modifier	D010505
10090880	1087	1090	FMF	SpecificDisease	D010505
10090880	1522	1525	FMF	SpecificDisease	D010505

10090885|t|Autoimmune lymphoproliferative syndrome  with defective Fas: genotype influences penetrance.
10090885|a|Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A (-1) T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS.
10090885	0	39	Autoimmune lymphoproliferative syndrome	SpecificDisease	D056735
10090885	93	132	Autoimmune lymphoproliferative syndrome	SpecificDisease	D056735
10090885	134	138	ALPS	SpecificDisease	D056735
10090885	145	207	disorder of lymphocyte homeostasis and immunological tolerance	CompositeMention	D008232|D007154
10090885	412	416	ALPS	Modifier	D056735
10090885	968	972	ALPS	SpecificDisease	D056735
10090885	1191	1195	ALPS	Modifier	D056735
10090885	1471	1475	ALPS	Modifier	D056735
10090885	1538	1542	ALPS	Modifier	D056735
10090885	1773	1777	ALPS	SpecificDisease	D056735

10190819|t|Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy.
10190819|a|BACKGROUND  X-linked adrenoleukodystrophy (ALD) is an inherited disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. The classic form of ALD usually has onset in childhood (childhood cerebral ALD), with rapid neurologic deterioration leading to a vegetative state. Adult-onset cerebral ALD also presents with rapidly progressive neurologic dysfunction. Milder phenotypes such as adrenomyeloneuropathy and Addison disease only also have been recognized. Despite discovery of the causative gene, a molecular basis for the diverse clinical presentations remains to be elucidated. OBJECTIVES  To conduct mutational analyses in 29 Japanese patients with ALD from 29 unrelated families, to obtain knowledge of the spectrum of mutations in this gene, and to study genotype-phenotype correlations in Japanese patients. METHODS  The 29 patients comprised 13 patients with childhood cerebral ALD, 11 patients with adult-onset cerebral ALD, and 5 patients with adrenomyeloneuropathy. We conducted detailed mutational analyses of 29 unrelated Japanese patients with ALD by genomic Southern blot analysis and direct nucleotide sequence analysis of reverse transcriptase-polymerase chain reaction products derived from total RNA that was extracted from cultured skin fibroblasts, lymphoblastoid cells, or peripheral blood leukocytes. RESULTS  Three patients with adult-onset cerebral ALD were identified as having large genomic rearrangements. The remaining 26 patients were identified as having 21 independent mutations, including 12 novel mutations resulting in small nucleotide alterations in the ALD gene. Eighteen (69%) of 26 mutations were missense mutations. Most missense mutations involved amino acids conserved in homologous gene products, including PMP70, mALDRP, and Pxa1p. The AG dinucleotide deletion at position 1081-1082, which has been reported previously to be the most common mutation in white patients (12% -17%), was also identified as the most common mutation in Japanese patients (12%). All phenotypes were associated with mutations resulting in protein truncation or subtle amino acid changes. There were no differences in phenotypic expressions between missense mutations involving conserved amino acids and those involving nonconserved amino acids. CONCLUSIONS  There are no obvious correlations between the phenotypes of patients with ALD and their genotypes, suggesting that other genetic or environmental factors modify the phenotypic expressions of ALD.. 
10190819	94	123	X-linked adrenoleukodystrophy	SpecificDisease	D000326
10190819	137	166	X-linked adrenoleukodystrophy	SpecificDisease	D000326
10190819	168	171	ALD	SpecificDisease	D000326
10190819	179	196	inherited disease	DiseaseClass	D030342
10190819	226	248	neurologic dysfunction	SpecificDisease	D009461
10190819	279	300	adrenal insufficiency	DiseaseClass	D000309
10190819	322	325	ALD	SpecificDisease	D000326
10190819	358	380	childhood cerebral ALD	SpecificDisease	D000326
10190819	394	418	neurologic deterioration	DiseaseClass	D009461
10190819	462	474	cerebral ALD	SpecificDisease	D000326
10190819	514	536	neurologic dysfunction	DiseaseClass	D009461
10190819	564	585	adrenomyeloneuropathy	SpecificDisease	D000326
10190819	590	605	Addison disease	SpecificDisease	D000224
10190819	834	837	ALD	SpecificDisease	D000326
10190819	1048	1070	childhood cerebral ALD	SpecificDisease	D000326
10190819	1101	1113	cerebral ALD	SpecificDisease	D000326
10190819	1135	1156	adrenomyeloneuropathy	SpecificDisease	D000326
10190819	1239	1242	ALD	SpecificDisease	D000326
10190819	1546	1558	cerebral ALD	SpecificDisease	D000326
10190819	1771	1774	ALD	Modifier	D000326
10190819	2533	2536	ALD	SpecificDisease	D000326
10190819	2650	2653	ALD	SpecificDisease	D000326

6859721|t|Absence of the seventh component of complement in a patient with chronic meningococcemia presenting as vasculitis.
6859721|a|A previously healthy 40-year-old man presenting with fever, arthritis, and cutaneous vasculitis was found to have chronic meningococcemia. Evaluation of his complement system showed an absence of functional and antigenic C7, compatible with a complete deficiency of the seventh component of complement. Study of the patients family spanning four generations showed heterozygous deficiency of C7 in five members. Chronic neisserial infection can be associated with C7 deficiency and must be distinguished from other causes of cutaneous vasculitis.. 
6859721	0	46	Absence of the seventh component of complement	SpecificDisease	OMIM:610102
6859721	65	88	chronic meningococcemia	SpecificDisease	D008589
6859721	103	113	vasculitis	SpecificDisease	D014657
6859721	168	173	fever	SpecificDisease	D005334
6859721	175	184	arthritis	SpecificDisease	D001168
6859721	190	210	cutaneous vasculitis	SpecificDisease	D018366
6859721	229	252	chronic meningococcemia	SpecificDisease	D008589
6859721	367	416	deficiency of the seventh component of complement	SpecificDisease	OMIM:610102
6859721	493	509	deficiency of C7	SpecificDisease	OMIM:610102
6859721	527	555	Chronic neisserial infection	SpecificDisease	D016870
6859721	579	592	C7 deficiency	SpecificDisease	OMIM:610102
6859721	640	660	cutaneous vasculitis	SpecificDisease	D018366

10071185|t|Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency.
10071185|a|Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, including 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14 + 1G > A)] and 4 missense mutations (85T > C, 703C > T, 2658G > A, 2983G > T). Analysis of the prevalence of the various mutations among DPD patients has shown that the G-- > A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations. A clear correlation between the genotype and phenotype has not been established. An altered beta-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.
10071185	40	82	dihydropyrimidine dehydrogenase deficiency	SpecificDisease	D054067
10071185	84	132	Dihydropyrimidine dehydrogenase (DPD) deficiency	SpecificDisease	D054067
10071185	139	166	autosomal recessive disease	DiseaseClass	D030342
10071185	356	370	DPD deficiency	SpecificDisease	D054067
10071185	438	455	deficiency of DPD	SpecificDisease	D054067
10071185	745	748	DPD	Modifier	D054067
10071185	985	1005	convulsive disorders	DiseaseClass	D004829
10071185	1007	1024	motor retardation	DiseaseClass	D019957
10071185	1029	1047	mental retardation	DiseaseClass	D008607
10071185	1252	1274	clinical abnormalities	DiseaseClass	D013568
10071185	1304	1318	DPD deficiency	SpecificDisease	D054067

1323345|t|Molecular characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency by natural and amplification created restriction sites: five mutations account for most G6PD deficiency cases in Taiwan.
1323345|a|We have developed a rapid and simple method to diagnose the molecular defects of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Chinese in Taiwan. This method involves the selective amplification of a DNA fragment from human G6PD gene with specific oligonucleotide primers followed by digestion with restriction enzymes that recognize artificially created or naturally occurring restriction sites. Ninety-four Chinese males with G6PD deficiency were studied. The results show that 50% (47 of 94) were G to T mutation at nucleotide (nt) 1376, 21. 3% (20 of 94) were G to A mutation at nt 1388, 7. 4% (7 of 94) were A to G mutation at nt 493, 7. 4% (7 of 94) were A to G mutation at nt 95, 4. 2% (4 of 94) were C to T mutation at nt 1024, 1. 1% (1 of 94) was G to T mutation at nt 392, and 1. 1% (1 of 94) was G to A mutation at nt 487. These results show that the former five mutations account for more than 90% of G6PD deficiency cases in Taiwan. Aside from showing that G to T change at nt 1376 is the most common mutation, our research indicates that nt 493 mutation is a frequent mutation among Chinese in Taiwan. We compared G6PD activity among different mutations, without discovering significant differences between them.
1323345	30	81	glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
1323345	170	185	G6PD deficiency	SpecificDisease	D005955
1323345	284	335	glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
1323345	640	655	G6PD deficiency	SpecificDisease	D005955
1323345	1125	1140	G6PD deficiency	SpecificDisease	D005955

2828430|t|Homozygous hypobetalipoproteinemia: a disease distinct from abetalipoproproteinemia at the molecular level.
2828430|a|apoB DNA, RNA, and protein from two patients with homozygous hypobetalipoproteinemia (HBL) were evaluated and compared with normal individuals. Southern blot analysis with 10 different cDNA probes revealed a normal gene without major insertions, deletions, or rearrangements. Northern and slot blot analyses of total liver mRNA from HBL patients documented a normal size apoB mRNA that was present in greatly reduced quantities. ApoB protein was detected within HBL hepatocytes utilizing immunohistochemical techniques; however, it was markedly reduced in quantity when compared with control samples. No apoB was detectable in the plasma of HBL individuals with an ELISA assay. These data are most consistent with a mutation in the coding portion of the apoB gene in HBL patients, leading to an abnormal apoB protein and apoB mRNA instability. These results are distinct from those previously noted in abetalipoproteinemia, which was characterized by an elevated level of hepatic apoB mRNA and accumulation of intracellular hepatic apoB protein.. 
2828430	0	34	Homozygous hypobetalipoproteinemia	SpecificDisease	D006995
2828430	60	83	abetalipoproproteinemia	SpecificDisease	D000012
2828430	158	192	homozygous hypobetalipoproteinemia	SpecificDisease	D006995
2828430	194	197	HBL	SpecificDisease	D006995
2828430	441	444	HBL	Modifier	D006995
2828430	570	573	HBL	Modifier	D006995
2828430	749	752	HBL	Modifier	D006995
2828430	875	878	HBL	Modifier	D006995
2828430	1010	1030	abetalipoproteinemia	SpecificDisease	D000012

10471457|t|A population-based study of the clinical expression of the hemochromatosis gene.
10471457|a|BACKGROUND AND METHODS  Hereditary hemochromatosis is associated with homozygosity for the C282Y mutation in the hemochromatosis (HFE) gene on chromosome 6, elevated serum transferrin saturation, and excess iron deposits throughout the body. To assess the prevalence and clinical expression of the HFE gene, we conducted a population-based study in Busselton, Australia. In 1994, we obtained blood samples for the determination of serum transferrin saturation and ferritin levels and the presence or absence of the C282Y mutation and the H63D mutation (which may contribute to increased hepatic iron levels) in 3011 unrelated white adults. We evaluated all subjects who had persistently elevated transferrin-saturation values (45 percent or higher) or were homozygous for the C282Y mutation. We recommended liver biopsy for subjects with serum ferritin levels of 300 ng per milliliter or higher. The subjects were followed for up to four years. RESULTS  Sixteen of the subjects (0. 5 percent) were homozygous for the C282Y mutation, and 424 (14. 1 percent) were heterozygous. The serum transferrin saturation was 45 percent or higher in 15 of the 16 who were homozygous; in 1 subject it was 43 percent. Four of the homozygous subjects had previously been given a diagnosis of hemochromatosis, and 12 had not. Seven of these 12 patients had elevated serum ferritin levels in 1994; 6 of the 7 had further increases in 1998, and 1 had a decrease, although the value remained elevated. The serum ferritin levels in the four other homozygous patients remained in the normal range. Eleven of the 16 homozygous subjects underwent liver biopsy; 3 had hepatic fibrosis, and 1, who had a history of excessive alcohol consumption, had cirrhosis and mild microvesicular steatosis. Eight of the 16 homozygous subjects had clinical findings that were consistent with the presence of hereditary hemochromatosis, such as hepatomegaly, skin pigmentation, and arthritis. CONCLUSIONS  In a population of white adults of northern European ancestry, 0. 5 percent were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one quarter had serum ferritin levels that remained normal over a four-year period.
10471457	59	74	hemochromatosis	Modifier	D006432
10471457	105	131	Hereditary hemochromatosis	SpecificDisease	D006432
10471457	194	209	hemochromatosis	Modifier	D006432
10471457	281	301	excess iron deposits	DiseaseClass	D019190
10471457	1357	1372	hemochromatosis	SpecificDisease	D006432
10471457	1724	1740	hepatic fibrosis	DiseaseClass	D008103
10471457	1770	1799	excessive alcohol consumption	SpecificDisease	D000435
10471457	1805	1814	cirrhosis	DiseaseClass	D008103
10471457	1824	1848	microvesicular steatosis	SpecificDisease	D005234
10471457	1950	1976	hereditary hemochromatosis	SpecificDisease	D006432
10471457	1986	1998	hepatomegaly	DiseaseClass	D006529
10471457	2000	2017	skin pigmentation	DiseaseClass	D010859
10471457	2023	2032	arthritis	DiseaseClass	D001168
10471457	2252	2267	hemochromatosis	SpecificDisease	D006432

7574457|t|Overexpression of DM20 messenger RNA in two brothers with Pelizaeus-Merzbacher disease.
7574457|a|Pelizaeus-Merzbacher disease is a rare, sex-linked recessive, dysmyelinating disease of the central nervous system that has been associated with mutations in the myelin proteolipid protein (PLP) gene. Only 25% of patients studied with Pelizaeus-Merzbacher disease have exonic mutations in this gene, the underlying cause of the disease in the remaining patients is unknown. The PLP gene encodes two major alternatively spliced transcripts called PLP and DM20. PLP messenger RNA is specifically expressed in central nervous system tissue, whereas DM20 messenger RNA is found in central nervous system, cardiac, and other tissues. We studied cultured skin fibroblasts from 2 brothers with Pelizaeus-Merzbacher disease who exhibited no detectable exonic mutation of the PLP gene. Examination of RNA from these cells showed that the level of DM20 messenger RNA is elevated sixfold relative to male control skin fibroblasts. An unrelated female carrier, also with no detectable exonic mutation, showed a threefold increase in DM20 messenger RNA in cultured skin fibroblasts. Our findings suggest that in some patients, Pelizaeus-Merzbacher disease is caused by overexpression of PLP gene transcripts, and that in these families a 50% increase of DM20 messenger RNA in females, relative to the increase in affected males, can identify a female carrier.. 
7574457	58	86	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
7574457	88	116	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
7574457	122	202	rare, sex-linked recessive, dysmyelinating disease of the central nervous system	DiseaseClass	D020279+D035583
7574457	323	351	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
7574457	775	803	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
7574457	1202	1230	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080

10466420|t|Homozygosity for a novel DTDST mutation in a child with a 'broad bone-platyspondylic' variant of diastrophic dysplasia.
10466420|a|Atypical or variant forms of well-known chondrodysplasias may pose diagnostic problems. We report on a girl with clinical features suggesting diastrophic dysplasia but with unusual radiographic features including severe platyspondyly, wide metaphyses, and fibular overgrowth, which are partially reminiscent of metatropic dysplasia. The diagnosis was clarified by molecular analysis of the DTDST gene, which revealed homozygosity for a previously undescribed mutation leading to a Q454P substitution in the 10th transmembrane domain of the DTDST sulfate transporter. Molecular analysis may be of particular value in such atypical cases.. 
10466420	97	118	diastrophic dysplasia	SpecificDisease	C536170
10466420	160	177	chondrodysplasias	DiseaseClass	D010009
10466420	262	283	diastrophic dysplasia	SpecificDisease	C536170
10466420	340	353	platyspondyly	DiseaseClass	D013122
10466420	431	451	metatropic dysplasia	SpecificDisease	C537356

1676565|t|Carrier detection and prenatal diagnosis of Pelizaeus-Merzbacher disease using a combination of anonymous DNA polymorphisms and the proteolipid protein (PLP) gene cDNA.
1676565|a|We report carrier identification and a prenatal diagnosis using DNA polymorphisms in 2 families with X-linked Pelizaeus-Merzbacher disease (PMD). In both families, the proteolipid protein (PLP) gene in the single affected male could be traced back to his unaffected maternal grandfather. Therefore, each family contains a new mutation. In the case of the prenatal diagnosis, the fetus was shown by cytogenetic analysis to be a female, who we predict will be a noncarrier of PMD based on her genotype with the PLP intragenic polymorphism.. 
1676565	44	72	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
1676565	270	307	X-linked Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
1676565	309	312	PMD	SpecificDisease	OMIM:312080
1676565	643	646	PMD	SpecificDisease	OMIM:312080

1776638|t|Gardner syndrome in a boy with interstitial deletion of the long arm of chromosome 5.
1776638|a|We described a 15-year-old boy with Gardner syndrome (GS), mental retardation, and craniofacial abnormalities. High-resolution banding analysis showed an interstitial deletion of the long arm of chromosome 5 (q22. 1----q31 1----q31. 1). The breakpoints in the present case and in 3 previously reported 5q- patients with adenomatous polyposis coli suggest that the gene responsible for GS/or familial polyposis coli (FPC) is in the 5q22 region, a result consistent with the findings of linkage studies 
1776638	0	16	Gardner syndrome	SpecificDisease	D005736
1776638	122	138	Gardner syndrome	SpecificDisease	D005736
1776638	140	142	GS	SpecificDisease	D005736
1776638	145	163	mental retardation	DiseaseClass	D008607
1776638	169	195	craniofacial abnormalities	DiseaseClass	D019465
1776638	406	432	adenomatous polyposis coli	SpecificDisease	D011125
1776638	471	473	GS	SpecificDisease	D005736
1776638	477	500	familial polyposis coli	SpecificDisease	D011125
1776638	502	505	FPC	SpecificDisease	D011125

1577763|t|Type I human complement C2 deficiency. A 28-base pair gene deletion causes skipping of exon 6 during RNA splicing.
1577763|a|Two variants of a genetic deficiency of complement protein C2 (C2D) have been previously identified. No C2 protein translation is detected in type I deficiency, while type II deficiency is characterized by a selective block in C2 secretion. Type I C2 deficiency was described in a family in which the C2 null allele (C2Q0) is associated with the major histocompatibility haplotype/complotype HLA-A25, B18, C2Q0, BfS, C4A4, C4B2, Drw2; this extended haplotype occurs in over 90% of C2-deficient individuals (common complotype/haplotype). To determine the molecular basis of type I C2 deficiency, the C2 gene and cDNA were characterized from a homozygous type I C2-deficient individual with the common associated haplotype/complotype. We found a 28-base pair deletion in the type I C2Q0 gene, beginning 9 base pairs upstream of the 3-end of exon 6, that generates a C2 transcript with a complete deletion of exon 6 (134 base pair) and a premature termination codon. In studies of eight kindred, the 28-base pair deletion was observed in all C2Q0 alleles associated with the common type I deficient complotype/haplotype; this deletion was not present in normal C2 nor in type II C2-deficient genes. These data demonstrate that  1) type I human complement C2 deficiency is caused by a 28-base pair genomic deletion that causes skipping of exon 6 during RNA splicing, resulting in generation of a premature termination codon, 2) the 28-base pair deletion in the type I C2Q0 gene is strongly associated with the HLA haplotype/complotype A25, B18, C2Q0, BfS, C4A4, C4B2, Drw2, suggesting that all C2-deficient individuals with this haplotype/complotype will harbor the 28-base pair C2 gene deletion, and 3) type II C2 deficiency is caused by a different, as yet uncharacterized, molecular genetic defect.. 
1577763	0	37	Type I human complement C2 deficiency	SpecificDisease	OMIM:217000
1577763	141	176	deficiency of complement protein C2	SpecificDisease	OMIM:217000
1577763	356	376	Type I C2 deficiency	SpecificDisease	OMIM:217000
1577763	596	608	C2-deficient	Modifier	OMIM:217000
1577763	688	708	type I C2 deficiency	SpecificDisease	OMIM:217000
1577763	768	787	type I C2-deficient	Modifier	OMIM:217000
1577763	1283	1303	type II C2-deficient	Modifier	OMIM:217000
1577763	1343	1380	type I human complement C2 deficiency	SpecificDisease	OMIM:217000
1577763	1705	1717	C2-deficient	Modifier	OMIM:217000
1577763	1815	1836	type II C2 deficiency	SpecificDisease	OMIM:217000
1577763	1897	1911	genetic defect	DiseaseClass	D030342

10767339|t|(Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features.
10767339|a|Fragile X syndrome is a common cause of mental retardation involving loss of expression of the FMR1 gene. The role of FMR1 remains undetermined but the protein appears to be involved in RNA metabolism. Fmr1 knockout mice exhibit a phenotype with some similarities to humans, such as macroorchidism and behavioral abnormalities. As a step toward understanding the function of FMR1 and the determination of the potential for therapeutic approaches to fragile X syndrome, yeast artificial chromosome (YAC) transgenic mice were generated in order to determine whether the Fmr1 knockout mouse phenotype could be rescued. Several transgenic lines were generated that carried the entire FMR1 locus with extensive amounts of flanking sequence. We observed that the YAC transgene supported production of the human protein (FMRP) which was present at levels 10 to 15 times that of endogenous protein and was expressed in a cell- and tissue-specific manner. Macro-orchidism was absent in knockout mice carrying the YAC transgene indicating functional rescue by the human protein. Given the complex behavioral phenotype in fragile X patients and the mild phenotype previously reported for the Fmr1 knockout mouse, we performed a more thorough evaluation of the Fmr1 knockout phenotype using additional behavioral assays that had not previously been reported for this animal model. The mouse displayed reduced anxiety-related responses with increased exploratory behavior. FMR1 YAC transgenic mice overexpressing the human protein did produce opposing behavioral responses and additional abnormal behaviors were also observed. These findings have significant implications for gene therapy for fragile X syndrome since overexpression of the gene may harbor its own phenotype.. 
10767339	20	35	FMR1 deficiency	SpecificDisease	OMIM:300624
10767339	92	110	Fragile X syndrome	SpecificDisease	D005600
10767339	132	150	mental retardation	DiseaseClass	D008607
10767339	375	389	macroorchidism	SpecificDisease	D005600
10767339	541	559	fragile X syndrome	SpecificDisease	D005600
10767339	1203	1212	fragile X	Modifier	D005600
10767339	1489	1496	anxiety	Modifier	D001008
10767339	1772	1790	fragile X syndrome	SpecificDisease	D005600

10208848|t|Fabry disease: identification of novel alpha-galactosidase A mutations and molecular carrier detection by use of fluorescent chemical cleavage of mismatches.
10208848|a|Fabry disease (FD) (angiokeratoma corporis diffusum) is an X-linked inborn error of glycosphingolipid metabolism caused by defects in the lysosomal alpha-galactosidase A gene (GLA). The enzymatic defect leads to the systemic accumulation of neutral glycosphingolipids with terminal alpha-galactosyl moieties. Clinically, affected hemizygous males have angiokeratoma, severe acroparesthesia, renal failure, and vasculopathy of the heart and brain. While demonstration of alpha-galactosidase deficiency in leukocytes is diagnostic in affected males, enzymatic detection of female carriers is often inconclusive, due to random X-chromosomal inactivation, underlining the need of molecular investigations for accurate genetic counseling. By use of chemical cleavage of mismatches adapted to fluorescence-based detection systems, we have characterized the mutations underlying alpha-Gal A deficiency in 16 individuals from six unrelated families with FD. The mutational spectrum included five missense mutations (C202W, C223G, N224D, R301Q, and Q327K) and one splice-site mutation [IVS3 G (-1) -- > C]. Studies at the mRNA level showed that the latter led to altered pre-mRNA splicing with consequent alteration of the mRNA translational reading frame and generation of a premature termination codon of translation. By use of this strategy, carrier status was accurately assessed in all seven at-risk females tested, whereas enzymatic dosages failed to diagnose or exclude heterozygosity.. 
10208848	0	13	Fabry disease	SpecificDisease	D000795
10208848	158	171	Fabry disease	SpecificDisease	D000795
10208848	173	175	FD	SpecificDisease	D000795
10208848	178	209	angiokeratoma corporis diffusum	SpecificDisease	D000795
10208848	217	270	X-linked inborn error of glycosphingolipid metabolism	DiseaseClass	D008052
10208848	510	523	angiokeratoma	SpecificDisease	D000794
10208848	525	547	severe acroparesthesia	SpecificDisease	D010292
10208848	549	562	renal failure	SpecificDisease	D051437
10208848	568	603	vasculopathy of the heart and brain	CompositeMention	D014652
10208848	628	658	alpha-galactosidase deficiency	SpecificDisease	D000795
10208848	1030	1052	alpha-Gal A deficiency	SpecificDisease	D000795
10208848	1104	1106	FD	SpecificDisease	D000795

8533768|t|Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect.
8533768|a|A susceptibility gene on chromosome 18 and a parent-of-origin effect have been suggested for bipolar affective disorder (BPAD). We have studied 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype, by using 31 polymorphic markers spanning chromosome 18. Evidence for linkage was tested with affected-sib-pair and LOD score methods under two definitions of the affected phenotype. The affected-sibpair analyses indicated excess allele sharing for markers on 18p within the region reported previously. The greatest sharing was at D18S37  64% in bipolar and recurrent unipolar (RUP) sib pairs (P =. 0006). In addition, excess sharing of the paternally, but not maternally, transmitted alleles was observed at three markers on 18q  at D18S41, 51 bipolar and RUP sib pairs were concordant for paternally transmitted alleles, and 21 pairs were discordant (P = 0004). The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees, i. e e., those in which the father or one of the fathers sibs is affected. In these pedigrees, the greatest allele sharing (81%; P =. 00002) and the highest LOD score (3. 51; phi = 0. 0) were observed at D18S41. Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-origin effect operating in this disorder. The number of loci involved, and their precise location, require further study 
8533768	24	40	bipolar disorder	SpecificDisease	D001714
8533768	183	209	bipolar affective disorder	SpecificDisease	D001714
8533768	211	215	BPAD	SpecificDisease	D001714
8533768	306	310	BPAD	Modifier	D001714
8533768	1345	1349	BPAD	SpecificDisease	D001714

8531967|t|BRCA1 mutations in a population-based sample of young women with breast cancer.
8531967|a|BACKGROUND. Inherited mutations in the BRCA1 gene are associated with a high risk of breast and ovarian cancer in some families. However, little is known about the contribution of BRCA1 mutations to breast cancer in the general population. We analyzed DNA samples from women enrolled in a population-based study of early-onset breast cancer to assess the spectrum and frequency of germ-line BRCA1 mutations in young women with breast cancer. METHODS. We studied 80 women in whom breast cancer was diagnosed before the age of 35, and who were not selected on the basis of family history. Genomic DNA was studied for BRCA1 mutations by analysis involving single-strand conformation polymorphisms and with allele-specific assays. Alterations were defined by DNA sequencing. RESULTS. Germ-line BRCA1 mutations were identified in 6 of the 80 women. Four additional rare sequence variants of unknown functional importance were also identified. Two of the mutations and three of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer. None of the mutations and only one of the rare variants was identified in a reference population of 73 unrelated subjects. CONCLUSIONS. Alterations in BRCA1 were identified in approximately 10 percent of this cohort of young women with breast cancer. The risk of harboring a mutation was not limited to women with family histories of breast or ovarian cancer. These results represent a minimal estimate of the frequency of BRCA1 mutations in this population. Comprehensive methods of identifying BRCA1 mutations and understanding their importance will be needed before testing of women in the general population can be undertaken.. 
8531967	65	78	breast cancer	SpecificDisease	D001943
8531967	165	190	breast and ovarian cancer	CompositeMention	D001943|D010051
8531967	279	292	breast cancer	SpecificDisease	D001943
8531967	407	420	breast cancer	SpecificDisease	D001943
8531967	507	520	breast cancer	SpecificDisease	D001943
8531967	559	572	breast cancer	SpecificDisease	D001943
8531967	1143	1167	breast or ovarian cancer	CompositeMention	D001943|D010051
8531967	1405	1418	breast cancer	SpecificDisease	D001943
8531967	1503	1527	breast or ovarian cancer	CompositeMention	D001943|D010051

10915776|t|Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells.
10915776|a|X-linked retinoschisis is characterized by microcystic-like changes of the macular region and schisis within the inner retinal layers, leading to visual deterioration in males. Many missense and protein-truncating mutations of the causative gene RS1 have now been identified and are thought to be inactivating. RS1 encodes a 224 amino acid protein, retinoschisin, which contains a discoidin domain but is of unknown function. We have generated a polyclonal antibody against a peptide from a unique region within retinoschisin, which detects a protein of approximately 28 kDa in retinal samples reduced with dithiothreitol, but multimers sized > 40 kDa under non-reducing conditions. A screen of human tissues with this antibody reveals retinoschisin to be retina specific and the antibody detects a protein of similar size in bovine and murine retinae. We investigated the expression pattern in the retina of both RS1 mRNA (using in situ hybridization with riboprobes) and retinoschisin (using immunohistochemistry). The antisense riboprobe detected RS1 mRNA only in the photoreceptor layer but the protein product of the gene was present both in the photoreceptors and within the inner portions of the retina. Furthermore, differentiated retinoblastoma cells (Weri-Rb1 cells) were found to express RS1 mRNA and to release retinoschisin. These results suggest that retinoschisin is released by photo-receptors and has functions within the inner retinal layers. Thus, X-linked retinoschisis is caused by abnormalities in a putative secreted photoreceptor protein and is the first example of a secreted photo-receptor protein associated with a retinal dystrophy.. 
10915776	19	41	X-linked retinoschisis	Modifier	D041441
10915776	137	159	X-linked retinoschisis	SpecificDisease	D041441
10915776	283	303	visual deterioration	DiseaseClass	C531604
10915776	1376	1390	retinoblastoma	Modifier	D012175
10915776	1604	1626	X-linked retinoschisis	SpecificDisease	D041441
10915776	1779	1796	retinal dystrophy	DiseaseClass	D058499

1302003|t|Aberrant splicing of the CHM gene is a significant cause of choroideremia.
1302003|a|Choroideremia (CHM) is an X-linked progressive degeneration of the choroid and retina. 12% of unrelated male patients carry deletions of the partially cloned CHM gene. In Finland, there are more than 120 living CHM patients belonging to eight apparently unrelated pedigrees. Molecular deletions involving the CHM gene have been detected in three families. We have screened the remaining five families for point mutations. In one large family a single nucleotide (T) insertion into the donor splice site of exon C leads to two aberrantly spliced mRNAs both producing a premature stop codon. The mutation can be assayed easily by amplification and digestion with Msel. Our findings provide additional evidence for the pathogenetic role of CHM mutations and provide a diagnostic tool for one fifth of the worlds known CHM patients.. 
1302003	25	28	CHM	Modifier	D015794
1302003	60	73	choroideremia	SpecificDisease	D015794
1302003	75	88	Choroideremia	SpecificDisease	D015794
1302003	90	93	CHM	SpecificDisease	D015794
1302003	101	160	X-linked progressive degeneration of the choroid and retina	DiseaseClass	D015785
1302003	233	236	CHM	Modifier	D015794
1302003	286	289	CHM	Modifier	D015794
1302003	384	387	CHM	Modifier	D015794
1302003	812	815	CHM	Modifier	D015794
1302003	890	893	CHM	Modifier	D015794

7811247|t|X-linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes.
7811247|a|Fragments of the adrenoleukodystrophy (ALD) cDNA from a patient with adolescent ALD were amplified by polymerase chain reaction and subcloned. Bidirectional sequencing of the entire coding ALD gene disclosed a cytosine to guanine transversion at nucleotide 1451 in exon five, resulting in substitution of proline 484 by arginine. Five of nine siblings of the patient, comprising two cerebral ALD, one adrenomyeloneuropathy, one Addison only as well as the symptomatic mother (all accumulating very long chain fatty acids) carried this mutation, which was not found in the unaffected persons, in five unrelated ALD patients, and in twenty controls. We propose that this missense mutation generated the disease per se as well as the metabolic defect; the different phenotypes, however, must have originated by means of additional pathogenetic factors.. 
7811247	0	29	X-linked adrenoleukodystrophy	SpecificDisease	D000326
7811247	31	34	ALD	SpecificDisease	D000326
7811247	61	64	ALD	Modifier	D000326
7811247	152	172	adrenoleukodystrophy	Modifier	D000326
7811247	174	177	ALD	Modifier	D000326
7811247	204	218	adolescent ALD	SpecificDisease	D000326
7811247	324	327	ALD	Modifier	D000326
7811247	518	530	cerebral ALD	SpecificDisease	D000326
7811247	536	557	adrenomyeloneuropathy	SpecificDisease	D000326
7811247	563	575	Addison only	SpecificDisease	D000224
7811247	745	748	ALD	Modifier	D000326

2352258|t|Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma.
2352258|a|Analysis of the age incidence curves for unilateral and bilateral retinoblastoma led Knudson to propose that hereditary tumours may arise by a single event and sporadic tumours by a two stage mutation process. It has been suggested recently that sporadic renal cell carcinoma may arise from a two stage mutation process. We analysed the age incidence curves for symptomatic renal cell carcinoma (n = 26) and cerebellar haemangioblastoma (n = 68) in 109 patients with von Hippel-Lindau (VHL) disease, and compared them to 104 patients with sporadic renal cell carcinoma and 43 patients with sporadic cerebellar haemangioblastoma. The age incidence curves for renal cell carcinoma and cerebellar haemangioblastoma in VHL disease were compatible with a single mutation model, whereas the age incidence curves for sporadic renal cell carcinoma and cerebellar haemangioblastoma suggested a two stage mutation process. These data are compatible with the VHL gene functioning as a recessive tumour suppressor gene. Sporadic cerebellar haemangioblastoma and some renal cell carcinoma may arise from somatic mutations inactivating both alleles at the VHL locus.. 
2352258	56	81	von Hippel-Lindau disease	SpecificDisease	D006623
2352258	90	127	sporadic cerebellar haemangioblastoma	SpecificDisease	D018325
2352258	132	152	renal cell carcinoma	SpecificDisease	D002292
2352258	195	234	unilateral and bilateral retinoblastoma	CompositeMention	D012175
2352258	263	281	hereditary tumours	DiseaseClass	D009386
2352258	314	330	sporadic tumours	DiseaseClass	D009369
2352258	400	429	sporadic renal cell carcinoma	SpecificDisease	D002292
2352258	528	548	renal cell carcinoma	SpecificDisease	D002292
2352258	562	590	cerebellar haemangioblastoma	SpecificDisease	D018325
2352258	621	652	von Hippel-Lindau (VHL) disease	SpecificDisease	D006623
2352258	693	722	sporadic renal cell carcinoma	SpecificDisease	D002292
2352258	744	781	sporadic cerebellar haemangioblastoma	SpecificDisease	D018325
2352258	812	832	renal cell carcinoma	SpecificDisease	D002292
2352258	837	865	cerebellar haemangioblastoma	SpecificDisease	D018325
2352258	869	880	VHL disease	SpecificDisease	D006623
2352258	964	993	sporadic renal cell carcinoma	SpecificDisease	D002292
2352258	998	1026	cerebellar haemangioblastoma	SpecificDisease	D018325
2352258	1102	1105	VHL	Modifier	D006623
2352258	1138	1144	tumour	Modifier	D009369
2352258	1162	1199	Sporadic cerebellar haemangioblastoma	SpecificDisease	D018325
2352258	1209	1229	renal cell carcinoma	SpecificDisease	D002292
2352258	1296	1299	VHL	Modifier	D006623

10364518|t|Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene.
10364518|a|The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys. Mutations in the OCRL1 gene have been associated with the disease. OCRL1 encodes a phosphatidylinositol 4, 5-biphosphate (PtdIns [4, 5] P2) 5-phosphatase. We have examined the OCRL1 gene in eight unrelated patients with OCRL and have found seven new mutations and one recurrent in-frame deletion. Among the new mutations, two nonsense mutations (R317X and E558X) and three other frameshift mutations caused premature termination of the protein. A missense mutation, R483G, was located in the highly conserved PtdIns (4, 5) P2 5-phosphatase domain. Finally, one frameshift mutation, 2799delC, modifies the C-terminal part of OCRL1, with an extension of six amino acids. Altogether, 70% of missense mutations are located in exon 15, and 52% of all mutations cluster in exons 11-15. We also identified two new microsatellite markers for the OCRL1 locus, and we detected a germline mosaicism in one family. This observation has direct implications for genetic counseling of Lowe syndrome families.. 
10364518	58	71	Lowe syndrome	SpecificDisease	D009800
10364518	140	174	oculocerebrorenal syndrome of Lowe	SpecificDisease	D009800
10364518	176	180	OCRL	SpecificDisease	D009800
10364518	188	205	X-linked disorder	DiseaseClass	D040181
10364518	229	279	abnormalities of eyes, nervous system, and kidneys	CompositeMention	D000015
10364518	501	505	OCRL	SpecificDisease	D009800
10364518	1251	1264	Lowe syndrome	Modifier	D009800

10449429|t|Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice.
10449429|a|Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene, leading to the absence of the dystrophin protein in striated muscle. A significant number of these mutations are premature stop codons. On the basis of the observation that aminoglycoside treatment can suppress stop codons in cultured cells, we tested the effect of gentamicin on cultured muscle cells from the mdx mouse - an animal model for DMD that possesses a premature stop codon in the dystrophin gene. Exposure of mdx myotubes to gentamicin led to the expression and localization of dystrophin to the cell membrane. We then evaluated the effects of differing dosages of gentamicin on expression and functional protection of the muscles of mdx mice. We identified a treatment regimen that resulted in the presence of dystrophin in the cell membrane in all striated muscles examined and that provided functional protection against muscular injury. To our knowledge, our results are the first to demonstrate that aminoglycosides can suppress stop codons not only in vitro but also in vivo. Furthermore, these results raise the possibility of a novel treatment regimen for muscular dystrophy and other diseases caused by premature stop codon mutations. This treatment could prove effective in up to 15% of patients with DMD.. 
10449429	88	115	Duchenne muscular dystrophy	SpecificDisease	D020388
10449429	117	120	DMD	SpecificDisease	D020388
10449429	512	515	DMD	SpecificDisease	D020388
10449429	1005	1020	muscular injury	DiseaseClass	D014947
10449429	1245	1263	muscular dystrophy	SpecificDisease	D009136
10449429	1392	1395	DMD	SpecificDisease	D020388

1939657|t|Molecular and metabolic basis for the metabolic disorder normotriglyceridemic abetalipoproteinemia.
1939657|a|We have previously described a disorder, normotriglyceridemic abetalipoproteinemia, that is characterized by the virtual absence of plasma low density lipoproteins and complete absence of apoB-100, but with apparently normal secretion of triglyceride-rich lipoproteins containing apoB-48. The patients plasma lipoproteins were shown on polyacrylamide gels and by antibody mapping to have a new truncated apoB variant, apoB-50, circulating along with her apoB-48. We have found this individual to be homozygous for a single C-to-T nucleotide substitution at apoB codon 2252, which produces a premature in-frame stop codon. Thus, this is a rare example of homozygous hypobetalipoproteinemia. Electron photomicrographs revealed that the diameters of particles in the d less than 1. 006 g/ml lipoprotein fraction, in both the postprandial and postabsorptive state, are bimodally distributed. The molar ratio of apoE to apoB in these particles is 3. 5  1, similar to normal VLDL. The plasma LDL interval contains both spherical and cuboidal particles. Autologous reinfusion of labeled d less than 1. 006 g/ml lipoproteins showed exponential disappearance from plasma, with an apparent half-removal time of 50 min, somewhat slower than for normal chylomicrons but within the normal range for VLDL. The calculated production rate for apoB was within the normal range in this subject. 
1939657	38	56	metabolic disorder	DiseaseClass	D008659
1939657	57	98	normotriglyceridemic abetalipoproteinemia	SpecificDisease	D000012
1939657	141	182	normotriglyceridemic abetalipoproteinemia	SpecificDisease	D000012
1939657	754	788	homozygous hypobetalipoproteinemia	SpecificDisease	D006995

1409710|t|von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib.
1409710|a|von Willebrand factor (vWF) is a multimeric glycoprotein that mediates the adhesion of platelets to the subendothelium by binding to platelet glycoprotein Ib. For human vWF, this interaction can be induced in vitro by the antibiotic ristocetin or the snake venom protein botrocetin. A missense mutation, Gly-561-- > Ser, was identified within the proposed glycoprotein Ib binding domain of vWF in the proband with von Willebrand disease type B, a unique variant characterized by no ristocetin-induced, but normal botrocetin-induced, binding to glycoprotein Ib. The corresponding mutant recombinant protein, rvWF (G561S), formed normal multimers and exhibited the same functional defect as the patients plasma vWF, confirming that this mutation causes von Willebrand disease type B. These data show that botrocetin and ristocetin cofactor activities of vWF can be dissociated by a point mutation and confirm that these mediators promote vWF binding to platelets by different mechanisms. The normal botrocetin-induced binding and the defective ristocetin-induced binding of rvWF (G561S) suggest that the primary defect in von Willebrand disease type B may be a failure of normal allosteric regulation of the glycoprotein Ib binding function of vWF.. 
1409710	0	29	von Willebrand disease type B	SpecificDisease	D014842
1409710	92	106	von Willebrand	Modifier	D014842
1409710	151	165	von Willebrand	Modifier	D014842
1409710	565	594	von Willebrand disease type B	SpecificDisease	D014842
1409710	902	931	von Willebrand disease type B	SpecificDisease	D014842
1409710	1271	1300	von Willebrand disease type B	SpecificDisease	D014842

8554067|t|A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families.
8554067|a|We have analyzed 20 breast-ovarian cancer families, the majority of which show positive evidence of linkage to chromosome 17q12 for germ-line mutations in the BRCA1 gene. BRCA1 mutations cosegregating with breast and ovarian cancer susceptibility were identified in 16 families, including 1 family with a case of male breast cancer. Nine of these mutations have not been reported previously. The majority of mutations were found to generate a premature stop codon leading to the formation of a truncated BRCA1 protein of 2% -88% of the expected normal length. Two mutations altered the RING finger domain. Sequencing of genomic DNA led to the identification of a mutation in the coding region of BRCA1 in 12 families, and cDNA analysis revealed an abnormal or missing BRCA1 transcript in 4 of the 8 remaining families. A total of eight mutations were associated with a reduced quantity of BRCA1 transcript. We were unable to detect BRCA1 mutations in 4 of the 20 families, but only 1 of these was clearly linked to BRCA1. It is expected that the majority of clear examples of the breast-ovarian syndrome will be associated with germ-line mutations in the coding region of BRCA1.. 
8554067	42	63	breast-ovarian cancer	Modifier	D061325
8554067	94	115	breast-ovarian cancer	Modifier	D061325
8554067	280	305	breast and ovarian cancer	Modifier	D061325
8554067	387	405	male breast cancer	SpecificDisease	D018567
8554067	1154	1177	breast-ovarian syndrome	SpecificDisease	D061325

8244393|t|Assignment of the human Na+/glucose cotransporter gene SGLT1 to chromosome 22q13.1.
8244393|a|The Na +/glucose cotransporter gene SGLT1 encodes the primary carrier protein responsible for the uptake of the dietary sugars glucose and galactose from the intestinal lumen. SGLT1 transport activity is currently exploited in oral rehydration therapy. The 75-kDa glycoprotein is localized in the brush border of the intestinal epithelium and is predicted to comprise 12 membrane spans. In two patients with the autosomal recessive disease glucose/galactose malabsorption, the underlying cause was found to be a missense mutation in SGLT1, and the Asp28-- > Asn change was demonstrated in vitro to eliminate SGLT1 transport activity. The SGLT1 gene was previously shown to reside on the distal q arm of chromosome 22 (11. 2-- > qter). We have used a cosmid probe for fluorescence in situ hybridization, which refines the localization to 22q13. 1, and provide an example of the utility of the SGLT1 probe as a diagnostic for genetic diseases associated with translocations of chromosome 22.
8244393	496	555	autosomal recessive disease glucose/galactose malabsorption	SpecificDisease	OMIM:606824
8244393	1008	1024	genetic diseases	DiseaseClass	D030342

1384323|t|A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening.
1384323|a|Deficiency of beta-hexosaminidase A (Hex A) activity typically results in Tay-Sachs disease. However, healthy subjects found to be deficient in Hex A activity (i. e., pseudodeficient) by means of in vitro biochemical tests have been described. We analyzed the HEXA gene of one pseudodeficient subject and identified both a C739-to-T substitution that changes Arg247----Trp on one allele and a previously identified Tay-Sachs disease mutation on the second allele. Six additional pseudodeficient subjects were found to have the C739-to-T mutation. This allele accounted for 32% (20/62) of non-Jewish enzyme-defined Tay-Sachs disease carriers but for none of 36 Jewish enzyme-defined carriers who did not have one of three known mutations common to this group. The C739-to-T allele, together with a " true " Tay-Sachs disease allele, causes Hex A pseudodeficiency. Given both the large proportion of non-Jewish carriers with this allele and that standard biochemical screening cannot differentiate between heterozygotes for the C739-to-T mutations and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential. 
1384323	47	56	Tay-Sachs	Modifier	D013661
1384323	103	138	Deficiency of beta-hexosaminidase A	SpecificDisease	D013661
1384323	177	194	Tay-Sachs disease	SpecificDisease	D013661
1384323	234	252	deficient in Hex A	SpecificDisease	D013661
1384323	518	535	Tay-Sachs disease	Modifier	D013661
1384323	717	734	Tay-Sachs disease	Modifier	D013661
1384323	909	926	Tay-Sachs disease	Modifier	D013661
1384323	1153	1170	Tay-Sachs disease	Modifier	D013661

1307230|t|The presence of two different infantile Tay-Sachs disease mutations in a Cajun population.
1307230|a|A study was undertaken to characterize the mutation (s) responsible for Tay-Sachs disease (TSD) in a Cajun population in southwest Louisiana and to identify the origins of these mutations. Eleven of 12 infantile TSD alleles examined in six families had the beta-hexosaminidase A (Hex A) alpha-subunit exon 11 insertion mutation that is present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The mutation in the remaining allele was a single-base transition in the donor splice site of the alpha-subunit intron 9. To determine the origins of these two mutations in the Cajun population, the TSD carrier status was enzymatically determined for 90 members of four of the six families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggest that this mutation has been in the Cajun population since its founding over 2 centuries ago and that it may be widely distributed within the population. In contrast, the intron 9 mutation apparently was introduced within the last century and probably is limited to a few Louisiana families.. 
1307230	40	57	Tay-Sachs disease	Modifier	D013661
1307230	163	180	Tay-Sachs disease	SpecificDisease	D013661
1307230	182	185	TSD	SpecificDisease	D013661
1307230	303	306	TSD	Modifier	D013661
1307230	476	479	TSD	Modifier	D013661
1307230	694	697	TSD	Modifier	D013661

8088831|t|Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.
8088831|a|Canavan disease, or spongy degeneration of the brain, is a severe leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Recently, a missense mutation was identified in human ASPA coding sequence from patients with Canavan disease. The human ASPA gene has been cloned and found to span 29 kb of the genome. Human aspartoacylase is coded by six exons intervened by five introns. The exons vary from 94 (exon III) to 514 (exon VI) bases. The exon/intron splice junction sites follow the gt/ag consensus sequence rule. Southern blot analysis of genomic DNA from human/mouse somatic cell hybrid cell lines localized ASPA to human chromosome 17. The human ASPA locus was further mapped in the 17p13-ter region by fluorescence in situ hybridization. The bovine aspa gene has also been cloned, and its exon/intron organization is identical to that of the human gene. The 500-base sequence upstream of the initiator ATG codon in the human gene and that in the bovine gene are 77% identical. Human ASPA coding sequences cross-hybridize with genomic DNA from yeast, chicken, rabbit, cow, dog, mouse, rat, and monkey. The specificity of cross-species hybridization of coding sequences suggests that aspartoacylase has been conserved during evolution. It should now be possible to identify mutations in the noncoding genomic sequences that lead to Canavan disease and to study the regulation of ASPA.. 
8088831	0	15	Canavan disease	SpecificDisease	D017825
8088831	134	149	Canavan disease	SpecificDisease	D017825
8088831	154	186	spongy degeneration of the brain	SpecificDisease	D017825
8088831	200	214	leukodystrophy	SpecificDisease	D007966
8088831	229	257	deficiency of aspartoacylase	SpecificDisease	D017825
8088831	360	375	Canavan disease	SpecificDisease	D017825
8088831	1481	1496	Canavan disease	SpecificDisease	D017825

6524872|t|Adrenoleukodystrophy: survey of 303 cases: biochemistry, diagnosis, and therapy.
6524872|a|Adrenoleukodystrophy (ALD) is a genetically determined disorder associated with progressive central demyelination and adrenal cortical insufficiency. All affected persons show increased levels of saturated unbranched very-long-chain fatty acids, particularly hexacosanoate (C26  0), because of impaired capacity to degrade these acids. This degradation normally takes place in a subcellular organelle called the peroxisome, and ALD, together with Zellwegers cerebrohepatorenal syndrome, is now considered to belong to the newly formed category of peroxisomal disorders. Biochemical assays permit prenatal diagnosis, as well as identification of most heterozygotes. We have identified 303 patients with ALD in 217 kindreds. These patients show a wide phenotypic variation. Sixty percent of patients had childhood ALD and 17% adrenomyeloneuropathy, both of which are X-linked, with the gene mapped to Xq28. Neonatal ALD, a distinct entity with autosomal recessive inheritance and points of resemblance to Zellwegers syndrome, accounted for 7% of the cases. Although excess C26  0 in the brain of patients with ALD is partially of dietary origin, dietary C26  0 restriction did not produce clear benefit. Bone marrow transplant lowered the plasma C26  0 level but failed to arrest neurological progression.. 
6524872	0	20	Adrenoleukodystrophy	SpecificDisease	D000326
6524872	81	101	Adrenoleukodystrophy	SpecificDisease	D000326
6524872	103	106	ALD	SpecificDisease	D000326
6524872	161	194	progressive central demyelination	DiseaseClass	D003711
6524872	199	229	adrenal cortical insufficiency	DiseaseClass	D000309
6524872	509	512	ALD	SpecificDisease	D000326
6524872	528	566	Zellwegers cerebrohepatorenal syndrome	SpecificDisease	D015211
6524872	628	649	peroxisomal disorders	DiseaseClass	D018901
6524872	783	786	ALD	SpecificDisease	D000326
6524872	893	896	ALD	SpecificDisease	D000326
6524872	905	926	adrenomyeloneuropathy	SpecificDisease	D000326
6524872	986	998	Neonatal ALD	SpecificDisease	OMIM:202370
6524872	1084	1103	Zellwegers syndrome	SpecificDisease	D015211
6524872	1189	1192	ALD	SpecificDisease	D000326

10441343|t|French Machado-Joseph disease patients do not exhibit gametic segregation distortion: a sperm typing analysis.
10441343|a|Segregation distortion has been reported to occur in a number of the trinucleotide repeat disorders. On the basis of a sperm typing study performed in patients of Japanese descent with Machado-Joseph disease (MJD), it was reported that disease alleles are preferentially transmitted during meiosis. We performed a sperm typing study of five MJD patients of French descent and analysis of the pooled data shows a ratio of mutant to normal alleles of 379  436 (46. 5  53. 5%), which does not support meiotic segregation distortion. To confirm these results, sperm typing analysis was also performed using a polymorphic marker, D14S1050, closely linked to the MJD1 gene. Among 910 sperm analyzed, the allele linked to the disease chromosome was detected in 50. 3% of the samples and the allele linked to the normal chromosome was found in 49. 6% of the sperm. The difference in frequency of these two alleles is not significant (P = 0. 8423). Likelihood-based analysis of segregation distortion in the single sperm data using the SPERMSEG program also showed no support for segregation distortion at the gamete level in this patient population. The previous report on the Japanese patients also suggested that disease allele stability may be influenced by a trans effect of an intragenic polymorphism (987 G/C) in the wild-type allele. All of the French patients were heterozygous for this polymorphism. However, analysis of the variance in repeat number in sperm from the French MJD patients overlapped significantly with the variance in repeat number observed in the C/C homozygous Japanese patients.
10441343	7	29	Machado-Joseph disease	Modifier	D017827
10441343	180	210	trinucleotide repeat disorders	DiseaseClass	D030342
10441343	296	318	Machado-Joseph disease	SpecificDisease	D017827
10441343	320	323	MJD	SpecificDisease	D017827
10441343	452	455	MJD	Modifier	D017827
10441343	1588	1591	MJD	Modifier	D017827

3346018|t|Nebulin seen in DMD males including one patient with a large DNA deletion encompassing the DMD gene.
3346018|a|The presence of nebulin in a muscle specimen from a patient with Duchenne muscular dystrophy (DMD) due to a large deletion precludes the possibility that this protein is the DMD gene product.. 
3346018	16	19	DMD	Modifier	D020388
3346018	91	94	DMD	Modifier	D020388
3346018	166	193	Duchenne muscular dystrophy	SpecificDisease	D020388
3346018	195	198	DMD	SpecificDisease	D020388
3346018	275	278	DMD	Modifier	D020388

8188241|t|The human gene for alkaptonuria (AKU) maps to chromosome 3q.
8188241|a|Alkaptonuria (AKU; McKusick no. 203500) is a rare autosomal recessive disorder caused by the lack of homogentisic acid oxidase activity. Patients excrete large amounts of homogentisic acid in their urine and a black ochronotic pigment is deposited in their cartilage and collagenous tissues. Ochronosis is the predominant clinical complication of the disease leading to ochronotic arthropathy, dark urine, pigment changes of the skin, and other clinical features. A mutation causing alkaptonuria in the mouse has mapped to chromosome 16. Considering conserved synteny, we were able to map the human gene to chromosome 3q in six alkaptonuria pedigrees of Slovak origin.. 
8188241	19	31	alkaptonuria	SpecificDisease	D000474
8188241	33	36	AKU	SpecificDisease	D000474
8188241	61	73	Alkaptonuria	SpecificDisease	D000474
8188241	75	78	AKU	SpecificDisease	D000474
8188241	111	139	autosomal recessive disorder	DiseaseClass	D030342
8188241	353	363	Ochronosis	SpecificDisease	D009794
8188241	431	453	ochronotic arthropathy	SpecificDisease	D009794+D007592
8188241	544	556	alkaptonuria	SpecificDisease	D000474
8188241	689	701	alkaptonuria	Modifier	D000474

1317264|t|The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer.
1317264|a|Although gastric cancer is the most common cancer in the world, genetic changes during its carcinogenesis are not well understood. Since some gastric cancers are considered to originate from the intestinal metaplasia, it is likely that the adenomatous polyposis coli (APC) gene, the mutation of which causes adenomatous polyps in the colon, is associated with carcinogenesis of gastric cancer. Based on this idea, DNAs isolated from gastric cancers were examined by means of a RNase protection analysis coupled with polymerase chain reaction followed by sequencing of the polymerase chain reaction products. By screening nearly one-half of the coding region of the APC gene in 44 tumors, somatic mutations were detected in three tumors  a missense mutation, a nonsense mutation, and a 5-base pair deletion resulting in a frame shift which causes truncation of the gene product. These results suggest that the mutation of the APC gene also plays an important role during the carcinogenesis of at least some gastric cancers.. 
1317264	4	7	APC	Modifier	D011125
1317264	30	60	familial adenomatous polyposis	SpecificDisease	D011125
1317264	82	96	gastric cancer	SpecificDisease	D013274
1317264	107	121	gastric cancer	SpecificDisease	D013274
1317264	141	147	cancer	DiseaseClass	D009369
1317264	240	255	gastric cancers	SpecificDisease	D013274
1317264	338	364	adenomatous polyposis coli	Modifier	D011125
1317264	366	369	APC	Modifier	D011125
1317264	406	437	adenomatous polyps in the colon	SpecificDisease	D018256
1317264	476	490	gastric cancer	SpecificDisease	D013274
1317264	531	546	gastric cancers	SpecificDisease	D013274
1317264	763	766	APC	Modifier	D011125
1317264	778	784	tumors	DiseaseClass	D009369
1317264	827	833	tumors	DiseaseClass	D009369
1317264	1023	1026	APC	Modifier	D011125
1317264	1104	1119	gastric cancers	SpecificDisease	D013274

10083734|t|Molecular epidemiology of C9 deficiency heterozygotes with an Arg95Stop mutation of the C9 gene in Japan.
10083734|a|Deficiency of the ninth component of human complement (C9) is the most common complement deficiency in Japan, with an incidence of approximately one homozygote in 1000, but is very rare in other countries. Genetic analyses of Japanese C9 deficiency have shown that a C-to-T transition leading to TGA stop codon for Arg95 in exon 4 of the C9 gene (Arg95Stop) is common in Japanese C9 deficiency. To determine the prevalence of heterozygous carriers of the Arg95Stop mutation in a Japanese population, we collected DNA samples from 300 individuals in two of the four main islands of Japan. Heterozygote detection was performed with an allele-specific polymerase chain reaction (PCR) system designed to detect exclusively only one of the normal and mutant alleles, followed by confirmation with PCR/single-strand conformation polymorphism (SSCP) analysis and direct sequencing. Twenty individuals were heterozygous for the Arg95Stop mutation. None was homozygous. The prevalence of carriers of the Arg95Stop mutation was 6. 7% (20/300). An estimated frequency (0. 12%) of complete C9 deficiency due to homozygous Arg95Stop mutation was consistent with frequencies determined by serological studies 
10083734	26	39	C9 deficiency	Modifier	OMIM:613825
10083734	106	159	Deficiency of the ninth component of human complement	SpecificDisease	OMIM:613825
10083734	184	205	complement deficiency	DiseaseClass	D007153
10083734	341	354	C9 deficiency	SpecificDisease	OMIM:613825
10083734	486	499	C9 deficiency	SpecificDisease	OMIM:613825
10083734	1184	1197	C9 deficiency	SpecificDisease	OMIM:613825

2760209|t|Molecular analysis of a female Lesch-Nyhan patient.
2760209|a|We report the identification of a female patient with the X-linked recessive Lesch-Nyhan syndrome (hypoxanthine phosphoribosyltransferase [HPRT] deficiency). Cytogenetic and carrier studies revealed structurally normal chromosomes for this patient and her parents and demonstrated that this mutation arose through a de novo gametic event. Comparison of this patients DNA with the DNA of her parents revealed that a microdeletion, which occurred within a maternal gamete and involved the entire HPRT gene, was partially responsible for the disease in this patient. Somatic cell hybrids, generated to separate maternal and paternal X chromosomes, showed that expression of two additional X-linked enzymes, phosphoglycerate kinase and glucose-6-phosphate dehydrogenase, were expressed only in cells that contained the maternal X chromosome, suggesting the presence of a functionally inactive paternal X chromosome. Furthermore, comparison of methylation patterns within a region of the HPRT gene known to be important in gene regulation revealed differences between DNA from the father and the patient, in keeping with an active HPRT locus in the father and an inactive HPRT locus in the patient. Together these data indicate that nonrandom inactivation of the cytogenetically normal paternal X chromosome and a microdeletion of the HPRT gene on an active maternal X chromosome were responsible for the absence of HPRT in this patient.. 
2760209	31	42	Lesch-Nyhan	Modifier	D007926
2760209	129	149	Lesch-Nyhan syndrome	SpecificDisease	D007926
2760209	151	207	hypoxanthine phosphoribosyltransferase [HPRT] deficiency	SpecificDisease	D007926

10323252|t|Changes at P183 of emerin weaken its protein-protein interactions resulting in X-linked Emery-Dreifuss muscular dystrophy.
10323252|a|Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive muscular dystrophy characterized by early contractures of the elbows, Achilles tendons and spine, slowly progressive muscle wasting and weakness, and cardiomyopathy associated with cardiac conduction defects. The emerin gene has been mapped to Xq28 and encodes a 34-kDa serine-rich protein, emerin, which has been localized to the nuclear envelope in a wide variety of tissues, including skeletal and cardiac muscle. Mutations spanning the emerin gene have been identified in patients with EDMD. We present here the effect, on emerin protein expression, of two missense mutations identified in unrelated EDMD patients. These alterations predict the replacement of a proline residue at position 183 with either a histidine or a threonine. Biochemical analysis has demonstrated that the mobility and expression levels of the mutant forms of emerin are indistinguishable from that of wild-type emerin, but that they have weakened interactions with nuclear lamina components. In comparison with the usual EDMD phenotype, patients with P183 missense mutations have a later age at onset of first symptoms, elbow contractures, ankle contractures, upper limb weakness and lower limb weakness, but there is no difference for the age at onset of cardiac involvement. This is the first report of protein studies on patients with missense mutations resulting in the clinical features of EDMD. These studies demonstrate the importance of proline 183 for the proper structure/function of emerin.. 
10323252	79	121	X-linked Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10323252	123	156	Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10323252	158	162	EDMD	SpecificDisease	D020389
10323252	170	207	X-linked recessive muscular dystrophy	DiseaseClass	D040181+D009136
10323252	231	285	contractures of the elbows, Achilles tendons and spine	CompositeMention	D003286
10323252	306	320	muscle wasting	DiseaseClass	D009133
10323252	325	333	weakness	DiseaseClass	D018908
10323252	339	353	cardiomyopathy	SpecificDisease	D009202
10323252	370	396	cardiac conduction defects	SpecificDisease	OMIM:115080
10323252	679	683	EDMD	SpecificDisease	D020389
10323252	793	797	EDMD	Modifier	D020389
10323252	1190	1194	EDMD	Modifier	D020389
10323252	1289	1307	elbow contractures	SpecificDisease	D003286
10323252	1309	1327	ankle contractures	SpecificDisease	D003286
10323252	1329	1348	upper limb weakness	SpecificDisease	D018908
10323252	1353	1372	lower limb weakness	SpecificDisease	D018908
10323252	1425	1444	cardiac involvement	DiseaseClass	D006331
10323252	1564	1568	EDMD	SpecificDisease	D020389

7795653|t|Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression.
7795653|a|We have characterized expression of the familial breast and ovarian cancer gene, BRCA1, in cases of non-hereditary (sporadic) breast cancer and analyzed the effect of antisense inhibition of BRCA1 on the proliferative rate of mammary epithelial cells. BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer. Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells, but had no effect on non-mammary epithelial cells. These studies suggest that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth whose function is compromised in breast cancer either by direct mutation or alterations in gene expression.. 
7795653	77	99	sporadic breast cancer	Modifier	D001943
7795653	153	187	familial breast and ovarian cancer	Modifier	D061325
7795653	213	252	non-hereditary (sporadic) breast cancer	SpecificDisease	D001943
7795653	433	450	carcinoma in situ	DiseaseClass	D002278
7795653	454	469	invasive cancer	DiseaseClass	D009362
7795653	808	821	breast cancer	SpecificDisease	D001943

10827108|t|Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome.
10827108|a|The proteolipid protein gene (PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD). Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. The results of FISH analysis showed an additional copy of PLP in Xp22. 1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another three affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inv (X) carried by several affected family members, FISH showed PLP signals at Xp11. 4 and Xq22. A third family has previously been reported, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of three separate families in which PLP is duplicated at a noncontiguous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.
10827108	58	86	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
10827108	275	303	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
10827108	305	308	PMD	SpecificDisease	OMIM:312080
10827108	374	377	PMD	SpecificDisease	OMIM:312080
10827108	894	897	PMD	SpecificDisease	OMIM:312080
10827108	1449	1466	genetic disorders	DiseaseClass	D030342

1975560|t|Linkage relationships of the apolipoprotein C1 gene and a cytochrome P450 gene (CYP2A) to myotonic dystrophy.
1975560|a|We have studied the genetic linkage of two markers, the apolipoprotein C1 (APOC1) gene and a cytochrome P450 (CYP2A) gene, in relation to the gene for myotonic dystrophy (DM). A peak lod score of 9. 29 at 2 cM was observed for APOC1-DM, with a lod score of 8. 55 at 4 cM for CYP2A-DM. These two markers also show close linkage to each other (theta max = 0. 05, Zmax = 9. 09). From examination of the genotypes of the recombinant individuals, CYP2A appears to map proximal to DM because in one recombinant individual CYP2A, APOC2 and CKMM had all recombined with DM. Evidence from another CYP2A-DM recombinant individual places CYP2A proximal to APOC2 and CKMM. Localisation of CYP2A on a panel of somatic cell hybrids also suggests that it is proximal to DM and APOC2/C1/E gene cluster. 
1975560	90	108	myotonic dystrophy	SpecificDisease	D009223
1975560	261	279	myotonic dystrophy	SpecificDisease	D009223
1975560	281	283	DM	SpecificDisease	D009223

10737981|t|beta-galactosidase gene mutations affecting the lysosomal enzyme and the elastin-binding protein in GM1-gangliosidosis patients with cardiac involvement.
10737981|a|GM1-gangliosidosis is a lysosomal storage disorder caused by deficiency of acid beta-galactosidase (GLB1). We report five new beta-galactosidase gene mutations in nine Italian patients and one fetus, segregating in seven unrelated families. Six of the eight patients with the infantile, severe form of the disease presented cardiac involvement, a feature rarely associated with GM1-gangliosidosis. Molecular analysis of the patients RNA and DNA identified two new RNA splicing defects, three new and three previously described amino acid substitutions. Interestingly, all patients with cardiac involvement were homozygous for one of these mutations  R59H, Y591C, Y591N, or IVS14-2A > G. In contrast, all other patients were compound heterozygous for one of the following mutations  R201H, R482H, G579D, IVS8 + 2T > C. Although we could not directly correlate the presence of cardiac abnormalities with specific genetic lesions, the mutations identified in patients with cardiomyopathy fell in the GLB1 cDNA region common to the lysosomal enzyme and the Hbeta-Gal-related protein, also known as the elastin binding protein (EBP). Consequently, both molecules are affected by the mutations, and they may contribute differently to the occurrence of specific clinical manifestations.. 
10737981	100	118	GM1-gangliosidosis	Modifier	D016537
10737981	133	152	cardiac involvement	SpecificDisease	D006331
10737981	154	172	GM1-gangliosidosis	SpecificDisease	D016537
10737981	178	204	lysosomal storage disorder	DiseaseClass	D016464
10737981	215	252	deficiency of acid beta-galactosidase	SpecificDisease	D016537
10737981	478	497	cardiac involvement	DiseaseClass	D006331
10737981	532	550	GM1-gangliosidosis	SpecificDisease	D016537
10737981	740	759	cardiac involvement	DiseaseClass	D006331
10737981	1029	1050	cardiac abnormalities	DiseaseClass	D018376
10737981	1065	1080	genetic lesions	DiseaseClass	D020022
10737981	1124	1138	cardiomyopathy	DiseaseClass	D009202

1679035|t|Exclusion of linkage between familial Mediterranean fever and the human serum amyloid A (SAA) gene cluster.
1679035|a|We studied the relationship between the autosomal recessive trait familial Mediterranean fever (FMF) and the serum amyloid A (SAA) genes by comparing alleles of a highly polymorphic dinucleotide repeat and a conventional restriction fragment length polymorphism (RFLP) in the SAA gene cluster in Israeli FMF kindreds. By haplotype analysis, our data indicate a minimum crossover frequency of 22% between the SAA gene marker and FMF. By conventional linkage analysis this eliminates a minimum of 10. 4 cM including and surrounding the SAA gene cluster as the site of the FMF mutation although SAA proteins are prominent physiologic markers of the acute attacks. 
1679035	29	57	familial Mediterranean fever	SpecificDisease	D010505
1679035	174	202	familial Mediterranean fever	SpecificDisease	D010505
1679035	204	207	FMF	SpecificDisease	D010505
1679035	412	415	FMF	Modifier	D010505
1679035	536	539	FMF	SpecificDisease	D010505
1679035	678	681	FMF	Modifier	D010505

10802667|t|Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.
10802667|a|Expansion of a CTG trinucleotide repeat in the 3 UTR of the gene DMPK at the DM1 locus on chromosome 19 causes myotonic dystrophy, a dominantly inherited disease characterized by skeletal muscle dystrophy and myotonia, cataracts and cardiac conduction defects. Targeted deletion of Dm15, the mouse orthologue of human DMPK, produced mice with a mild myopathy and cardiac conduction abnormalities, but without other features of myotonic dystrophy, such as myotonia and cataracts. We, and others, have demonstrated that repeat expansion decreases expression of the adjacent gene SIX5 (refs 7, 8), which encodes a homeodomain transcription factor. To determine whether SIX5 deficiency contributes to the myotonic dystrophy phenotype, we disrupted mouse Six5 by replacing the first exon with a beta-galactosidase reporter. Six5-mutant mice showed reporter expression in multiple tissues, including the developing lens. Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. Our results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder.. 
10802667	5	22	deficient in Six5	SpecificDisease	D030342
10802667	31	40	cataracts	SpecificDisease	D002386
10802667	59	77	myotonic dystrophy	SpecificDisease	D009223
10802667	190	208	myotonic dystrophy	SpecificDisease	D009223
10802667	212	240	dominantly inherited disease	DiseaseClass	D030342
10802667	267	283	muscle dystrophy	SpecificDisease	D009136
10802667	288	296	myotonia	DiseaseClass	D009222
10802667	298	307	cataracts	SpecificDisease	D002386
10802667	312	338	cardiac conduction defects	DiseaseClass	OMIM:115080
10802667	429	437	myopathy	DiseaseClass	D009135
10802667	442	474	cardiac conduction abnormalities	DiseaseClass	D006327
10802667	506	524	myotonic dystrophy	SpecificDisease	D009223
10802667	534	542	myotonia	DiseaseClass	D009222
10802667	547	556	cataracts	SpecificDisease	D002386
10802667	745	760	SIX5 deficiency	SpecificDisease	D030342
10802667	780	798	myotonic dystrophy	Modifier	D009223
10802667	1033	1074	abnormalities of skeletal muscle function	DiseaseClass	D009139
10802667	1090	1110	lenticular opacities	SpecificDisease	D002386
10802667	1168	1183	SIX5 deficiency	SpecificDisease	D030342
10802667	1203	1211	cataract	Modifier	D002386
10802667	1225	1243	myotonic dystrophy	SpecificDisease	D009223
10802667	1254	1272	myotonic dystrophy	SpecificDisease	D009223
10802667	1286	1305	multigenic disorder	DiseaseClass	D030342

1338764|t|Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients.
1338764|a|We report here the result of a screening for germ-line mutations in the adenomatous polyposis coli (APC) gene in 61 new familial adenomatous polyposis (FAP) patients as well as a summary of the results of 150 patients. Examination of the entire coding region of the APC gene, based on a ribonuclease protection assay coupled with the polymerase chain reaction (PCR), disclosed mutations that were considered to cause significant defects in the APC product in 97 of 150 unrelated FAP patients. Our findings revealed the following characteristics of the germ-line mutations of APC  1) the great majority of the mutations were found to truncate the APC product; 2) almost all of the mutations were located within the first half of the coding region; 3) no correlation was observed between the locations of germ-line mutations and extracolonic manifestations in FAP patients; 4) more than 80% of base substitutions in the APC gene were from cytosine to other nucleotides, nearly one-third of which occurred at the GpG site. Our results provide information helpful to an understanding of the APC gene and will also contribute to presymptomatic diagnosis of members in FAP families.. 
1338764	37	67	familial adenomatous polyposis	Modifier	D011125
1338764	207	233	adenomatous polyposis coli	Modifier	D011125
1338764	235	238	APC	Modifier	D011125
1338764	255	285	familial adenomatous polyposis	Modifier	D011125
1338764	287	290	FAP	Modifier	D011125
1338764	401	404	APC	Modifier	D011125
1338764	579	582	APC	Modifier	D011125
1338764	614	617	FAP	Modifier	D011125
1338764	781	784	APC	Modifier	D011125
1338764	993	996	FAP	Modifier	D011125
1338764	1053	1056	APC	Modifier	D011125
1338764	1222	1225	APC	Modifier	D011125
1338764	1298	1301	FAP	Modifier	D011125

1999552|t|Hereditary deficiency of C5 in association with discoid lupus erythematosus.
1999552|a|A 29-year-old woman with discoid lupus erythematosus had undetectable classic pathway complement activity. Hypocomplementemia was due to selective deficiency of C5. One of her children was also deficient. To our knowledge this is the first documented case of an association between discoid lupus erythematosus and C5 deficiency.. 
1999552	11	27	deficiency of C5	SpecificDisease	OMIM:609536
1999552	48	75	discoid lupus erythematosus	SpecificDisease	D008179
1999552	102	129	discoid lupus erythematosus	SpecificDisease	D008179
1999552	184	202	Hypocomplementemia	DiseaseClass	D007153
1999552	224	240	deficiency of C5	SpecificDisease	OMIM:609536
1999552	359	386	discoid lupus erythematosus	SpecificDisease	D008179
1999552	391	404	C5 deficiency	SpecificDisease	OMIM:609536

10818206|t|Isolation, genomic organization, and expression analysis of the mouse and rat homologs of MEFV, the gene for familial mediterranean fever.
10818206|a|Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. Recently the FMF gene (MEFV) was cloned; the protein product, pyrin/marenostrin, is thought to regulate inflammation in myeloid cells. In this manuscript we report the mouse and rat homologs of MEFV. The murine gene contains ten exons with a coding sequence of 2304 bp, while the rat homolog has nine exons with a coding sequence of 2253 bp. A considerable amino acid sequence homology was observed between the mouse and human (47. 6% identity and 65. 5% similarity) and between the mouse and rat genes (73. 5% identity and 82. 1% similarity). The predicted rodent proteins have several important domains and signals found in human pyrin, including a B-box zinc finger domain, Robbins-Dingwall nuclear localization signal, and coiled-coil domain. However, perhaps because of an ancient frame-shift mutation, neither the mouse nor the rat protein has an intact C-terminal B30. 2 domain, in which most FMF-associated mutations have been found in human MEFV. Nevertheless, like the human gene, mouse Mefv is expressed in peripheral blood granulocytes but not lymphocytes. Consistent with its expression in granulocytes, Mefv was detected at high levels in the primary follicles and marginal zones of the splenic white pulp. Mefv is localized on mouse Chromosome (Chr) 16, region A3-B1, extending a region of synteny with human Chr 16p13. 3. Development of knockout and knockin mouse models may provide further insights into the functional evolution of this gene. 
10818206	109	137	familial mediterranean fever	SpecificDisease	D010505
10818206	139	167	Familial Mediterranean fever	SpecificDisease	D010505
10818206	169	172	FMF	SpecificDisease	D010505
10818206	179	197	recessive disorder	DiseaseClass	D030342
10818206	227	232	fever	DiseaseClass	D005334
10818206	238	247	serositis	SpecificDisease	D012700
10818206	251	260	synovitis	SpecificDisease	D013585
10818206	275	278	FMF	Modifier	D010505
10818206	1162	1165	FMF	Modifier	D010505

1684569|t|Analysis of X-chromosome inactivation and presumptive expression of the Wiskott-Aldrich syndrome (WAS) gene in hematopoietic cell lineages of a thrombocytopenic carrier female of WAS.
1684569|a|We report on a thrombocytopenic female belonging to a pedigree with the Wiskott-Aldrich syndrome (WAS). Restriction fragment length polymorphism (RFLP) analysis with probe M27 beta, closely linked to the WAS gene, demonstrated that she is a carrier of WAS. Both small-sized and normal-sized platelets were present, suggesting that, unlike the vast majority of WAS carriers, she does not manifest nonrandom X-chromosome inactivation in the thrombopoietic cell lineage. Study of X-chromosome inactivation by means of RFLP and methylation analysis demonstrated that the pattern of X-chromosome inactivation was nonrandom in T lymphocytes, but random in granulocytes. While this is the first complete report on the occurrence of thrombocytopenia in a carrier female of WAS as the result of atypical lyonization, it also suggests that expression of the WAS gene occurs at (or extends up to) a later stage than the multipotent stem cell along the hematopoietic differentiation pathway.. 
1684569	72	96	Wiskott-Aldrich syndrome	Modifier	D014923
1684569	98	101	WAS	Modifier	D014923
1684569	179	182	WAS	SpecificDisease	D014923
1684569	199	215	thrombocytopenic	Modifier	D013921
1684569	256	280	Wiskott-Aldrich syndrome	SpecificDisease	D014923
1684569	282	285	WAS	SpecificDisease	D014923
1684569	388	391	WAS	Modifier	D014923
1684569	436	439	WAS	SpecificDisease	D014923
1684569	544	547	WAS	Modifier	D014923
1684569	909	925	thrombocytopenia	SpecificDisease	D013921
1684569	949	952	WAS	SpecificDisease	D014923
1684569	1032	1035	WAS	Modifier	D014923

10724175|t|hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response.
10724175|a|Mutations in the BRCA1 (ref. 1) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer. Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair and cell-cycle checkpoint. BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage. It is not known whether BRCA1 phosphorylation and dispersion and its function in DNA damage response are related. In yeast the DNA damage response and the replication-block checkpoint are mediated partly through the Cds1 kinase family. Here we report that the human Cds1 kinase (hCds1/Chk2) regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1. We show that hCds1 and BRCA1 interact and co-localize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937.. 
10724175	107	113	tumour	Modifier	D009369
10724175	175	211	inherited breast and ovarian cancers	CompositeMention	D061325
10724175	253	266	breast cancer	SpecificDisease	D001943

10556285|t|Ataxin-3 with an altered conformation that exposes the polyglutamine domain is associated with the nuclear matrix.
10556285|a|Spinocerebellar ataxia type-3 or Machado-Joseph disease (SCA3/MJD) is a member of the CAG/polyglutamine repeat disease family. In this family of disorders, a normally polymorphic CAG repeat becomes expanded, resulting in expression of an expanded polyglutamine domain in the disease gene product. Experimental models of polyglutamine disease implicate the nucleus in pathogenesis; however, the link between intranuclear expression of expanded polyglutamine and neuronal dysfunction remains unclear. Here we demonstrate that ataxin-3, the disease protein in SCA3/MJD, adopts a unique conformation when expressed within the nucleus of transfected cells. The monoclonal antibody 1C2 is known preferentially to bind expanded polyglutamine, but we find that it also binds a fragment of ataxin-3 containing a normal glutamine repeat. In addition, expression of ataxin-3 within the nucleus exposes the glutamine domain of the full-length non-pathological protein, allowing it to bind the monoclonal antibody 1C2. Fractionation and immunochemical experiments indicate that this novel conformation of intranuclear ataxin-3 is not due to proteolysis, suggesting instead that association with nuclear protein (s) alters the structure of full-length ataxin-3 which exposes the polyglutamine domain. This conformationally altered ataxin-3 is bound to the nuclear matrix. The pathological form of ataxin-3 with an expanded polyglutamine domain also associates with the nuclear matrix. These data suggest that an early event in the pathogenesis of SCA3/MJD may be an altered conformation of ataxin-3 within the nucleus that exposes the polyglutamine domain.. 
10556285	115	144	Spinocerebellar ataxia type-3	SpecificDisease	D017827
10556285	148	170	Machado-Joseph disease	SpecificDisease	D017827
10556285	172	176	SCA3	SpecificDisease	D017827
10556285	177	180	MJD	SpecificDisease	D017827
10556285	201	233	CAG/polyglutamine repeat disease	DiseaseClass	D030342
10556285	435	456	polyglutamine disease	DiseaseClass	D030342
10556285	576	596	neuronal dysfunction	DiseaseClass	D009461
10556285	672	676	SCA3	SpecificDisease	D017827
10556285	677	680	MJD	SpecificDisease	D017827
10556285	1648	1652	SCA3	SpecificDisease	D017827
10556285	1653	1656	MJD	SpecificDisease	D017827

10077614|t|A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome .
10077614|a|The Wilms tumor -suppressor gene, WT1, plays a key role in urogenital development, and WT1 dysfunction is implicated in both neoplastic (Wilms tumor, mesothelioma, leukemias, and breast cancer) and nonneoplastic (glomerulosclerosis) disease. The analysis of diseases linked specifically with WT1 mutations, such as Denys-Drash syndrome (DDS), can provide valuable insight concerning the role of WT1 in development and disease. DDS is a rare childhood disease characterized by a nephropathy involving mesangial sclerosis, XY pseudohermaphroditism, and/or Wilms tumor (WT). DDS patients are constitutionally heterozygous for exonic point mutations in WT1, which include mutations predicted to truncate the protein within the C-terminal zinc finger (ZF) region. We report that heterozygosity for a targeted murine Wt1 allele, Wt1 (tmT396), which truncates ZF3 at codon 396, induces mesangial sclerosis characteristic of DDS in adult heterozygous and chimeric mice. Male genital defects also were evident and there was a single case of Wilms tumor in which the transcript of the nontargeted allele showed an exon 9 skipping event, implying a causal link between Wt1 dysfunction and Wilms tumorigenesis in mice. However, the mutant WT1 (tmT396) protein accounted for only 5% of WT1 in both heterozygous embryonic stem cells and the WT. This has implications regarding the mechanism by which the mutant allele exerts its effect.
10077614	69	93	urogenital abnormalities	DiseaseClass	D014564
10077614	97	117	Denys-Drash syndrome	SpecificDisease	D030321
10077614	124	135	Wilms tumor	Modifier	D009396
10077614	207	222	WT1 dysfunction	SpecificDisease	D030342
10077614	245	255	neoplastic	Modifier	D009369
10077614	257	268	Wilms tumor	SpecificDisease	D009396
10077614	270	282	mesothelioma	SpecificDisease	D008654
10077614	284	293	leukemias	SpecificDisease	D007938
10077614	299	312	breast cancer	SpecificDisease	D001943
10077614	318	331	nonneoplastic	Modifier	D004194
10077614	333	351	glomerulosclerosis	SpecificDisease	D005921
10077614	435	455	Denys-Drash syndrome	SpecificDisease	D030321
10077614	457	460	DDS	SpecificDisease	D030321
10077614	547	550	DDS	SpecificDisease	D030321
10077614	598	609	nephropathy	SpecificDisease	D007674
10077614	620	639	mesangial sclerosis	SpecificDisease	C537346
10077614	644	665	pseudohermaphroditism	SpecificDisease	D012734
10077614	674	685	Wilms tumor	SpecificDisease	D009396
10077614	687	689	WT	SpecificDisease	D009396
10077614	692	695	DDS	Modifier	D030321
10077614	999	1018	mesangial sclerosis	SpecificDisease	C537346
10077614	1037	1040	DDS	SpecificDisease	D030321
10077614	1082	1102	Male genital defects	DiseaseClass	D005832
10077614	1152	1163	Wilms tumor	SpecificDisease	D009396
10077614	1278	1293	Wt1 dysfunction	SpecificDisease	D030342
10077614	1298	1317	Wilms tumorigenesis	SpecificDisease	D009396
10077614	1447	1449	WT	SpecificDisease	D009396

7106752|t|Heterogeneity of "Mediterranean type" glucose-6-phosphate dehydrogenase (G6PD) deficiency in Spain and description of two new variants associated with favism.
7106752|a|Glucose-6-phosphate dehydrogenase (G6PD); EC 1. 1. 1. 49 from thirty-six unrelated Spanish males was partially purified from blood, and the variants were characterized biochemically and electrophoretically according to the methods recommended by the world Health Organization. Subjects were from multiple geographic regions within Spain, and all suffered from hemolytic anemia, either acute (34 cases) or chronic nonspherocytic (2 cases). Almost all the variants studied presented residual erythrocyte G6PD activity ranging from 0 to 10% of normal, and five different mutants were responsible for the deficient phenotype. Three variants were similar to others previously described  G6PD Mediterranean (11 cases), G6PD Athens-like (3 cases), and G6PD Union (2 cases). The remaining variants were different from the numerous variants already reported and have been considered as new mutants. Provisionally they are called G6PD Betica (19 cases) and G6PD Menorca (1 case). The present study constitutes the first attempt to characterize the deficient G6PD variants found in Spain and supplies new data on the relationship between molecular characteristics of deficient variants and their clinical manifestations. The most important findings can be summarized as follows  (1) The Spanish population is characterized by an important heterogeneity in G6PD deficiency. (2) Although G6PD Mediterranean is very frequent, it presents a relatively high degree of polymorphism. (3) Favism has been observed associated with all kinds of variants described here. (4) G6PD Betica, which is the most frequent variant found in subjects of Southern Spanish origin, has been observed associated with favism in all cases except one. 
7106752	38	89	glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
7106752	151	157	favism	SpecificDisease	D005236
7106752	519	535	hemolytic anemia	SpecificDisease	D000743
7106752	1197	1211	deficient G6PD	Modifier	D005955
7106752	1504	1519	G6PD deficiency	SpecificDisease	D005955
7106752	1629	1635	Favism	SpecificDisease	D005236
7106752	1840	1846	favism	SpecificDisease	D005236

10480214|t|Early onset of X-linked Emery-Dreifuss muscular dystrophy in a boy with emerin gene deletion.
10480214|a|A boy developed contractures of the Achilles tendons at 3 years and of the postcervical muscles at 7 years, although neither contractures of the elbows nor cardiac abnormality were recognized by the age of 9 years. Muscle computed tomography scanning revealed changes characteristic of muscle involvement. Emerin was not detected in the biopsied muscle, and RT-PCR and PCR-based genomic DNA analyses of the emerin gene demonstrated no amplification product in the patient. These results confirmed the diagnosis of X-linked Emery-Dreifuss muscular dystrophy (EDMD), and reinforce the necessity of molecular genetic diagnosis of the membrane protein emerin in younger patients with possible EDMD before appearance of the typical symptoms, to avoid sudden cardiac death.. 
10480214	15	57	X-linked Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10480214	110	146	contractures of the Achilles tendons	DiseaseClass	D003286
10480214	219	245	contractures of the elbows	DiseaseClass	D003286
10480214	250	269	cardiac abnormality	DiseaseClass	D018376
10480214	608	650	X-linked Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10480214	652	656	EDMD	SpecificDisease	D020389
10480214	783	787	EDMD	SpecificDisease	D020389
10480214	840	860	sudden cardiac death	SpecificDisease	D016757

1682919|t|PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma.
1682919|a|Rearrangement of the BCL1 (B-cell lymphoma 1) region on chromosome 11q13 appears to be highly characteristic of centrocytic lymphoma and also is found infrequently in other B-cell neoplasms. Rearrangement is thought to deregulate a nearby protooncogene, but transcribed sequences in the immediate vicinity of BCL1 breakpoints had not been identified. PRAD1, previously designated D11S287E, was identified on 11q13 as a chromosomal breakpoint region rearranged with the parathyroid hormone gene in a subset of parathyroid adenomas; this highly conserved putative oncogene, which encodes a novel cyclin, has been linked to BCL1 and implicated also in subsets of breast and squamous cell neoplasms with 11q13 amplification. We report pulsed-field gel electrophoresis data showing BCL1 and PRAD1 to be no more than 130 kilobases apart. PRAD1 mRNA is abundantly expressed in seven of seven centrocytic lymphomas (Kiel classification), in contrast to 13 closely related but noncentrocytic lymphomas. Three of the seven centrocytic lymphomas had detectable BCL1 DNA rearrangement. Also, two unusual cases of CLL with BCL1 rearrangement overexpressed PRAD1, in contrast to five CLL controls. Thus, PRAD1 is an excellent candidate " BCL1 oncogene. " Its overexpression may be a key consequence of rearrangement of the BCL1 vicinity in B-cell neoplasms and a unifying pathogenetic feature in centrocytic lymphoma. 
1682919	60	80	centrocytic lymphoma	DiseaseClass	D008223
1682919	194	214	centrocytic lymphoma	DiseaseClass	D008223
1682919	255	271	B-cell neoplasms	SpecificDisease	D016393
1682919	591	611	parathyroid adenomas	DiseaseClass	D010282
1682919	742	776	breast and squamous cell neoplasms	CompositeMention	D001943|D018307
1682919	967	988	centrocytic lymphomas	DiseaseClass	D008223
1682919	1050	1074	noncentrocytic lymphomas	DiseaseClass	D008223
1682919	1095	1116	centrocytic lymphomas	DiseaseClass	D008223
1682919	1408	1424	B-cell neoplasms	SpecificDisease	D016393
1682919	1464	1484	centrocytic lymphoma	DiseaseClass	D008223

7202134|t|Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids.
7202134|a|With a new method we measured the saturated very long chain fatty acids in the plasma of adrenoleukodystrophy (ALD) hemizygotes, ALD heterozygotes, and controls. ALD hemizygotes showed increased levels of hexacosanoate (C26 fatty acid) which represented 0. 081 +/- 0. 0066% (SEM) of total fatty acids, compared to 0. 015 +/- 0. 0032% in the controls. C25, C24, and C23 fatty acids were also increased, but the C22 and C20 fatty acids were normal. C26 levels were also increased in most ALD heterozygotes, with a mean level 0. 057 +/- 0. 0063% of total fatty acids. The technique can be used for diagnosis and carrier identification, and in the evaluation of therapy.
7202134	0	20	Adrenoleukodystrophy	SpecificDisease	D000326
7202134	178	198	adrenoleukodystrophy	Modifier	D000326
7202134	200	203	ALD	Modifier	D000326
7202134	218	221	ALD	Modifier	D000326
7202134	251	254	ALD	Modifier	D000326
7202134	575	578	ALD	Modifier	D000326

6337374|t|Glucose-6-phosphate dehydrogenase deficiency inhibits in vitro growth of Plasmodium falciparum.
6337374|a|Glucose-6-phosphate dehydrogenase (G6PD; EC 1. 1. 1. 49) -deficient red blood cells from male hemizygotes and female heterozygotes from the island of Sardinia were studied for their ability to support growth in vitro of the malaria-causing organism Plasmodium falciparum. Parasite growth was approximately one-third of normal in both hemi- and heterozygotes for G6PD deficiency. In Sardinians with the beta 0-thalassemia trait, parasite growth was normal except when G6PD deficiency occurred together with the thalassemia trait. The data support the hypothesis that G6PD deficiency may confer a selective advantage in a malarious area; the female heterozygote may be at a particular advantage because resistance to malaria equals that of male hemizygotes, but the risk of fatal hemolysis may be less. However, more female heterozygotes must be studied to confirm this hypothesis. No protective effect of beta 0-thalassemia trait could be demonstrated in vitro. 
6337374	0	44	Glucose-6-phosphate dehydrogenase deficiency	SpecificDisease	D005955
6337374	96	163	Glucose-6-phosphate dehydrogenase (G6PD; EC 1. 1. 1. 49) -deficient	Modifier	D005955
6337374	320	327	malaria	Modifier	D008288
6337374	458	473	G6PD deficiency	SpecificDisease	D005955
6337374	563	578	G6PD deficiency	SpecificDisease	D005955
6337374	606	617	thalassemia	Modifier	D013789
6337374	662	677	G6PD deficiency	SpecificDisease	D005955
6337374	716	725	malarious	Modifier	D008288
6337374	811	818	malaria	SpecificDisease	D008288
6337374	868	883	fatal hemolysis	SpecificDisease	D006461

3718019|t|Heterozygous C2 deficiency associated with angioedema, myasthenia gravis, and systemic lupus erythematosus.
3718019|a|We describe a patient with myasthenia gravis, systemic lupus erythematosus, and angioedema associated with heterozygous complement factor 2 (C2) deficiency. The significance of this association is controversial, though the association of C2 deficiency with certain histocompatibility antigens suggests possible linkage to immune response genes. To our knowledge this is the first report of heterozygous C2 deficiency in association with this combination of autoimmune disorders, and we discuss the aetiological implications.. 
3718019	0	26	Heterozygous C2 deficiency	SpecificDisease	OMIM:217000
3718019	43	53	angioedema	SpecificDisease	D000799
3718019	55	72	myasthenia gravis	SpecificDisease	D009157
3718019	78	106	systemic lupus erythematosus	SpecificDisease	D008180
3718019	135	152	myasthenia gravis	SpecificDisease	D009157
3718019	154	182	systemic lupus erythematosus	SpecificDisease	D008180
3718019	188	198	angioedema	SpecificDisease	D000799
3718019	228	263	complement factor 2 (C2) deficiency	SpecificDisease	OMIM:217000
3718019	346	359	C2 deficiency	SpecificDisease	OMIM:217000
3718019	511	524	C2 deficiency	SpecificDisease	OMIM:217000
3718019	565	585	autoimmune disorders	DiseaseClass	D001327

2963536|t|Inherited C3 deficiency with recurrent infections and glomerulonephritis.
2963536|a|A 10-year-old Laotian boy had homozygous deficiency of the third component of complement and recurrent bacterial infections beginning at age 5 months. Cellular and humoral immunity were normal, as were polymorphonuclear leukocyte chemotaxis and bactericidal activities. Serum complement-mediated hemolytic, chemotactic, and opsonic activities were deficient. In vitro addition of purified C3 to patient serum restored hemolytic complement to normal levels, and plasma infusion during each of four episodes of pneumonia significantly enhanced serum opsonic activity for as long as 36 hours. A renal biopsy specimen revealed mesangiopathic glomerulonephritis, although significant levels of circulating IgG immune complexes were not detected. These findings further support the association of C3 deficiency with immune-complex disease and suggest that plasma infusion may be an adjunct to antibiotic therapy in the management of severe pyogenic infections in patients with C3 deficiency.. 
2963536	10	23	C3 deficiency	SpecificDisease	OMIM:613779
2963536	54	72	glomerulonephritis	SpecificDisease	D005921
2963536	115	162	deficiency of the third component of complement	SpecificDisease	OMIM:613779
2963536	177	197	bacterial infections	DiseaseClass	D001424
2963536	583	592	pneumonia	SpecificDisease	D011014
2963536	697	730	mesangiopathic glomerulonephritis	SpecificDisease	D005921
2963536	865	878	C3 deficiency	SpecificDisease	OMIM:613779
2963536	884	906	immune-complex disease	DiseaseClass	D007105
2963536	1008	1027	pyogenic infections	DiseaseClass	D007239
2963536	1045	1058	C3 deficiency	SpecificDisease	OMIM:613779

7586656|t|Southern analysis reveals a large deletion at the hypoxanthine phosphoribosyltransferase locus in a patient with Lesch-Nyhan syndrome.
7586656|a|Whole genomic hprt clones were used in Southern analysis to screen the integrity of the hprt gene in a family that includes a patient with HPRT enzyme deficiency causal to Lesch-Nyhan syndrome. A 5 kb DNA sequence deletion was found to have its endpoints in the first and third introns. The probes identified the carrier status of female family members, aided by an RFLP carried by the mothers normal X-chromosome.. 
7586656	113	133	Lesch-Nyhan syndrome	SpecificDisease	D007926
7586656	274	296	HPRT enzyme deficiency	SpecificDisease	D007926
7586656	307	327	Lesch-Nyhan syndrome	SpecificDisease	D007926

10426999|t|Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.
10426999|a|BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50. Formation of irradiation-induced foci positive for BRCA1, hRad50, hMre11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wild-type BRCA1. Ectopic expression of wild-type, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent, methyl methanesulfonate. These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex.. 
10426999	101	106	tumor	Modifier	D009369
10426999	137	172	familial breast and ovarian cancers	CompositeMention	D061325
10426999	515	528	breast cancer	Modifier	D001943

3678494|t|Nebulin and titin expression in Duchenne muscular dystrophy appears normal.
3678494|a|Monoclonal antibodies which recognize different epitopes on either titin or nebulin show normal staining patterns on frozen sections of three muscle biopsies of Duchenne muscular dystrophy (DMD). Gel electrophoresis and immunoblotting performed on two of these muscle biopsies show the normal pattern of titin and nebulin polypeptides. Since the donor of one of these biopsies has a large deletion of the 5-region of the DMD gene, our results argue against the recent proposal that nebulin is the gene mutated in DMD.. 
3678494	32	59	Duchenne muscular dystrophy	SpecificDisease	D020388
3678494	237	264	Duchenne muscular dystrophy	SpecificDisease	D020388
3678494	266	269	DMD	SpecificDisease	D020388
3678494	497	500	DMD	Modifier	D020388
3678494	589	592	DMD	SpecificDisease	D020388

8281152|t|Myotonic dystrophy kinase is a component of neuromuscular junctions.
8281152|a|The clinical manifestation of myotonic dystrophy (DM) is correlated to the extent of expansion of an unstable [CTG] n DNA motif. Recent studies have demonstrated that this trinucleotide motif forms part of the last, 3 untranslated exon of a gene which potentially encodes multiple protein isoforms of a serine/threonine protein kinase (myotonic dystrophy protein kinase, DM-PK). We report here on the development of antisera against synthetic DM-PK peptide antigens and their use in biochemical and histochemical studies. Immunoreactive DM-kinase protein of 53 kD is present at low levels in skeletal and cardiac muscle extracts of DM patients and normal controls. Immunohistochemical staining revealed that DM-PK is localised prominently at sites of neuromuscular and myotendinous junctions (NMJs and MTJs) of human and rodent skeletal muscles. Furthermore, very low levels of immunoreactive DM-PK protein are present in the sarcoplasm of predominantly type I fibres in various muscles. Strikingly, presence of the protein can also be demonstrated for NMJs of muscular tissues of adult and congenital cases of DM, with no gross changes in structural organisation. Our findings provide a basis for further characterisation of the role of the kinase in protein assembly processes or signal mediation at synaptic sites and ultimately for the understanding of the complex pathophysiology of DM.. 
8281152	0	18	Myotonic dystrophy	Modifier	D009223
8281152	99	117	myotonic dystrophy	SpecificDisease	D009223
8281152	119	121	DM	SpecificDisease	D009223
8281152	405	423	myotonic dystrophy	Modifier	D009223
8281152	701	703	DM	Modifier	D009223
8281152	1180	1182	DM	SpecificDisease	D009223
8281152	1457	1459	DM	SpecificDisease	D009223

7316485|t|New genetic variants of glucose 6-phosphate dehydrogenase (G6PD) in Italy.
7316485|a|Six new variants of human erythrocyte G6PD have been characterized. All of them were found in Italian males and all were associated with enzyme deficiency, but only two with signs of haemolysis. These and other variants reported in the literature, which must thus far be regarded as sporadic, are found to map in parts of Italy where common types of G6PD deficiency are also prevalent.. 
7316485	212	229	enzyme deficiency	DiseaseClass	D008661
7316485	258	268	haemolysis	SpecificDisease	D006461
7316485	425	440	G6PD deficiency	SpecificDisease	D005955

10677309|t|ATM-heterozygous germline mutations contribute to breast cancer-susceptibility.
10677309|a|Approximately 0. 5% -1% of the general population has been estimated to be heterozygous for a germline mutation in the ATM gene. Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM 208900). The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age < 45 and had survived >/= 5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8. 5%) ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T-- > G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are " A-T disease-causing " mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may explain why such a high frequency was not found in other series. 
10677309	50	63	breast cancer	Modifier	D001943
10677309	259	287	autosomal recessive disorder	DiseaseClass	D030342
10677309	288	309	ataxia-telangiectasia	SpecificDisease	D001260
10677309	311	314	A-T	SpecificDisease	D001260
10677309	401	414	breast cancer	SpecificDisease	D001943
10677309	598	611	breast cancer	SpecificDisease	D001943
10677309	836	858	sporadic breast cancer	SpecificDisease	D001943
10677309	913	926	breast cancer	SpecificDisease	D001943

10709732|t|Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?
10709732|a|Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis. This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes. Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely. Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain. The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous. The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype. The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive.. 
10709732	0	39	Autoimmune lymphoproliferative syndrome	SpecificDisease	D056735
10709732	41	45	ALPS	SpecificDisease	D056735
10709732	120	159	Autoimmune lymphoproliferative syndrome	SpecificDisease	D056735
10709732	161	165	ALPS	SpecificDisease	D056735
10709732	349	353	ALPS	SpecificDisease	D056735
10709732	959	963	ALPS	Modifier	D056735
10709732	1024	1028	ALPS	Modifier	D056735

8551426|t|A prevalent mutation for galactosemia among black Americans.
8551426|a|OBJECTIVE  To define the mutation causing galactosemia in patients of black American origin who have no galactose-1-phosphate uridyltransferase (GALT) activity in erythrocytes but good clinical outcome. METHODS  We discovered a mutation caused by a C-- > T transition at base-pair 1158 of the GALT gene that results in a serine-to-leucine substitution at codon 135 (S135L). We developed a method with which to screen populations for its prevalence. We compared galactose-1-phosphate uridyltransferase among erythrocytes, leukocytes, and transformed lymphoblasts, as well as total body oxidation of D- (13C) -galactose to 13CO2 among three genotypes for GALT (S135L/S135L, Q188R/Q188R, and Normal/Normal). RESULTS  We found a 48% prevalence of the S135L mutation among 17 black American patients with classic galactosemia and a 1% prevalence in a population of 50 black Americans without galactosemia. The S135L mutation was not found in 84 white patients with G/G galactosemia nor in 87 white control subjects without galactosemia. We found normal whole body oxidation of D- (13C) -galactose by the patient homozygous for S135L and various degrees of enzyme impairment among different tissues. CONCLUSIONS  The S135L mutation in the GALT gene is a prevalent cause of galactosemia among black patients. Because GALT activity varies in different tissues of patients homozygous for S135L, they may have a better clinical outcome than patients who are homozygous for Q188R when both are treated from infancy.. 
8551426	25	37	galactosemia	SpecificDisease	D005693
8551426	103	115	galactosemia	SpecificDisease	D005693
8551426	861	881	classic galactosemia	SpecificDisease	D005693
8551426	948	960	galactosemia	SpecificDisease	D005693
8551426	1025	1037	galactosemia	SpecificDisease	D005693
8551426	1079	1091	galactosemia	SpecificDisease	D005693
8551426	1328	1340	galactosemia	SpecificDisease	D005693

10699184|t|Constitutive and regulated modes of splicing produce six major myotonic dystrophy protein kinase (DMPK) isoforms with distinct properties.
10699184|a|Myotonic dystrophy (DM) is the most prevalent inherited neuromuscular disease in adults. The genetic defect is a CTG triplet repeat expansion in the 3-untranslated region of the myotonic dystrophy protein kinase (DMPK) gene, consisting of 15 exons. Using a transgenic DMPK-overexpressor mouse model, we demonstrate here that the endogenous mouse DMPK gene and the human DMPK transgene produce six major alternatively spliced mRNAs which have almost identical cell type-dependent distribution frequencies and expression patterns. Use of a cryptic 5 splice site in exon 8, which results in absence or presence of 15 nucleotides specifying a VSGGG peptide motif, and/or use of a cryptic 3 splice site in exon 14, which leads to a frameshift in the mRNA reading frame, occur as independent stochastic events in all tissues examined. In contrast, the excision of exons 13/14 that causes a frameshift and creates a C-terminally truncated protein is clearly cell type dependent and occurs predominantly in smooth muscle. We generated all six full-length mouse cDNAs that result from combinations of these three major splicing events and show that their transfection into cells in culture leads to production of four different approximately 74 kDa full-length (heart-, skeletal muscle- or brain-specific) and two C-terminally truncated approximately 68 kDa (smooth muscle-specific) isoforms. Information on DMPK mRNA and protein isoform expression patterns will be useful for recognizing differential effects of (CTG) (n) expansion in DM manifestation.. 
10699184	63	81	myotonic dystrophy	Modifier	D009223
10699184	139	157	Myotonic dystrophy	SpecificDisease	D009223
10699184	159	161	DM	SpecificDisease	D009223
10699184	185	216	inherited neuromuscular disease	DiseaseClass	D009468+D030342
10699184	232	246	genetic defect	DiseaseClass	D030342
10699184	317	335	myotonic dystrophy	Modifier	D009223
10699184	1666	1668	DM	Modifier	D009223

10417286|t|Linkage analysis in a large Brazilian family with van der Woude syndrome suggests the existence of a susceptibility locus for cleft palate at 17p11.2-11.1.
10417286|a|van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk < 40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS. Our results suggest that a gene at 17p11. 2-11 2-11. 1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes. If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene. 
10417286	50	72	van der Woude syndrome	SpecificDisease	C536528
10417286	126	138	cleft palate	SpecificDisease	D002972
10417286	156	178	van der Woude syndrome	SpecificDisease	C536528
10417286	180	183	VWS	SpecificDisease	C536528
10417286	240	276	pits and/or sinuses of the lower lip	CompositeMention	D008047
10417286	278	294	cleft lip/palate	SpecificDisease	D002971|D002972
10417286	296	300	CL/P	SpecificDisease	D002971|D002972
10417286	303	315	cleft palate	SpecificDisease	D002972
10417286	317	319	CP	SpecificDisease	D002972
10417286	322	333	bifid uvula	SpecificDisease	C531732
10417286	339	349	hypodontia	SpecificDisease	D000848
10417286	351	352	H	SpecificDisease	D000848
10417286	373	376	VWS	SpecificDisease	C536528
10417286	454	458	CL/P	SpecificDisease	D002971|D002972
10417286	463	465	CP	SpecificDisease	D002972
10417286	524	526	CP	SpecificDisease	D002972
10417286	550	553	VWS	SpecificDisease	C536528
10417286	593	599	clefts	DiseaseClass	D002971|D002972
10417286	759	762	VWS	SpecificDisease	C536528
10417286	809	811	CP	SpecificDisease	D002972
10417286	881	884	VWS	SpecificDisease	C536528
10417286	960	963	VWS	Modifier	C536528
10417286	1009	1011	CP	SpecificDisease	D002972
10417286	1102	1105	VWS	Modifier	C536528

3393536|t|Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia.
3393536|a|Glucose-6-phosphate dehydrogenase (G6PD; EC 1. 1. 1. 49) deficiency is a common genetic abnormality affecting an estimated 400 million people worldwide. Clinical and biochemical analyses have identified many variants exhibiting a range of phenotypes, which have been well characterized from the hematological point of view. However, until now, their precise molecular basis has remained unknown. We have cloned and sequenced seven mutant G6PD alleles. In the nondeficient polymorphic African variant G6PD A we have found a single point mutation. The other six mutants investigated were all associated with enzyme deficiency. In one of the commonest, G6PD Mediterranean, which is associated with favism among other clinical manifestations, a single amino acid replacement was found (serine----phenylalanine)  it must be responsible for the decreased stability and the reduced catalytic efficiency of this enzyme. Single point mutations were also found in G6PD Metaponto (Southern Italy) and in G6PD Ilesha (Nigeria), which are asymptomatic, and in G6PD Chatham, which was observed in an Indian boy with neonatal jaundice. In G6PD " Matera, " which is now known to be the same as G6PD A-, two separate point mutations were found, one of which is the same as in G6PD A. In G6PD Santiago, a de novo mutation (glycine----arginine) is associated with severe chronic hemolytic anemia. The mutations observed show a striking predominance of C----T transitions, with CG doublets involved in four of seven cases. Thus, diverse point mutations may account largely for the phenotypic heterogeneity of G6PD deficiency. 
3393536	82	99	enzyme deficiency	DiseaseClass	D008661
3393536	119	135	hemolytic anemia	SpecificDisease	D000743
3393536	137	204	Glucose-6-phosphate dehydrogenase (G6PD; EC 1. 1. 1. 49) deficiency	SpecificDisease	D005955
3393536	217	236	genetic abnormality	DiseaseClass	D030342
3393536	743	760	enzyme deficiency	DiseaseClass	D008661
3393536	832	838	favism	DiseaseClass	D005236
3393536	1239	1256	neonatal jaundice	DiseaseClass	D007567
3393536	1497	1513	hemolytic anemia	SpecificDisease	D000743
3393536	1726	1741	G6PD deficiency	SpecificDisease	D005955

2215607|t|Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation.
2215607|a|BACKGROUND AND METHODS. The plasma cholesteryl-ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins. We recently described a Japanese family with increased HDL levels and CETP deficiency due to a splicing defect of the CETP gene. To assess the frequency and phenotype of this condition, we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis. RESULTS. We found the same CETP gene mutation in four families from three different regions of Japan. Analysis of restriction-fragment-length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype. Family members homozygous for CETP deficiency (n = 10) had moderate hypercholesterolemia (mean total cholesterol level [+/- SD], 7. 01 +/- 0. 83 mmol per liter), markedly increased levels of HDL cholesterol (4. 24 +/- 1. 01 mmol per liter) and apolipoprotein A-I, and decreased levels of low-density lipoprotein cholesterol (1. 99 +/- 0. 80 mmol per liter) and apolipoprotein B. Members heterozygous for the deficiency (n = 20), whose CETP levels were in the lower part of the normal range, had moderately increased levels of HDL cholesterol and apolipoprotein A-I and an increased ratio of HDL subclass 2 to HDL subclass 3, as compared with unaffected family members (1. 5 +/- 0. 8 vs. 0. 7 +/- 0. 4). CETP deficiency was not found in six unrelated subjects with elevated HDL cholesterol levels who were from different parts of the United States. CONCLUSIONS. CETP deficiency appears to be a frequent cause of increased HDL levels in the population of Japan, possibly because of a founder effect. The results that we observed in heterozygotes suggest that CETP normally plays a part in the regulation of levels of HDL subclass 2. There was no evidence of premature atherosclerosis in the families with CETP deficiency. In fact, the lipoprotein profile of persons with CETP deficiency is potentially antiatherogenic and may be associated with an increased life span.  
2215607	362	377	CETP deficiency	SpecificDisease	OMIM:143470
2215607	874	889	CETP deficiency	SpecificDisease	OMIM:143470
2215607	912	932	hypercholesterolemia	SpecificDisease	D006937
2215607	1547	1562	CETP deficiency	SpecificDisease	OMIM:143470
2215607	1705	1720	CETP deficiency	SpecificDisease	OMIM:143470
2215607	2000	2025	premature atherosclerosis	SpecificDisease	D050197
2215607	2047	2062	CETP deficiency	SpecificDisease	OMIM:143470
2215607	2113	2128	CETP deficiency	SpecificDisease	OMIM:143470

7523157|t|Hereditary deficiency of the seventh component of complement and recurrent meningococcal infection: investigations of an Irish family using a novel haemolytic screening assay for complement activity and C7 M/N allotyping.
7523157|a|Terminal complement component deficiency predisposes to meningococcal infection and is inherited in an autosomal co-dominant manner. An Irish family is described, in which 2 of 3 brothers had recurrent meningococcal infection. A novel screening assay was used to investigate for terminal complement deficiency and the 2 affected brothers were found to be completely deficient in the seventh component of complement (C7). Enzyme-linked immunosorbent assay for C7 revealed lower than normal levels in the remaining brother and parents. C7 M/N protein polymorphism allotyping, used to investigate the segregation of the C7 deficiency genes, showed that the apparently complement sufficient brother was heterozygous C7 deficient and a carrier of one of the deficiency genes. Complement screening should be carried out in any individual suffering recurrent meningococcal infection or infection with an uncommon meningococcal serogroup. Identification of complement deficient patients allows the implementation of strategies to prevent recurrent infection.. 
7523157	11	60	deficiency of the seventh component of complement	SpecificDisease	OMIM:610102
7523157	75	98	meningococcal infection	SpecificDisease	D008589
7523157	222	262	Terminal complement component deficiency	SpecificDisease	D007153
7523157	278	301	meningococcal infection	SpecificDisease	D008589
7523157	424	447	meningococcal infection	SpecificDisease	D008589
7523157	501	531	terminal complement deficiency	SpecificDisease	D007153
7523157	577	636	completely deficient in the seventh component of complement	SpecificDisease	OMIM:610102
7523157	839	852	C7 deficiency	Modifier	OMIM:610102
7523157	934	946	C7 deficient	SpecificDisease	OMIM:610102
7523157	1074	1097	meningococcal infection	SpecificDisease	D008589
7523157	1128	1141	meningococcal	Modifier	D008589
7523157	1171	1191	complement deficient	Modifier	D007153

3162536|t|Mild and severe muscular dystrophy associated with deletions in Xp21 of the human X chromosome.
3162536|a|We have analysed over 300 patients suffering from Duchenne or Becker muscular dystrophy (DMD or BMD). Deletions have been characterised which encompass either the pERT87 (DXS164) locus only, the XJ1. 1 (DXS206) and HIP25 loci only, or all three loci. These loci have been shown to lie within the DMD region covering several hundred kilobases (kb) of DNA. One mildly affected BMD patient possesses a deletion of at least 110 kb including exons of the DMD gene. Other patients with similar exon deletions, or smaller deletions, show the more severe phenotype typical of DMD. We conclude from these studies that the severity of the clinical phenotype cannot be explained on the basis of the size of the deletion. We discuss this in the context of candidate gene sequences. 
3162536	16	34	muscular dystrophy	DiseaseClass	D009136
3162536	146	183	Duchenne or Becker muscular dystrophy	CompositeMention	D020388|C537666
3162536	185	188	DMD	SpecificDisease	D020388
3162536	192	195	BMD	SpecificDisease	C537666
3162536	392	395	DMD	Modifier	D020388
3162536	471	474	BMD	Modifier	C537666
3162536	546	549	DMD	Modifier	D020388
3162536	664	667	DMD	SpecificDisease	D020388

10631148|t|Meiotic segregation analysis of RB1 alleles in retinoblastoma pedigrees by use of single-sperm typing.
10631148|a|In hereditary retinoblastoma, different epidemiological studies have indicated a preferential paternal transmission of mutant retinoblastoma alleles to offspring, suggesting the occurrence of a meiotic drive. To investigate this mechanism, we analyzed sperm samples from six individuals from five unrelated families affected with hereditary retinoblastoma. Single-sperm typing techniques were performed for each sample by study of two informative short tandem repeats located either in or close to the retinoblastoma gene (RB1). The segregation probability of mutant RB1 alleles in sperm samples was assessed by use of the SPERMSEG program, which includes experimental parameters, recombination fractions between the markers, and segregation parameters. A total of 2, 952 single sperm from the six donors were analyzed. We detected a significant segregation distortion in the data as a whole (P =. 0099) and a significant heterogeneity in the segregation rate across donors (. 0092). Further analysis shows that this result can be explained by segregation distortion in favor of the normal allele in one donor only and that it does not provide evidence of a significant segregation distortion in the other donors. The segregation distortion favoring the mutant RB1 allele does not seem to occur during spermatogenesis, and, thus, meiotic drive may result either from various mechanisms, including a fertilization advantage or a better mobility in sperm bearing a mutant RB1 gene, or from the existence of a defectively imprinted gene located on the human X chromosome.
10631148	47	61	retinoblastoma	Modifier	D012175
10631148	106	131	hereditary retinoblastoma	SpecificDisease	D012175
10631148	229	243	retinoblastoma	Modifier	D012175
10631148	433	458	hereditary retinoblastoma	SpecificDisease	D012175
10631148	605	619	retinoblastoma	Modifier	D012175

10861298|t|Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4).
10861298|a|The PDS gene encodes a transmembrane protein, known as pendrin, which functions as a transporter of iodide and chloride. Mutations in this gene are responsible for Pendred syndrome and autosomal recessive non-syndromic hearing loss at the DFNB4 locus on chromosome 7q31. A screen of 20 individuals from the midwestern USA with non-syndromic hearing loss and dilated vestibular aqueducts identified three people (15%) with PDS mutations. To determine whether PDS mutations in individuals with Pendred syndrome differ functionally from PDS mutations in individuals with non-syndromic hearing loss, we compared three common Pendred syndrome allele variants (L236P, T416P and E384G), with three PDS mutations reported only in individuals with non-syndromic hearing loss (V480D, V653A and I490L/G497S). The mutations associated with Pendred syndrome have complete loss of pendrin-induced chloride and iodide transport, while alleles unique to people with DFNB4 are able to transport both iodide and chloride, albeit at a much lower level than wild-type pendrin. We hypothesize that this residual level of anion transport is sufficient to eliminate or postpone the onset of goiter in individuals with DFNB4. We propose a model for pendrin function in the thyroid in which pendrin transports iodide across the apical membrane of the thyrocyte into the colloid space.. 
10861298	30	33	PDS	Modifier	C536648
10861298	105	121	Pendred syndrome	SpecificDisease	C536648
10861298	126	152	non-syndromic hearing loss	SpecificDisease	C537845
10861298	154	159	DFNB4	SpecificDisease	OMIM:600791
10861298	166	169	PDS	Modifier	C536648
10861298	326	342	Pendred syndrome	SpecificDisease	C536648
10861298	347	393	autosomal recessive non-syndromic hearing loss	SpecificDisease	OMIM:600791
10861298	401	406	DFNB4	Modifier	OMIM:600791
10861298	489	515	non-syndromic hearing loss	SpecificDisease	C537845
10861298	584	587	PDS	Modifier	C536648
10861298	620	623	PDS	Modifier	C536648
10861298	654	670	Pendred syndrome	SpecificDisease	C536648
10861298	696	699	PDS	Modifier	C536648
10861298	730	756	non-syndromic hearing loss	SpecificDisease	C537845
10861298	783	799	Pendred syndrome	Modifier	C536648
10861298	853	856	PDS	Modifier	C536648
10861298	901	927	non-syndromic hearing loss	SpecificDisease	C537845
10861298	990	1006	Pendred syndrome	SpecificDisease	C536648
10861298	1112	1117	DFNB4	SpecificDisease	OMIM:600791
10861298	1330	1336	goiter	DiseaseClass	D006042
10861298	1357	1362	DFNB4	SpecificDisease	OMIM:600791

1353340|t|Late-onset metachromatic leukodystrophy: molecular pathology in two siblings.
1353340|a|We report on a new allele at the arylsulfatase A (ARSA) locus causing late-onset metachromatic leukodystrophy (MLD). In that allele arginine84, a residue that is highly conserved in the arylsulfatase gene family, is replaced by glutamine. In contrast to alleles that cause early-onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity. A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD.. 
1353340	11	39	metachromatic leukodystrophy	SpecificDisease	D007966
1353340	159	187	metachromatic leukodystrophy	SpecificDisease	D007966
1353340	189	192	MLD	SpecificDisease	D007966
1353340	363	366	MLD	SpecificDisease	D007966
1353340	576	579	MLD	Modifier	D007966
1353340	712	715	MLD	SpecificDisease	D007966

10200300|t|Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia.
10200300|a|Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.. 
10200300	63	111	autoimmune lymphoproliferative syndrome, type Ia	SpecificDisease	D056735
10200300	200	239	autoimmune lymphoproliferative syndrome	SpecificDisease	D056735
10200300	241	245	ALPS	SpecificDisease	D056735
10200300	424	428	ALPS	Modifier	D056735
10200300	584	588	ALPS	Modifier	D056735
10200300	774	778	ALPS	SpecificDisease	D056735

10408771|t|Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene.
10408771|a|Classical galactosemia is caused by a deficiency in activity of the enzyme galactose-1-phosphate uridyl transferase (GALT), which, in turn, is caused by mutations at the GALT gene. The disorder exhibits considerable allelic heterogeneity and, at the end of 1998, more than 150 different base changes were recorded in 24 different populations and ethnic groups in 15 countries worldwide. The mutations most frequently cited are Q188R, K285N, S135L, and N314D. Q188R is the most common mutation in European populations or in those predominantly of European descent. Overall, it accounts for 60-70% of mutant chromosomes, but there are significant differences in its relative frequency in individual populations. Individuals homoallelic for Q188R tend to have a severe phenotype and this is in keeping with the virtually complete loss of enzyme activity observed in in vitro expression systems. Globally, K285N is rarer, but in many European populations it can be found on 25-40% of mutant chromosomes. It is invariably associated with a severe phenotype. S135L is found almost exclusively in African Americans. In vitro expression results are discrepant, but some individuals carrying S135L appear to exhibit GALT activity in some tissues. Duarte 1 (or Los Angeles) and Duarte 2 (or Duarte) variants carry the same amino acid substitution, N314D, even though D1 is associated with increased erythrocyte GALT activity and D2 with reduced activity. N314D is in linkage disequilibrium with other base changes that differ on the D1 and D2 alleles. N314D does not impair GALT activity in in vitro expression systems. However, there are differences in the abundance of GALT protein in lymphoblastoid cells lines from D2 and D1 individuals. It is unclear whether the specific molecular changes that distinguish the D1 and D2 alleles account for the different activities. The considerable genetic heterogeneity documented to date undoubtedly contributes to the phenotypic heterogeneity that is observed in galactosemia. The additional effects of nonallelic variation and other constitutional factors on phenotypic variability remain to be elucidated.. 
10408771	0	22	Classical galactosemia	SpecificDisease	D005693
10408771	98	120	Classical galactosemia	SpecificDisease	D005693
10408771	2094	2106	galactosemia	SpecificDisease	D005693

10636421|t|X-linked retinoschisis with point mutations in the XLRS1 gene.
10636421|a|BACKGROUND  X-linked retinoschisis (XLRS) is a relatively rare vitreoretinal dystrophy that causes visual loss in young men. Recently, a gene responsible for this disease, designated XLRS1, was identified, and several deleterious gene mutations were reported. OBJECTIVE  To analyze Japanese patients clinically diagnosed as having XLRS formutational changes in the XLRS1 gene. METHODS  Ten patients with XLRS underwent full ophthalmologic examination, including slitlamp biomicroscopy and dilated funduscopy. Genomic DNA was isolated from leukocytes, and all exons of the XLRS1 gene were amplified by polymerase chain reaction and analyzed using a direct sequencing method. RESULTS  Point mutations in the XLRS1 gene were identified in all 10 patients. The mutations were identical in each of 2 pairs of brothers. Six of the point mutations represented missense mutations, 1 was a nonsense mutation, and 1 was a frameshift mutation. Five of the mutations are newly reported herein. CONCLUSIONS  The discovery of new point mutations in this study increases the available information regarding the spectrum of genetic abnormalities and clinical manifestations of XLRS. However, the limited data failed to reveal a correlation between mutation and disease phenotype. CLINICAL RELEVANCE  Identification of mutations in the XLRS1 gene and expanded information on clinical manifestations will facilitate early diagnosis, appropriate early therapy, and genetic counseling regarding the prognosis of XLRS.. 
10636421	0	22	X-linked retinoschisis	SpecificDisease	D041441
10636421	75	97	X-linked retinoschisis	SpecificDisease	D041441
10636421	99	103	XLRS	SpecificDisease	D041441
10636421	126	149	vitreoretinal dystrophy	DiseaseClass	D058499
10636421	162	173	visual loss	SpecificDisease	C531604
10636421	394	398	XLRS	Modifier	D041441
10636421	467	471	XLRS	SpecificDisease	D041441
10636421	1171	1192	genetic abnormalities	DiseaseClass	D030342
10636421	1224	1228	XLRS	SpecificDisease	D041441
10636421	1555	1559	XLRS	SpecificDisease	D041441

10429004|t|Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study.
10429004|a|OBJECTIVE  To examine the relationship of phenylalanine hydroxylase (PAH) genotypes to biochemical phenotype and cognitive development in maternal phenylketonuria (PKU). METHODOLOGY  PAH gene mutations were examined in 222 hyperphenylalaninemic females enrolled in the Maternal PKU Collaborative Study (MPKUCS). A total of 84 different mutations were detected, and complete genotype was obtained in 199 individuals. Based on previous knowledge about mutation-phenotype associations, 78 of the mutations could be assigned to one of four classes of severity (severe PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). Then, 189 MPKUCS subjects were grouped according to the various combinations of mutation classifications. The sample sizes were large enough for statistical testing in four groups with at least one mutation that completely abolishes enzyme activity. These patients are considered functionally hemizygous. RESULTS  The biochemical phenotype predicted from the genotype in functionally hemizygous patients was related significantly to the assigned phenylalanine level. Cognitive performance (IQ) was also significantly related to genotype. The IQ of PAH-deficient mothers with a severe PKU mutation in combination with a MHP mutation or a mild PKU mutation was 99 and 96, respectively, whereas the IQ of PKU mothers with two severe PKU mutations or with one severe and one moderate PKU mutation was 83 and 84, respectively. Of the patients with PKU, 92% had been treated during childhood. Those who were untreated or treated late had lower than average IQ scores for their group of mutation combinations. Females with moderate or mild PKU who were treated early and treated for > 6 years showed IQ scores 10 points above average for their group. CONCLUSIONS  The reproductive outcome in maternal phenylketonuria is dependent on prenatal metabolic control and postnatal environmental circumstances. Both factors depend on the intellectual resources of the mother with PKU. The significant relationship among genotype, biochemical phenotype, and cognitive performance observed in the present study is of importance for the development of an optimal strategy for future treatment of females with PKU who plan pregnancy.. 
10429004	94	130	phenylalanine hydroxylase deficiency	SpecificDisease	OMIM:261600
10429004	148	172	Maternal Phenylketonuria	Modifier	D017042
10429004	332	356	maternal phenylketonuria	SpecificDisease	D017042
10429004	358	361	PKU	SpecificDisease	D010661
10429004	417	438	hyperphenylalaninemic	Modifier	D010661
10429004	463	475	Maternal PKU	Modifier	D017042
10429004	758	761	PKU	SpecificDisease	D010661
10429004	772	775	PKU	SpecificDisease	D010661
10429004	782	785	PKU	SpecificDisease	D010661
10429004	791	817	mild hyperphenylalaninemia	SpecificDisease	D010661
10429004	819	822	MHP	SpecificDisease	D010661
10429004	1374	1387	PAH-deficient	Modifier	OMIM:261600
10429004	1410	1413	PKU	Modifier	D010661
10429004	1445	1448	MHP	Modifier	D010661
10429004	1468	1471	PKU	Modifier	D010661
10429004	1528	1531	PKU	Modifier	D010661
10429004	1556	1559	PKU	Modifier	D010661
10429004	1606	1609	PKU	Modifier	D010661
10429004	1669	1672	PKU	SpecificDisease	D010661
10429004	1859	1862	PKU	SpecificDisease	D010661
10429004	2011	2035	maternal phenylketonuria	SpecificDisease	D017042
10429004	2191	2194	PKU	SpecificDisease	D010661
10429004	2417	2420	PKU	SpecificDisease	D010661

1380672|t|Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene.
1380672|a|Proteolipid protein (PLP; M (r) 30, 000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure. Neurological mutant mice can often provide model systems for human genetic disorders . Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse and subsequently in patients with Pelizaeus-Merzbacher disease. The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination. Here we show that a new mouse mutant rumpshaker is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP. Surprisingly, rumpshaker mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration. We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease.. 
1380672	14	29	hypomyelination	SpecificDisease	D003711
1380672	34	50	glial cell death	SpecificDisease	D004194
1380672	314	331	genetic disorders	DiseaseClass	D030342
1380672	462	490	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
1380672	546	603	degeneration and premature cell death of oligodendrocytes	CompositeMention	D056784
1380672	620	635	hypomyelination	SpecificDisease	D003711
1380672	831	847	myelin-deficient	SpecificDisease	D003711
1380672	937	952	Hypomyelination	SpecificDisease	D003711
1380672	1010	1038	oligodendrocyte degeneration	SpecificDisease	D056784
1380672	1228	1256	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080

10594001|t|Mutational analysis of the HGO gene in Finnish alkaptonuria patients.
10594001|a|Alkaptonuria (AKU), the prototypic inborn error of metabolism, has recently been shown to be caused by loss of function mutations in the homogentisate-1, 2-dioxygenase gene (HGO). So far 17 mutations have been characterised in AKU patients of different ethnic origin. We describe three novel mutations (R58fs, R330S, and H371R) and one common AKU mutation (M368V), detected by mutational and polymorphism analysis of the HGO gene in five Finnish AKU pedigrees. The three novel AKU mutations are most likely specific for the Finnish population and have originated recently.. 
10594001	47	59	alkaptonuria	Modifier	D000474
10594001	70	82	Alkaptonuria	SpecificDisease	D000474
10594001	84	87	AKU	SpecificDisease	D000474
10594001	105	131	inborn error of metabolism	DiseaseClass	D008661
10594001	297	300	AKU	Modifier	D000474
10594001	413	416	AKU	Modifier	D000474
10594001	516	519	AKU	Modifier	D000474
10594001	547	550	AKU	Modifier	D000474

8441467|t|Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters.
8441467|a|Adrenoleukodystrophy (ALD) is an X-linked disease affecting 1/20, 000 males either as cerebral ALD in childhood or as adrenomyeloneuropathy (AMN) in adults. Childhood ALD is the more severe form, with onset of neurological symptoms between 5-12 years of age. Central nervous system demyelination progresses rapidly and death occurs within a few years. AMN is a milder form of the disease with onset at 15-30 years of age and a more progressive course. Adrenal insufficiency (Addisons disease) may remain the only clinical manifestation of ALD. The principal biochemical abnormality of ALD is the accumulation of very-long-chain fatty acids (VLCFA) because of impaired beta-oxidation in peroxisomes. The normal oxidation of VLCFA-CoA in patients fibroblasts suggested that the gene coding for the VLCFA-CoA synthetase could be a candidate gene for ALD. Here we use positional cloning to identify a gene partially deleted in 6 of 85 independent patients with ALD. In familial cases, the deletions segregated with the disease. An identical deletion was detected in two brothers presenting with different clinical ALD phenotypes. Candidate exons were identified by computer analysis of genomic sequences and used to isolate complementary DNAs by exon connection and screening of cDNA libraries. The deduced protein sequence shows significant sequence identity to a peroxisomal membrane protein of M (r) 70K that is involved in peroxisome biogenesis and belongs to the ATP-binding cassette superfamily of transporters.. 
8441467	9	38	X-linked adrenoleukodystrophy	Modifier	D000326
8441467	94	114	Adrenoleukodystrophy	SpecificDisease	D000326
8441467	116	119	ALD	SpecificDisease	D000326
8441467	127	143	X-linked disease	DiseaseClass	D040181
8441467	180	192	cerebral ALD	SpecificDisease	D000326
8441467	212	233	adrenomyeloneuropathy	SpecificDisease	D000326
8441467	235	238	AMN	SpecificDisease	D000326
8441467	261	264	ALD	SpecificDisease	D000326
8441467	353	389	Central nervous system demyelination	DiseaseClass	D003711
8441467	446	449	AMN	SpecificDisease	D000326
8441467	546	567	Adrenal insufficiency	DiseaseClass	D000309
8441467	569	585	Addisons disease	SpecificDisease	D000224
8441467	633	636	ALD	SpecificDisease	D000326
8441467	679	682	ALD	SpecificDisease	D000326
8441467	941	944	ALD	SpecificDisease	D000326
8441467	1051	1054	ALD	SpecificDisease	D000326
8441467	1204	1207	ALD	Modifier	D000326

10618304|t|Cardiac Na(+) channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit.
10618304|a|BACKGROUND  Mutations in the gene encoding the human cardiac Na (+) channel alpha-subunit (hH1) are responsible for chromosome 3-linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliary beta (1) -subunit, widely expressed in excitable tissues, shifts the voltage dependence of steady-state inactivation toward more negative potentials and restores normal gating kinetics of brain and skeletal muscle Na (+) channels expressed in Xenopus oocytes but has little if any functional effect on the cardiac isoform. Here, we characterize the altered effects of a human beta (1) -subunit (hbeta (1)) on the heterologously expressed hH1 mutation (T1620M) previously associated with IVF. METHODS AND RESULTS  When expressed alone in Xenopus oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V (1/2)) was significantly shifted toward more positive potentials than for wild-type hH1. Coexpression of hbeta (1) did not significantly alter current decay or recovery from inactivation of wild-type hH1; however, it further shifted the V (1/2) and accelerated the recovery from inactivation of T1620M. Oocyte macropatch analysis revealed that the activation kinetics of T1620M were normal. CONCLUSIONS  It is suggested that coexpression of hbeta (1) exposes a more severe functional defect that results in a greater overlap in the relationship between channel inactivation and activation (window current) in T1620M, which is proposed to be a potential pathophysiological mechanism of IVF in vivo. One possible explanation for our finding is an altered alpha-/beta (1) -subunit association in the mutant.. 
10618304	37	53	Brugada syndrome	SpecificDisease	D053840
10618304	224	251	congenital long-QT syndrome	SpecificDisease	D008133
10618304	253	257	LQT3	SpecificDisease	C537034
10618304	263	298	idiopathic ventricular fibrillation	SpecificDisease	C537182
10618304	300	303	IVF	SpecificDisease	C537182
10618304	806	809	IVF	SpecificDisease	C537182
10618304	933	937	LQT3	Modifier	C537034
10618304	1689	1692	IVF	SpecificDisease	C537182

10369876|t|Autosomal recessive familial neurohypophyseal diabetes insipidus with continued secretion of mutant weakly active vasopressin.
10369876|a|Familial neurohypophyseal diabetes insipidus is an autosomal dominant disorder characterized by post-natal development of arginine vasopressin (AVP) deficiency due to mutations in the AVP gene. All published mutations affect the signal peptide or the neurophysin-II carrier protein and are presumed to interfere with processing of the preprohormone, leading to neuronal damage. We studied an unusual Palestinian family consisting of asymptomatic first cousin parents and three children affected with neurohypophyseal diabetes insipidus, suggesting autosomal recessive inheritance. All three affected children were homozygous and the parents heterozygous for a single novel mutation (C301- > T) in exon 1, replacing Pro7 of mature AVP with Leu (Leu-AVP). Leu-AVP was a weak agonist with approximately 30-fold reduced binding to the human V2 receptor. Measured by radioimmunoassay with a synthetic Leu-AVP standard, serum Leu-AVP levels were elevated in all three children and further increased during water deprivation to as high as 30 times normal. The youngest child (2 years old) was only mildly affected but had Leu-AVP levels similar to her severely affected 8-year-old brother, suggesting that unknown mechanisms may partially compensate for a deficiency of active AVP in very young children.. 
10369876	0	64	Autosomal recessive familial neurohypophyseal diabetes insipidus	SpecificDisease	OMIM:125700
10369876	127	171	Familial neurohypophyseal diabetes insipidus	SpecificDisease	OMIM:125700
10369876	178	205	autosomal dominant disorder	DiseaseClass	D030342
10369876	249	286	arginine vasopressin (AVP) deficiency	SpecificDisease	OMIM:125700
10369876	488	503	neuronal damage	DiseaseClass	D009410
10369876	627	662	neurohypophyseal diabetes insipidus	SpecificDisease	D020790
10369876	1376	1400	deficiency of active AVP	DiseaseClass	OMIM:125700

2575483|t|Autosomal dominant aniridia linked to the chromosome 11p13 markers catalase and D11S151 in a large Dutch family.
2575483|a|In a large pedigree with autosomal dominant aniridia, we found close linkage between the aniridia locus AN2 and the markers catalase (CAT) (zeta = 7. 27 at theta = 0. 00) and D11S151 (zeta = 3. 86 at theta = 0. 10) flanking the AN2 locus on 11p13. Positive lod scores were also obtained for the 11p13----11p14 markers D11S16 and FSHB with the linkage group CAT/AN2/D11S151. We conclude that the autosomal dominant aniridia in this family is due to a mutation at the AN2 locus on 11p13. We have excluded linkage (zeta less than -2 at theta less than 0. 18) between the aniridia and the chromosome 2p25 marker D2S1 (linked to ACP1).
2575483	19	27	aniridia	SpecificDisease	D015783
2575483	157	165	aniridia	SpecificDisease	D015783
2575483	202	210	aniridia	Modifier	D015783
2575483	527	535	aniridia	SpecificDisease	D015783
2575483	681	689	aniridia	SpecificDisease	D015783

10607954|t|Knobloch syndrome involving midline scalp defect of the frontal region.
10607954|a|We report on a 4-year-old boy with Knobloch syndrome. He has vitreoretinal degeneration, high myopia, cataract, telecanthus, hypertelorism, and a high-arched palate. He also has a defect of the anterior midline scalp with involvement of the frontal bone as documented by a computed tomography (CT) scan. The brain was normal on CT scan and magnetic resonance imaging. We present a review of the 23 published cases with this syndrome. Our patient illustrates the importance of investigating for underlying ocular and central nervous system pathology whenever midline scalp defects are present.. 
10607954	0	17	Knobloch syndrome	SpecificDisease	C537209
10607954	28	70	midline scalp defect of the frontal region	DiseaseClass	C538225
10607954	107	124	Knobloch syndrome	SpecificDisease	C537209
10607954	133	159	vitreoretinal degeneration	SpecificDisease	D012162
10607954	161	172	high myopia	SpecificDisease	D009216
10607954	174	182	cataract	SpecificDisease	D002386
10607954	184	195	telecanthus	SpecificDisease	D030342
10607954	197	210	hypertelorism	SpecificDisease	D006972
10607954	218	236	high-arched palate	SpecificDisease	D007569
10607954	252	288	defect of the anterior midline scalp	DiseaseClass	C538225
10607954	630	651	midline scalp defects	DiseaseClass	C538225

10602116|t|Pendred syndrome: phenotypic variability in two families carrying the same PDS missense mutation.
10602116|a|Pendred syndrome comprises congenital sensorineural hearing loss, thyroid goiter, and positive perchlorate discharge test. Recently, this autosomal recessive disorder was shown to be caused by mutations in the PDS gene, which encodes an anion transporter called pendrin. Molecular analysis of the PDS gene was performed in two consanguineous large families from Southern Tunisia comprising a total of 23 individuals affected with profound congenital deafness; the same missense mutation, L445W, was identified in all affected individuals. A widened vestibular aqueduct was found in all patients who underwent computed tomography (CT) scan exploration of the inner ear. In contrast, goiter was present in only 11 affected individuals, who interestingly had a normal result of the perchlorate discharge test whenever performed. The present results question the sensitivity of the perchlorate test for the diagnosis of Pendred syndrome and support the use of a molecular analysis of the PDS gene in the assessment of individuals with severe to profound congenital hearing loss associated with inner ear morphological anomaly even in the absence of a thyroid goiter.. 
10602116	0	16	Pendred syndrome	SpecificDisease	C536648
10602116	75	78	PDS	Modifier	C536648
10602116	98	114	Pendred syndrome	SpecificDisease	C536648
10602116	125	162	congenital sensorineural hearing loss	SpecificDisease	D006319
10602116	164	178	thyroid goiter	SpecificDisease	D006042
10602116	236	264	autosomal recessive disorder	DiseaseClass	D030342
10602116	308	311	PDS	Modifier	C536648
10602116	395	398	PDS	Modifier	C536648
10602116	537	556	congenital deafness	SpecificDisease	D003638
10602116	639	666	widened vestibular aqueduct	SpecificDisease	OMIM:600791
10602116	780	786	goiter	SpecificDisease	D006042
10602116	1014	1030	Pendred syndrome	SpecificDisease	C536648
10602116	1082	1085	PDS	Modifier	C536648
10602116	1148	1171	congenital hearing loss	SpecificDisease	D003638
10602116	1188	1219	inner ear morphological anomaly	SpecificDisease	D007759
10602116	1245	1259	thyroid goiter	SpecificDisease	D006042

10470088|t|The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's 'two-hit' hypothesis.
10470088|a|APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations. Clues from attenuated polyposis, missense germline variants with mild disease and the somatic mutation cluster region (codons 1, 250-1, 450) indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1, 194-1, 392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose second hits tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1, 300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1, 300. A different germline-somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity  if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.. 
10470088	39	69	familial adenomatous polyposis	SpecificDisease	D011125
10470088	212	217	tumor	Modifier	D009369
10470088	319	325	tumors	DiseaseClass	D009369
10470088	329	332	FAP	SpecificDisease	D011125
10470088	334	364	familial adenomatous polyposis	SpecificDisease	D011125
10470088	372	399	sporadic colorectal cancers	SpecificDisease	D015179
10470088	414	417	APC	Modifier	D011125
10470088	440	460	attenuated polyposis	Modifier	C538265
10470088	594	597	APC	Modifier	D011125
10470088	680	683	FAP	Modifier	D011125
10470088	707	710	APC	Modifier	D011125
10470088	808	827	colorectal adenomas	SpecificDisease	D000236
10470088	850	853	FAP	Modifier	D011125
10470088	988	991	APC	Modifier	D011125
10470088	1233	1236	APC	Modifier	D011125
10470088	1268	1280	FAP desmoids	SpecificDisease	D018222
10470088	1317	1322	tumor	Modifier	D009369
10470088	1450	1456	tumors	DiseaseClass	D009369
10470088	1515	1521	tumors	DiseaseClass	D009369

7769092|t|Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients.
7769092|a|Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) was purified from human liver. The molecular masses of the native enzyme and the subunit were estimated to be 154 and 70 kD, respectively. The enzyme was found to catalyze the major part of mitochondrial palmitoylcoenzyme A dehydrogenation in liver, heart, skeletal muscle, and skin fibroblasts (89-97, 86-99, 96-99, and 78-87%, respectively). Skin fibroblasts from 26 patients suspected of having a disorder of mitochondrial beta-oxidation were analyzed for VLCAD protein using immunoblotting, and 7 of them contained undetectable or trace levels of the enzyme. The seven deficient fibroblast lines were characterized by measuring acyl-coenzyme A dehydrogenation activities, overall palmitic acid oxidation, and VLCAD protein synthesis using pulse-chase, further confirming the diagnosis of VLCAD deficiency. These results suggested the heterogenous nature of the mutations causing the deficiency in the seven patients. Clinically, all patients with VLCAD deficiency exhibited cardiac disease. At least four of them presented with hypertrophic cardiomyopathy. This frequency (> 57%) was much higher than that observed in patients with other disorders of mitochondrial long-chain fatty acid oxidation that may be accompanied by cardiac disease in infants.. 
7769092	986	1002	VLCAD deficiency	SpecificDisease	C536353
7769092	1145	1161	VLCAD deficiency	SpecificDisease	C536353
7769092	1172	1187	cardiac disease	DiseaseClass	D006331
7769092	1226	1253	hypertrophic cardiomyopathy	SpecificDisease	D002312
7769092	1422	1437	cardiac disease	DiseaseClass	D006331

1282899|t|A germ line mutation within the coding sequence for the putative 5-phosphoribosyl-1-pyrophosphate binding site of hypoxanthine-guanine phosphoribosyltransferase (HPRT) in a Lesch-Nyhan patient: missense mutations within a functionally important region probably cause disease.
1282899|a|Lesch-Nyhan syndrome caused by a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) is the result of a heterogeneous group of germ line mutations. Identification of each mutant gene provides valuable information as to the type of mutation that occurs spontaneously. We report here a newly identified HPRT mutation in a Japanese patient with Lesch-Nyhan syndrome. This gene, designated HPRT Tokyo, had a single nucleotide change from G to A, as identified by sequencing cDNA amplified by the polymerase chain reaction. Allele specific oligonucleotide hybridization analysis using amplified genomic DNA showed that the mutant gene was transmitted from the maternal germ line. This mutation would lead to an amino acid substitution of Asp for Gly at the amino acid position 140 located within the putative 5-phosphoribosyl-1-pyrophosphate (PRPP) binding region. Missense mutations in human HPRT deficient patients thus far reported tend to accumulate in this functionally active region. However, a comparison of the data suggested that both missense and synonymous mutations can occur at any coding sequence of the human germ line HPRT gene, but that a limited percentage of all the missense mutations cause disease. The probability that a mutation will cause disease tends to be higher when the missense mutation is within a functionally important sequence.. 
1282899	173	184	Lesch-Nyhan	Modifier	D007926
1282899	276	296	Lesch-Nyhan syndrome	SpecificDisease	D007926
1282899	309	378	complete deficiency of hypoxanthine guanine phosphoribosyltransferase	SpecificDisease	D007926
1282899	643	663	Lesch-Nyhan syndrome	SpecificDisease	D007926
1282899	1189	1203	HPRT deficient	Modifier	D007926

1301201|t|In vitro and in vivo correlations for I65T and M1V mutations at the phenylalanine hydroxylase locus.
1301201|a|Mutations at the phenylalanine hydroxylase (PAH) locus are the major cause of hyperphenylalaninemia. We have previously described four mutations (M1V, IVS12nt1, R408W, and S349P) at the PAH locus in French Canadians with ancestry in eastern Quebec. Here we report (1) identification of another mutation, on a haplotype 9 chromosome, which converts codon 65 from isoleucine (ATT) to threonine (ACT), (2) expression analysis of the I65T mutation in COS cells demonstrating 75% loss of both immunoreactive protein and enzyme activity, and (3) expression analysis of the most prevalent PKU allele (M1V) in eastern Quebec, showing nondetectable levels of PAH protein and activity, a finding compatible with a mutation in the translation initiation codon. Homozygosity for M1V and codominant inheritance of I65T/R408W were both associated with classical phenylketonuria.. 
1301201	179	200	hyperphenylalaninemia	DiseaseClass	D010661
1301201	683	686	PKU	Modifier	D010661
1301201	939	964	classical phenylketonuria	SpecificDisease	D010661

10557317|t|Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism.
10557317|a|The puzzling linkage between genetic hemochromatosis and histocompatibility loci became even more so when the gene involved, HFE, was identified. Indeed, within the well defined, mainly peptide-binding, MHC class I family of molecules, HFE seems to perform an unusual yet essential function. As yet, our understanding of HFE function in iron homeostasis is only partial; an even more open question is its possible role in the immune system. To advance on both of these avenues, we report the deletion of HFE alpha1 and alpha2 putative ligand binding domains in vivo. HFE-deficient animals were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion develop iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allows a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. Finally, an extensive phenotyping of primary and secondary lymphoid organs including the gut provides no compelling evidence for an obvious immune-linked function for HFE.. 
10557317	13	28	hemochromatosis	SpecificDisease	D006432
10557317	48	62	HFE deficiency	SpecificDisease	D006432
10557317	136	151	hemochromatosis	SpecificDisease	D006432
10557317	666	679	HFE-deficient	Modifier	D006432
10557317	789	804	hemochromatosis	SpecificDisease	D006432

144081|t|[Genetic heterogeneity of G6PD deficiency: mutant alleles of G6PD in the Shekii district of Azerbaijan]
144081|a|Examination on G6PD deficiency in 349 patients of Shekii district hospital (Azerbaijan) revealed 16 hemi-, 4 homo- and 9 heterozygotic carriers of the defect. Gd- frequency, calculated from the data obtained (7. 7%), may be compared to neighbouring regions frequencies (6-30%). Carriers of G6PD deficiency are residents of 11 villages located in Alasani-Aphtalan valley, highly endemic with malaria in the past; nearly all marriages are endogamic. Physico-chemical and kinetic study of 10 mutant forms of G6PD, according to WHO program, led to identification of 5 variants of the II class (Shekii, Bideiz, Shirin-Bulakh, Okhut I and Zakataly) and 2 variants of the III class (Okhut II and Martinique-like). Resemblance of the majority of variants in electrophoretic mobility and the level of erythrocyte enzyme activity permit to suggest the existence of a common parental mutant G6PD allele distributed in this area. 
144081	26	41	G6PD deficiency	SpecificDisease	D005955
144081	119	134	G6PD deficiency	SpecificDisease	D005955
144081	394	409	G6PD deficiency	SpecificDisease	D005955
144081	495	502	malaria	SpecificDisease	D008288

6453040|t|[Gd- allele distribution patterns in Azerbaijan. III. The identification of mutant forms of glucose-6-phosphate dehydrogenase]
6453040|a|In 28 families with G6PD deficiency living in 3 settlements of Shekii district of Azerbaijan 11 G6PD variants of II and III classes differing by kinetic properties were identified according WHO program. 9 of them are characterized with the same electrophoretic mobility. Comparison of G6PD spectra in two subpopulations and in a mixed group permits to make a conclusion about existence of common and rare G6PD alleles in examined population. They distribute by gene drift supported by natural selection. Among 7 samples of G6PD with normal and increased activity two new variants of IV class -- Nukha and Bash-Kungut -- were found.. 
6453040	147	162	G6PD deficiency	SpecificDisease	D005955

10878391|t|Determination of carrier status for the Wiskott-Aldrich syndrome by flow cytometric analysis of Wiskott-Aldrich syndrome protein expression in peripheral blood mononuclear cells.
10878391|a|The Wiskott-Aldrich syndrome (WAS) is caused by defects in the WAS protein (WASP) gene on the X chromosome. Previous study disclosed that flow cytometric analysis of intracellular WASP expression (FCM-WASP analysis) in lymphocytes was useful for the diagnosis of WAS patients. Lymphocytes from all WAS patients showed WASPdim instead of WASPbright. Here we report that FCM-WASP analysis in monocytes could be a useful tool for the WAS carrier diagnosis. Monocytes from all nine WAS carriers showed varied population of WASPdim together with WASPbright. None of control individuals possessed the WASPdim population. In contrast, lymphocytes from all the carriers except two lacked the WASPdim population. The difference of the WASPdim population in monocytes and lymphocytes observed in WAS carriers suggests that WASP plays a more critical role in the development of lymphocytes than in that of monocytes. The present studies suggest that a skewed X-chromosomal inactivation pattern observed in WAS carrier peripheral blood cells is not fixed at the hemopoietic stem cell level but progresses after the lineage commitment.. 
10878391	40	64	Wiskott-Aldrich syndrome	SpecificDisease	D014923
10878391	96	120	Wiskott-Aldrich syndrome	Modifier	D014923
10878391	183	207	Wiskott-Aldrich syndrome	SpecificDisease	D014923
10878391	209	212	WAS	SpecificDisease	D014923
10878391	242	245	WAS	Modifier	D014923
10878391	442	445	WAS	Modifier	D014923
10878391	477	480	WAS	Modifier	D014923
10878391	610	613	WAS	Modifier	D014923
10878391	657	660	WAS	Modifier	D014923
10878391	965	968	WAS	Modifier	D014923
10878391	1174	1177	WAS	Modifier	D014923

2161209|t|Linkage of DNA markers at Xq28 to adrenoleukodystrophy and adrenomyeloneuropathy present within the same family.
2161209|a|We present a large kindred that contained patients with either adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN). The pedigree clearly supported the X-linked mode of inheritance of the nonneonatal form of ALD/AMN. Analysis with DNA markers at Xq28 suggested segregation of both ALD and AMN with an identical haplotype. This indicated that nonneonatal ALD and AMN are caused by a mutation in the same gene at Xq28. It showed, furthermore, that phenotypic differences between ALD and AMN are not necessarily the consequence of allelic heterogeneity due to different mutations within the same gene. The maximal lod score for linkage of the ALD/AMN gene and the multiallelic anonymous DNA marker at DXS52 was 3. 0 at a recombination fraction of 0. 00. This made a prenatal or presymptomatic diagnosis and heterozygote detection by DNA analysis with this marker reliable. 
2161209	34	54	adrenoleukodystrophy	SpecificDisease	D000326
2161209	59	80	adrenomyeloneuropathy	SpecificDisease	D000326
2161209	176	196	adrenoleukodystrophy	SpecificDisease	D000326
2161209	198	201	ALD	SpecificDisease	D000326
2161209	206	227	adrenomyeloneuropathy	SpecificDisease	D000326
2161209	229	232	AMN	SpecificDisease	D000326
2161209	326	329	ALD	SpecificDisease	D000326
2161209	330	333	AMN	SpecificDisease	D000326
2161209	399	402	ALD	SpecificDisease	D000326
2161209	407	410	AMN	SpecificDisease	D000326
2161209	472	475	ALD	SpecificDisease	D000326
2161209	480	483	AMN	SpecificDisease	D000326
2161209	595	598	ALD	SpecificDisease	D000326
2161209	603	606	AMN	SpecificDisease	D000326
2161209	758	761	ALD	Modifier	D000326
2161209	762	765	AMN	Modifier	D000326

8326491|t|Further investigation of the HEXA gene intron 9 donor splice site mutation frequently found in non-Jewish Tay-Sachs disease patients from the British Isles.
8326491|a|In a previous study we found that a Tay-Sachs disease (TSD) causing mutation in the intron 9 donor splice site of the HEXA gene occurs at high frequency in non-Jewish patients and carriers from the British Isles. It was found more frequently in subjects of Irish, Scottish, and Welsh origin compared with English origin (63% and 31% respectively). We have now tested, in a blind study, 26 American TSD carriers and 28 non-carriers who have British ancestry for the intron 9 splice site mutation. Six of the carriers and none of the controls were positive for the mutation. All six had Irish ancestry, compared with nine of the 20 other (intron 9 mutation negative) TSD carriers (p < 0. 05). These results confirm the previously found high frequency of the intron 9 mutation in non-Jewish TSD families of British Isles, particularly Irish, origin, and reinforce the need to screen such families for this mutation. 
8326491	106	123	Tay-Sachs disease	Modifier	D013661
8326491	193	210	Tay-Sachs disease	SpecificDisease	D013661
8326491	212	215	TSD	SpecificDisease	D013661
8326491	555	558	TSD	Modifier	D013661
8326491	822	825	TSD	Modifier	D013661
8326491	945	948	TSD	Modifier	D013661

7959767|t|The murine homologues of the Huntington disease gene (Hdh) and the alpha-adducin gene (Add1) map to mouse chromosome 5 within a region of conserved synteny with human chromosome 4p16.3.
7959767|a|Huntington disease (HD) is a severe autosomal dominant neurodegenerative disorder associated with a novel gene (IT15). Recently, we reported the cloning of Hdh, the murine homologue of IT15. Here, using an interspecific backcross, we have mapped both Hdh and the mouse homologue of human alpha-adducin (Add1), a membrane-associated cytoskeletal protein gene. Both of these genes map in the same position on mouse chromosome 5 in a region associated with ancestral chromosomal rearrangements and show no recombination with D5H4S43, D5H4S115, and D5H4S62, the murine homologues of D4S43, D4S115, and D4S62, respectively. Further mapping studies of humans, mice, and other mammalian species should reveal the nature of the rearrangements affecting this chromosomal segment during mammalian evolution.. 
7959767	29	47	Huntington disease	Modifier	D006816
7959767	186	204	Huntington disease	SpecificDisease	D006816
7959767	206	208	HD	SpecificDisease	D006816
7959767	222	267	autosomal dominant neurodegenerative disorder	DiseaseClass	D019636

2562820|t|Linkage analysis of the apolipoprotein C2 gene and myotonic dystrophy on human chromosome 19 reveals linkage disequilibrium in a French-Canadian population.
2562820|a|The gene for human apolipoprotein C2 (APOC2), situated on the proximal long arm of chromosome 19, is closely linked to the gene for the most common form of adult muscular dystrophy, myotonic dystrophy (DM). Six APOC2 RFLPs (TaqI, BglI, BanI, BamHI, NcoI, and AvaII) have been identified to date. We have conducted a comprehensive DM linkage study utilizing all six RFLPs and involving 50 families and 372 individuals. The most informative RFLPs are, in descending order, NcoI (lod = 6. 64, theta = 0. 05), BglI (lod = 6. 12, theta = 0. 05), AvaII (lod = 6. 02, theta = 0. 03), BanI (lod = 5. 76, theta = 0. 04), TaqI (lod = 4. 29, theta = 0. 06), and BamHI (lod = 1. 75, theta = 0. 01). A substantial increase in the lod scores over those seen with the individual RFLPs was obtained when the linkage of the entire APOC2 haplotype (composed of the six RFLPs) was studied (lod = 17. 87, theta = 0. 04). We have observed significant inter-APOC2 RFLP linkage disequilibrium. Consequently, the three most informative RFLPs have been found to be BanI, TaqI, and either BglI, AvaII, or NcoI polymorphisms. We also demonstrate linkage disequilibrium between DM and APOC2 in our French-Canadian population (standardized disequilibrium constant phi =. 22, chi 2 = 5. 12, df = 1, P less than 0. 04). This represents the first evidence of linkage disequilibrium between APOC2 and the DM locus. 
2562820	51	69	myotonic dystrophy	SpecificDisease	D009223
2562820	319	337	muscular dystrophy	DiseaseClass	D009136
2562820	339	357	myotonic dystrophy	SpecificDisease	D009223
2562820	359	361	DM	SpecificDisease	D009223
2562820	487	489	DM	Modifier	D009223
2562820	1529	1531	DM	Modifier	D009223

10094552|t|A retrospective anonymous pilot study in screening newborns for HFE mutations in Scandinavian populations.
10094552|a|We have retrospectively analyzed 837 random anonymized dried blood spot (DBS) samples from neonatal screening programs in Scandinavia for mutations in HFE, the candidate gene for hemochromatosis. We have found C282Y allele frequencies of 2. 3% (+ 2. 0%) (-1. 3%) in Greenland, 4. 5% +/-1. 9% in Iceland, 5. 1% +/-2. 3% in the Faeroe Islands, and 8. 2% +/-2. 7% in Denmark. The high prevalence of HFE mutations in Denmark suggests that population screening for the C282Y mutation could be highly advantageous in terms of preventive health care. Long-term follow-up evaluation of C282Y homozygotes and H63D/C282Y compound heterozygotes will give an indication of the penetrance of the mutations.
10094552	286	301	hemochromatosis	SpecificDisease	D006432

10484981|t|Hereditary TP53 codon 292 and somatic P16INK4A codon 94 mutations in a Li-Fraumeni syndrome family.
10484981|a|Li-Fraumeni syndrome is an autosomal dominant disorder that is characterized by various types of cancer in childhood and adult cases. Although hereditary TP53 mutation is very rare in different human cancers, it has been frequently reported in Li-Fraumeni syndrome. On the other hand, hereditary mutations of TP57KIP2, P15INK4B, and P16INK4A, which affect the cell cycle similar to TP53, were observed in some types of cancer. In a Turkish family with the diagnosis of Li-Fraumeni syndrome, we analyzed the mutation pattern of TP53, P57KIP2, P15INK4B, and P16INK4A in the peripheral blood, and loss of heterozygosity (homo/hemizygous deletion) pattern of TP53 and P15INK4B/P16INK4A in two tumor tissues. The propositus had a seminoma, his daughter a medulloblastoma, and one of his healthy cousins, a TP53 codon 292 missense point mutation (AAA-- > ATA; Lys-- > Ile) in the peripheral blood cells. Tumor tissue obtained from the propositus with the seminoma revealed loss of heterozygosity in the TP53 gene. In the analyses of tumor tissues from the propositus and his daughter, a P16INK4A codon 94 missense point mutation (GCG-- > GAG; Ala-- > Glu) was observed with the hereditary TP53 mutation. P16INK4A codon 94 mutation observed in our family is a novel mutation in Li-Fraumeni syndrome. No other gene alteration in TP53, P57KIP2, P15INK4B, and P16INK4A was observed. Existence of the P16INK4A mutation and the hereditary TP53 mutation with or without loss of heterozygosity in the TP53 gene (seminoma/medulloblastoma) may be evidence for a common mechanism involved in tumorogenesis. The gene alterations in TP53 and P16INK4A genes may be used as tumor markers in our family.. 
10484981	71	91	Li-Fraumeni syndrome	Modifier	D016864
10484981	100	120	Li-Fraumeni syndrome	SpecificDisease	D016864
10484981	127	154	autosomal dominant disorder	DiseaseClass	D030342
10484981	197	203	cancer	DiseaseClass	D009369
10484981	300	307	cancers	DiseaseClass	D009369
10484981	344	364	Li-Fraumeni syndrome	SpecificDisease	D016864
10484981	519	525	cancer	DiseaseClass	D009369
10484981	569	589	Li-Fraumeni syndrome	SpecificDisease	D016864
10484981	789	794	tumor	Modifier	D009369
10484981	825	833	seminoma	SpecificDisease	D018239
10484981	850	865	medulloblastoma	SpecificDisease	D008527
10484981	1049	1057	seminoma	SpecificDisease	D018239
10484981	1127	1132	tumor	Modifier	D009369
10484981	1371	1391	Li-Fraumeni syndrome	SpecificDisease	D016864
10484981	1598	1606	seminoma	SpecificDisease	D018239
10484981	1607	1622	medulloblastoma	SpecificDisease	D008527
10484981	1675	1688	tumorogenesis	DiseaseClass	D002471
10484981	1753	1758	tumor	Modifier	D009369

2884570|t|An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2.
2884570|a|Phenylketonuria (PKU) is an autosomal recessive human genetic disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH, phenylalanine 4-monooxygenase, EC 1. 14. 16. 1). PKU is a common inborn error of amino-acid metabolism in caucasian populations and approximately 1 in 50 individuals are carriers of a PKU allele. To define the molecular basis of PKU, we characterized twelve restriction fragment-length polymorphism (RFLP) haplotypes of the PAH locus in the northern European population and observed that 90% of the PKU alleles in this population are confined to four common RFLP haplotypes. We have recently reported a splicing mutation in the PAH gene that is associated with RFLP haplotype 3 which is present at about 40% of mutant alleles. We now report the molecular lesion associated with the RFLP haplotype 2 mutant allele. This defect is caused by a C-to-T transition in exon 12 resulting in an amino-acid substitution (Arg to Trp) at residue 408 of PAH. Direct hybridization analysis of the point mutation using a specific oligonucleotide probe demonstrated that this mutation is also in linkage disequilibrium with RFLP haplotype 2 alleles that make up about 20% of mutant PAH genes 
2884570	39	54	phenylketonuria	SpecificDisease	D010661
2884570	106	121	Phenylketonuria	SpecificDisease	D010661
2884570	123	126	PKU	SpecificDisease	D010661
2884570	134	176	autosomal recessive human genetic disorder	DiseaseClass	D030342
2884570	189	236	deficiency of hepatic phenylalanine hydroxylase	SpecificDisease	OMIM:261600
2884570	292	295	PKU	SpecificDisease	D010661
2884570	308	345	inborn error of amino-acid metabolism	DiseaseClass	D000592
2884570	427	430	PKU	Modifier	D010661
2884570	472	475	PKU	SpecificDisease	D010661
2884570	642	645	PKU	Modifier	D010661
2884570	888	904	molecular lesion	DiseaseClass	D030342

8258524|t|The effects of dystrophin gene mutations on the ERG in mice and humans.
8258524|a|PURPOSE. The authors earlier findings of a negative electroretinogram (ERG) in a boy with Duchenne muscular dystrophy (DMD) led them to investigate dystrophin gene deletions and ERGs in five boys with DMD. The authors wanted to determined whether there were similar ERG findings in an animal model for DMD, the mdx mouse. METHODS. Ganzfeld ERGs were recorded in five boys with DMD after a complete ophthalmic examination. The dystrophin gene was analyzed by Southern blot hybridization. ERGs were recorded in anesthetized mdx and control mice with a modified Grass photostimulator (Grass Instrument Company, Quincy, MA). RESULTS. Ophthalmic examinations in all five boys had normal findings, yet an abnormal negative ERG was recorded for each subject. The subjects gene deletions were variable, ranging from large deletions to no detectable deletions. The ERGs of the mdx mice were normal and did not differ significantly from those of the control mice. CONCLUSIONS. The authors believe the unique ERG recorded for the human subjects is a manifestation of DMD associated with defects at the dystrophin gene locus and represents a new clinical entity. The ERG of the mdx mouse may be spared for several reasons, including milder effects of the mouse gene defect, differences in muscle and retinal gene product, or species differences in the biochemical role of dystrophin. The ERG shows promise of becoming a noninvasive diagnostic tool for DMD and its milder allelic forms.. 
8258524	162	189	Duchenne muscular dystrophy	SpecificDisease	D020388
8258524	191	194	DMD	SpecificDisease	D020388
8258524	273	276	DMD	SpecificDisease	D020388
8258524	374	377	DMD	SpecificDisease	D020388
8258524	449	452	DMD	SpecificDisease	D020388
8258524	1128	1131	DMD	SpecificDisease	D020388
8258524	1512	1515	DMD	SpecificDisease	D020388

1324223|t|Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis.
1324223|a|Familial adenomatous polyposis (FAP) is a dominantly inherited condition predisposing to colorectal cancer. The recent isolation of the responsible gene (adenomatous polyposis coli or APC) has facilitated the search for germ line mutations in affected individuals. Previous authors have used the RNase protection assay and the single-strand conformation polymorphisms procedure to screen for mutations. In this study we used denaturing gradient gel electrophoresis (DGGE). DGGE analysis of 10 APC exons (4, 5, 7, 8, 9, 10, 12, 13, 14, and part of 15) in 33 unrelated Dutch FAP patients has led to the identification of eight novel germ line mutations resulting in stop codons or frameshifts. The results reported here indicate that (1) familial adenomatous polyposis is caused by an extremely heterogeneous spectrum of point mutations; (2) all the mutations found in this study are chain terminating; and (3) DGGE represents a rapid and sensitive technique for the detection of mutations in the unusually large APC gene. An extension of the DGGE analysis to the entire coding region in a sufficient number of clinically well-characterized, unrelated patients will facilitate the establishment of genotype-phenotype correlations. On the other hand, the occurrence of an extremely heterogeneous spectrum of mutations spread throughout the entire length of the large APC gene among the FAP patients indicates that this approach may not be useful as a rapid presymptomatic diagnostic procedure in a routine laboratory. Nevertheless, the above DGGE approach has incidentally led to the identification of a common polymorphism in exon 13. Such intragenic polymorphisms offer a practical approach to a more rapid procedure for presymptomatic diagnosis of FAP by linkage analysis in informative families.. 
1324223	52	55	APC	Modifier	D011125
1324223	116	146	Familial adenomatous polyposis	SpecificDisease	D011125
1324223	148	151	FAP	SpecificDisease	D011125
1324223	205	222	colorectal cancer	SpecificDisease	D015179
1324223	270	296	adenomatous polyposis coli	SpecificDisease	D011125
1324223	300	303	APC	SpecificDisease	D011125
1324223	609	612	APC	Modifier	D011125
1324223	689	692	FAP	Modifier	D011125
1324223	852	882	familial adenomatous polyposis	SpecificDisease	D011125
1324223	1127	1130	APC	Modifier	D011125
1324223	1480	1483	APC	Modifier	D011125
1324223	1499	1502	FAP	Modifier	D011125
1324223	1864	1867	FAP	SpecificDisease	D011125

10533068|t|Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change.
10533068|a|Juvenile retinoschisis is an X-linked recessive disease caused by mutations in the XLRS1 gene. We screened 31 new unrelated patients and families for XLRS1 mutations in addition to previously reported mutations for 60 of our families (Retinoschisis Consortium, Hum Mol Genet 1998; 7  1185-1192). Twenty-three different mutations including 12 novel ones were identified in 28 patients. Mutations identified in this study include 19 missense mutations, two nonsense mutations, one intragenic deletion, four microdeletions, one insertion, and one intronic sequence substitution that is likely to result in a splice site defect. Two novel mutations, c. 38T-- > C (L13P) and c. 667T-- > C (C223R), respectively, present the first genetic evidence for the functional significance of the putative leader peptide sequence and for the functional significance at the carboxyl terminal of the XLRS1 protein beyond the discoidin domain. Mutations in 25 of the families were localized to exons 4-6, emphasizing the critical functional significance of the discoidin domain of the XLRS1 protein 
10533068	33	46	retinoschisis	SpecificDisease	D041441
10533068	109	131	Juvenile retinoschisis	SpecificDisease	D041441
10533068	138	164	X-linked recessive disease	DiseaseClass	D040181
10533068	344	357	Retinoschisis	Modifier	D041441

6585184|t|Clinical use of DNA markers linked to the gene for Duchenne muscular dystrophy.
6585184|a|Seventy families with Duchenne muscular dystrophy (DMD) known to the Institute of Child Health fall into three categories with respect to potential linkage analysis with the X chromosome DNA markers RC8 and L1. 28 that bridge the DMD gene. Families in which there is at least one obligatory female heterozygote (n = 13). Here prediction and exclusion of DMD gene transmission may be possible, the accuracy being dependent on the closeness of the linkage of the DNA marker (s) to the DMD gene; an illustrative case is reported. Families in which there is a single affected boy, who also has one or more healthy brothers (n = 26). Given an informative restriction fragment length polymorphism (RFLP), the probability that the boy represents a new mutation can be reassessed; it is also possible to exclude the DMD gene in a sister. Families with a single affected boy with no brother (n = 30). Here exclusion of the DMD gene in a sister may be possible. Only in one family was there no possibility of useful linkage analysis. The linkage analysis required is described, and the need to check DMD families for informative RFLPs is stressed. 
6585184	51	78	Duchenne muscular dystrophy	SpecificDisease	D020388
6585184	102	129	Duchenne muscular dystrophy	SpecificDisease	D020388
6585184	131	134	DMD	SpecificDisease	D020388
6585184	310	313	DMD	Modifier	D020388
6585184	434	437	DMD	Modifier	D020388
6585184	563	566	DMD	Modifier	D020388
6585184	888	891	DMD	Modifier	D020388
6585184	994	997	DMD	Modifier	D020388
6585184	1170	1173	DMD	Modifier	D020388

8471773|t|Molecular characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency in patients of Chinese descent and identification of new base substitutions in the human G6PD gene.
8471773|a|The underlying DNA changes associated with glucose-6-phosphate dehydrogenase (G6PD) -deficient Asians have not been extensively investigated. To fill this gap, we sequenced the G6PD gene of 43 G6PD-deficient Chinese whose G6PD was well characterized biochemically. DNA samples were obtained from peripheral blood of these individuals for sequencing using a direct polymerase chain reaction (PCR) sequencing procedure. From these 43 samples, we have identified five different types of nucleotide substitutions in the G6PD gene  at cDNA 1388 from G to A (Arg to His); at cDNA 1376 from G to T (Arg to Leu); at cDNA 1024 from C to T (Leu to Phe); at cDNA 392 from G to T (Gly to Val); at cDNA 95 from A to G (His to Arg). These five nucleotide substitutions account for over 83% of our 43 G6PD-deficient samples and these substitutions have not been reported in non-Asians. The substitutions found at cDNA 392 and cDNA 1024 are new findings. The substitutions at cDNA 1376 and 1388 account for over 50% of the 43 samples examined indicating a high prevalence of these two alleles among G6PD-deficient Chinese. Our findings add support to the notion that diverse point mutations may account largely for much of the phenotypic heterogeneity of G6PD deficiency.. 
8471773	30	81	glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
8471773	225	276	glucose-6-phosphate dehydrogenase (G6PD) -deficient	Modifier	D005955
8471773	375	389	G6PD-deficient	Modifier	D005955
8471773	968	982	G6PD-deficient	Modifier	D005955
8471773	1265	1279	G6PD-deficient	Modifier	D005955
8471773	1421	1436	G6PD deficiency	SpecificDisease	D005955

8314592|t|Norrie disease gene: characterization of deletions and possible function.
8314592|a|Positional cloning experiments have resulted recently in the isolation of a candidate gene for Norrie disease (pseudoglioma; NDP), a severe X-linked neurodevelopmental disorder. Here we report the isolation and analysis of human genomic DNA clones encompassing the NDP gene. The gene spans 28 kb and consists of 3 exons, the first of which is entirely contained within the 5 untranslated region. Detailed analysis of genomic deletions in Norrie patients shows that they are heterogeneous, both in size and in position. By PCR analysis, we found that expression of the NDP gene was not confined to the eye or to the brain. An extensive DNA and protein sequence comparison between the human NDP gene and related genes from the database revealed homology with cysteine-rich protein-binding domains of immediate--early genes implicated in the regulation of cell proliferation. We propose that NDP is a molecule related in function to these genes and may be involved in a pathway that regulates neural cell differentiation and proliferation.. 
8314592	0	14	Norrie disease	Modifier	C537849
8314592	169	183	Norrie disease	SpecificDisease	C537849
8314592	185	197	pseudoglioma	SpecificDisease	C537849
8314592	199	202	NDP	SpecificDisease	C537849
8314592	214	250	X-linked neurodevelopmental disorder	DiseaseClass	D038901
8314592	339	342	NDP	Modifier	C537849
8314592	512	518	Norrie	Modifier	C537849
8314592	642	645	NDP	Modifier	C537849
8314592	763	766	NDP	Modifier	C537849

122435|t|Prenatal diagnosis of Wolman disease.
122435|a|Two pregnancies at risk for Wolman disease were monitored by assay and electrophoresis of acid lipase in cultured amniotic-fluid cells. Cells from patient 1 had 5% of control levels of acid lipase, using 14C-triolein as substrate; however, when artificial substrates (esters of 4-methylumbelliferone and p-nitrophenol) were used to measure acid lipase, these cells had 30% of control levels. Electrophoresis of cell extracts revealed the absence of the A form of acid lipase, consistent with the diagnosis of Wolman disease. Analysis of fetal tissues following prostaglandin termination of this pregnancy confirmed the diagnosis. Assay of fetal-skin fibroblasts with 14C-triolein, as well as with artificial substrates, showed marked deficiency of acid lipase activity. Electrophoresis of fetal-tissue extracts also demonstrated the absence of the A form of acid lipase. Amniotic-fluid cells from patient 2 showed normal levels of acid lipase with all substrates tested; the electrophoretic pattern of acid lipase was normal. The results suggest that the prenatal diagnosis of Wolman disease be made using the radioassay of acid lipase and/or electrophoresis.. 
122435	22	36	Wolman disease	SpecificDisease	D015223
122435	66	80	Wolman disease	SpecificDisease	D015223
122435	547	561	Wolman disease	SpecificDisease	D015223
122435	1115	1129	Wolman disease	SpecificDisease	D015223

7795652|t|Somatic mutations in the BRCA1 gene in sporadic ovarian tumours.
7795652|a|The BRCA1 gene on chromosome 17q21 is responsible for an autosomal dominant syndrome of increased susceptibility to breast and ovarian cancer but no somatic mutations in tumours have yet been described. To study the potential role of BRCA1 in sporadic carcinogenesis, we analysed the genomic DNA of tumour and normal fractions of 47 ovarian cancers for mutations in BRCA1 using the single-strand conformation polymorphism technique. We now describe somatic mutations in the DNA of four tumours which also had loss of heterozygosity (LOH) at a BRCA1 intragenic marker. Our data support a tumour suppressor mechanism for BRCA1; somatic mutations and LOH may result in inactivation of BRCA1 in at least a small number of ovarian cancers.. 
7795652	39	63	sporadic ovarian tumours	SpecificDisease	D010051
7795652	122	149	autosomal dominant syndrome	DiseaseClass	D030342
7795652	181	206	breast and ovarian cancer	CompositeMention	D061325
7795652	235	242	tumours	DiseaseClass	D009369
7795652	364	370	tumour	DiseaseClass	D009369
7795652	398	413	ovarian cancers	SpecificDisease	D010051
7795652	551	558	tumours	DiseaseClass	D009369
7795652	652	658	tumour	Modifier	D009369
7795652	783	798	ovarian cancers	SpecificDisease	D010051

2180286|t|Skewed X inactivation in a female MZ twin results in Duchenne muscular dystrophy.
2180286|a|One of female MZ twins presented with muscular dystrophy. Physical examination, creatine phosphokinase levels, and muscle biopsy were consistent with Duchenne muscular dystrophy (DMD). However, because of her sex she was diagnosed as having limb-girdle muscular dystrophy. With cDNA probes to the DMD gene, a gene deletion was detected in the twins and their mother. The de novo mutation which arose in the mother was shown by novel junction fragments generated by HindIII, PstI, or TaqI when probed with cDNA8. Additional evidence of a large gene deletion was given by novel SfiI junction fragments detected by probes p20, J-Bir, and J-66 on pulsed-field gel electrophoresis (PFGE). Immunoblot analysis of muscle from the affected twin showed dystrophin of normal size but of reduced amount. Immunofluorescent visualization of dystrophin revealed foci of dystrophin-positive fibers adjacent to foci of dystrophin-negative fibers. These data indicate that the affected twin is a manifesting carrier of an abnormal DMD gene, her myopathy being a direct result of underexpression of dystrophin. Cytogenetic analysis revealed normal karyotypes, eliminating the possibility of a translocation affecting DMD gene function. Both linkage analysis and DNA fingerprint analysis revealed that each twin has two different X chromosomes, eliminating the possibility of uniparental disomy as a mechanism for DMD expression. On the basis of methylation differences of the paternal and maternal X chromosomes in these MZ twins, we propose uneven lyonization (X chromosome inactivation) as the underlying mechanism for disease expression in the affected female.. 
2180286	53	80	Duchenne muscular dystrophy	SpecificDisease	D020388
2180286	120	138	muscular dystrophy	DiseaseClass	D009136
2180286	232	259	Duchenne muscular dystrophy	SpecificDisease	D020388
2180286	261	264	DMD	SpecificDisease	D020388
2180286	323	353	limb-girdle muscular dystrophy	SpecificDisease	D049288
2180286	379	382	DMD	Modifier	D020388
2180286	1096	1099	DMD	Modifier	D020388
2180286	1110	1118	myopathy	DiseaseClass	D009135
2180286	1281	1284	DMD	Modifier	D020388
2180286	1439	1457	uniparental disomy	SpecificDisease	D024182
2180286	1477	1480	DMD	Modifier	D020388

1316718|t|Coincident Kaposi sarcoma and T-cell lymphoma in a patient with the Wiskott-Aldrich syndrome.
1316718|a|A 24 year old male with a history of eczema, recurrent mild infections, and thrombocytopenia consistent with the Wiskott-Aldrich syndrome (WAS) presented with a mediastinal mass, generalized lymphadenopathy, splenomegaly, and severe thrombocytopenia. Studies of immune function including immunoglobulin levels and T-cell subsets were normal. Furthermore, his T lymphocytes proliferated normally in response to phytohemagglutinin, concanavalin A, and the combination of neuraminidase/galactose oxidase. However, their proliferative responses to anti-CD43 antibody and periodate were diminished, consistent with the clinical diagnosis of WAS. An initial inguinal lymph node biopsy surprisingly revealed Kaposi sarcoma. However, following splenectomy to increase the platelet count, biopsy of the mediastinal mass revealed T-cell large cell lymphoma. Studies of biopsied tissue for the presence of Epstein-Barr virus and cytomegalovirus were negative, as were studies of blood, including the polymerase chain reaction, for the presence of the human immunodeficiency virus (HIV). This is the first report of Kaposi sarcoma arising in a patient with a congenital immunodeficiency syndrome. Although Kaposi sarcoma can arise in the face of the severe immunosuppression that follows allograft transplantation and in patients infected with HIV, we postulate that longevity in the face of mild immunosuppression was the major factor in the development of Kaposi sarcoma in this patient.. 
1316718	11	25	Kaposi sarcoma	SpecificDisease	D012514
1316718	30	45	T-cell lymphoma	SpecificDisease	D016399
1316718	68	92	Wiskott-Aldrich syndrome	SpecificDisease	D014923
1316718	131	137	eczema	DiseaseClass	D004485
1316718	170	186	thrombocytopenia	SpecificDisease	D013921
1316718	207	231	Wiskott-Aldrich syndrome	SpecificDisease	D014923
1316718	233	236	WAS	SpecificDisease	D014923
1316718	285	300	lymphadenopathy	SpecificDisease	D008206
1316718	302	314	splenomegaly	SpecificDisease	D013163
1316718	327	343	thrombocytopenia	SpecificDisease	D013921
1316718	730	733	WAS	SpecificDisease	D014923
1316718	795	809	Kaposi sarcoma	SpecificDisease	D012514
1316718	914	940	T-cell large cell lymphoma	SpecificDisease	D016399
1316718	989	1007	Epstein-Barr virus	SpecificDisease	D020031
1316718	1012	1027	cytomegalovirus	SpecificDisease	D003586
1316718	1134	1162	human immunodeficiency virus	SpecificDisease	D015658
1316718	1164	1167	HIV	SpecificDisease	D015658
1316718	1198	1212	Kaposi sarcoma	SpecificDisease	D012514
1316718	1241	1277	congenital immunodeficiency syndrome	DiseaseClass	D007153
1316718	1288	1302	Kaposi sarcoma	SpecificDisease	D012514
1316718	1426	1429	HIV	SpecificDisease	D015658
1316718	1540	1554	Kaposi sarcoma	SpecificDisease	D012514

7964884|t|Treatment of cerebrotendinous xanthomatosis: effects of chenodeoxycholic acid, pravastatin, and combined use.
7964884|a|Treatments by oral administration of chenodeoxycholic acid (CDCA) alone, 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitor (pravastatin) alone, and combination of the two drugs were attempted for 7 patients with cerebrotendinous xanthomatosis (CTX). CDCA treatment at a dose of 300 mg/day reduced serum cholestanol (67. 3% reduction), lathosterol (50. 8%), campesterol (61. 7%) and sitosterol (12. 7%). However, the sera of the patients changed to be " atherogenic "; total cholesterol, triglyceride and low-density lipoprotein (LDL) -cholesterol were increased, while high-density lipoprotein (HDL) -cholesterol was decreased. Contrarily, pravastatin at a dose of 10 mg/day improved the sera of the patients to be markedly " anti-atherogenic ", but the reductions of cholestanol (30. 4%), lathosterol (44. 0%), campesterol (22. 9%) and sitosterol (9. 6%) were inadequate. Combined treatment with CDCA and pravastatin showed good overlapping of the effects of each drug alone. The sera of the patients were apparently more " anti-atherogenic " than those after CDCA treatment. Serum cholestanol concentration was still 2. 7 times higher than in controls, but the serum lathosterol level was within the normal range, indicating that the enhancement of overall cholesterol synthesis in the patients was sufficiently suppressed. Plant sterol levels were also within the normal range. The combination of CDCA and pravastatin was a good treatment for CTX, based on the improvement of serum lipoprotein metabolism, the suppression of cholesterol synthesis, and reductions of cholestanol and plant sterol levels. In all of 7 patients, the progression of disease was arrested, but dramatic effects on clinical manifestations, xanthoma, and electrophysiological findings could not be found after the treatment of these drugs 
7964884	13	43	cerebrotendinous xanthomatosis	SpecificDisease	D019294
7964884	329	359	cerebrotendinous xanthomatosis	SpecificDisease	D019294
7964884	361	364	CTX	SpecificDisease	D019294
7964884	1563	1566	CTX	SpecificDisease	D019294
7964884	1835	1843	xanthoma	DiseaseClass	D014973

102474|t|Combined genetic deficiency of C6 and C7 in man.
102474|a|By routine screening of sera, a subject was discovered who showed a sub-total deficiency of C6 and C7. No clinical disease was associated with this deficiency which was transmitted through the subjects family as a single genetic characteristic, the C6 deficiency being associated with a silent allele at the structural locus. The propositus was found to have low quantities of an abnormal C6 which was both antigenically deficient and smaller in size than normal C6 (110, 000 daltons compared with 140, 000 daltons) and small quantities of apparently normal C7. It is concluded that the most likely explanation for this defect is that the subject has a structural mutation in his C6 gene which produces hyopsynthesis not only of C6 but also of the closely linked gene for C7. These findings suggest the possibility that C6 and C7 may function as a single genetic unit and that the primary transcript copied from the genome includes information for both proteins.. 
102474	0	40	Combined genetic deficiency of C6 and C7	CompositeMention	OMIM:610102|OMIM:612446
102474	117	150	sub-total deficiency of C6 and C7	CompositeMention	OMIM:610102|OMIM:612446
102474	298	311	C6 deficiency	SpecificDisease	OMIM:612446

2651669|t|Partial deletion 8q without Langer-Giedion syndrome: a recognisable syndrome.
2651669|a|We report two de novo cases of del (8) (pter----q24. 1 ) with breakpoints involving the distal part of band 8q24. 1 1. The clinical features were similar and there were no obvious stigmata of Langer-Giedion syndrome (LGS). There are three other cases reported with a deletion of chromosome 8 at approximately the same breakpoint, one without LGS and some similarities to our cases, the other two with LGS. Our findings would support the observation that the critical segment for the assignment of LGS is proximal to or involves the proximal part of 8q24. 1, but a review of published reports suggests that the aetiology of LGS may be a more complex issue 
2651669	28	51	Langer-Giedion syndrome	SpecificDisease	D015826
2651669	270	293	Langer-Giedion syndrome	SpecificDisease	D015826
2651669	295	298	LGS	SpecificDisease	D015826
2651669	420	423	LGS	SpecificDisease	D015826
2651669	479	482	LGS	SpecificDisease	D015826
2651669	575	578	LGS	SpecificDisease	D015826
2651669	701	704	LGS	SpecificDisease	D015826

10930361|t|Iron-dependent self-assembly of recombinant yeast frataxin: implications for Friedreich ataxia.
10930361|a|Frataxin deficiency is the primary cause of Friedreich ataxia (FRDA), an autosomal recessive cardiodegenerative and neurodegenerative disease. Frataxin is a nuclear-encoded mitochondrial protein that is widely conserved among eukaryotes. Genetic inactivation of the yeast frataxin homologue (Yfh1p) results in mitochondrial iron accumulation and hypersensitivity to oxidative stress. Increased iron deposition and evidence of oxidative damage have also been observed in cardiac tissue and cultured fibroblasts from patients with FRDA. These findings indicate that frataxin is essential for mitochondrial iron homeostasis and protection from iron-induced formation of free radicals. The functional mechanism of frataxin, however, is still unknown. We have expressed the mature form of Yfh1p (mYfh1p) in Escherichia coli and have analyzed its function in vitro. Isolated mYfh1p is a soluble monomer (13, 783 Da) that contains no iron and shows no significant tendency to self-associate. Aerobic addition of ferrous iron to mYfh1p results in assembly of regular spherical multimers with a molecular mass of approximately 1. 1 MDa (megadaltons) and a diameter of 13 +/-2 nm. Each multimer consists of approximately 60 subunits and can sequester > 3, 000 atoms of iron. Titration of mYfh1p with increasing iron concentrations supports a stepwise mechanism of multimer assembly. Sequential addition of an iron chelator and a reducing agent results in quantitative iron release with concomitant disassembly of the multimer, indicating that mYfh1p sequesters iron in an available form. In yeast mitochondria, native mYfh1p exists as monomer and a higher-order species with a molecular weight > 600, 000. After addition of (55) Fe to the medium, immunoprecipitates of this species contain > 16 atoms of (55) Fe per molecule of mYfh1p. We propose that iron-dependent self-assembly of recombinant mYfh1p reflects a physiological role for frataxin in mitochondrial iron sequestration and bioavailability.. 
10930361	77	94	Friedreich ataxia	SpecificDisease	D005621
10930361	96	115	Frataxin deficiency	SpecificDisease	D005621
10930361	140	157	Friedreich ataxia	SpecificDisease	D005621
10930361	159	163	FRDA	SpecificDisease	D005621
10930361	169	237	autosomal recessive cardiodegenerative and neurodegenerative disease	DiseaseClass	D030342+D019636
10930361	406	437	mitochondrial iron accumulation	SpecificDisease	D028361
10930361	442	478	hypersensitivity to oxidative stress	SpecificDisease	D004194
10930361	625	629	FRDA	SpecificDisease	D005621

10698963|t|Human mutations in glucose 6-phosphate dehydrogenase reflect evolutionary history.
10698963|a|Glucose 6-phosphate dehydrogenase (G6PD) is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. Inherited G6PD deficiency is associated with either episodic hemolytic anemia (triggered by fava beans or other agents) or life-long hemolytic anemia. We show here that an evolutionary analysis is a key to understanding the biology of a housekeeping gene. From the alignment of the amino acid (aa) sequence of 52 glucose 6-phosphate dehydrogenase (G6PD) species from 42 different organisms, we found a striking correlation between the aa replacements that cause G6PD deficiency in humans and the sequence conservation of G6PD  two-thirds of such replacements are in highly and moderately conserved (50-99%) aa; relatively few are in fully conserved aa (where they might be lethal) or in poorly conserved aa, where presumably they simply would not cause G6PD deficiency. This is consistent with the notion that all human mutants have residual enzyme activity and that null mutations are lethal at some stage of development. Comparing the distribution of mutations in a human housekeeping gene with evolutionary conservation is a useful tool for pinpointing amino acid residues important for the stability or the function of the corresponding protein. In view of the current explosive increase in full genome sequencing projects, this tool will become rapidly available for numerous other genes.. 
10698963	339	354	G6PD deficiency	SpecificDisease	D005955
10698963	381	406	episodic hemolytic anemia	SpecificDisease	D000743
10698963	452	478	life-long hemolytic anemia	SpecificDisease	D000745
10698963	791	806	G6PD deficiency	SpecificDisease	D005955
10698963	1082	1097	G6PD deficiency	SpecificDisease	D005955

8162051|t|Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli.
8162051|a|Germline mutation in APC at 5q21-22 results in the dominantly inherited syndrome adenomatous polyposis coli (APC). Somatic mutation in this gene is an early event in colorectal tumourigenesis. Both types of mutation are concentrated in the 5 half of exon 15. We have used single strand conformational polymorphism (SSCP) and heteroduplex analysis to screen for variants in this region of the gene in a total of 45 affected but unrelated individuals. Eighteen patients had no family history of the disease; of these 11 were classified as having a severe phenotype, based on an early age at presentation or cancer development. This compared with 6 of 27 familial cases. A 5 bp deletion at codon 1309 reported to occur in 10-15% of unselected APC patients worldwide, was found in 5 of the 18 new mutation cases and 4 of the 27 familial cases  all nine were classed as severe. A further 3 new mutations and 1 familial mutation were located downstream from codon 1309, these individuals similarly being classed as phenotypically severe. In contrast all of the APC mutations detected in affected individuals with an average phenotype were located prior to codon 1309. The frequent association of a severe phenotype with fresh mutation may explain the apparent conflict of a high mutation rate (20-30%) in a condition, which on average, is lethal at a post-reproductive age.. 
8162051	21	24	APC	Modifier	D011125
8162051	129	155	adenomatous polyposis coli	SpecificDisease	D011125
8162051	238	264	adenomatous polyposis coli	SpecificDisease	D011125
8162051	266	269	APC	SpecificDisease	D011125
8162051	762	768	cancer	Modifier	D009369
8162051	897	900	APC	Modifier	D011125
8162051	1212	1215	APC	Modifier	D011125

10205262|t|Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO).
10205262|a|We recently showed that alkaptonuria (AKU) is caused by loss-of-function mutations in the homogentisate 1, 2 dioxygenase gene (HGO). Herein we describe haplotype and mutational analyses of HGO in seven new AKU pedigrees. These analyses identified two novel single-nucleotide polymorphisms (INV4 + 31A-- > G and INV11 + 18A-- > G) and six novel AKU mutations (INV1-1G-- > A, W60G, Y62C, A122D, P230T, and D291E), which further illustrates the remarkable allelic heterogeneity found in AKU. Reexamination of all 29 mutations and polymorphisms thus far described in HGO shows that these nucleotide changes are not randomly distributed; the CCC sequence motif and its inverted complement, GGG, are preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in HGO do not involve CpG dinucleotides, which illustrates important differences between HGO and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34. 5%) of all mutated bases that have been observed in HGO, we conclude that the CCC triplet is a mutational hot spot in HGO. 
10205262	12	24	alkaptonuria	Modifier	D000474
10205262	26	29	AKU	Modifier	D000474
10205262	193	205	alkaptonuria	SpecificDisease	D000474
10205262	207	210	AKU	SpecificDisease	D000474
10205262	375	378	AKU	Modifier	D000474
10205262	513	516	AKU	Modifier	D000474
10205262	653	656	AKU	SpecificDisease	D000474

7450778|t|Further evidence for heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Papua New Guinea.
7450778|a|Four new G6PD variants have been characterized in individuals from Papua New Guinea. This study demonstrates that the previously reported Markham variant and the newly characterized Salata variant may be widely distributed in Papua New Guinea. Th data presented here together with those of previously published studies demonstrate a degree of heterogeneity of G6PD deficiency that is much higher than that in other regions of the world where G6PD deficiency is common.. 
7450778	38	82	glucose-6-phosphate dehydrogenase deficiency	SpecificDisease	D005955
7450778	464	479	G6PD deficiency	SpecificDisease	D005955
7450778	546	561	G6PD deficiency	SpecificDisease	D005955

10353787|t|Overgrowth of oral mucosa and facial skin, a novel feature of aspartylglucosaminuria.
10353787|a|Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by deficiency of aspartylglucosaminidase (AGA). The main symptom is progressive mental retardation. A spectrum of different mutations has been reported in this disease, one missense mutation (Cys163Ser) being responsible for the majority of Finnish cases. We were able to examine 66 Finnish AGU patients for changes in the oral mucosa and 44 of these for changes in facial skin. Biopsy specimens of 16 oral lesions, 12 of them associated with the teeth, plus two facial lesions were studied histologically. Immunohistochemical staining for AGA was performed on 15 oral specimens. Skin was seborrhoeic in adolescent and adult patients, with erythema of the facial skin already common in childhood. Of 44 patients, nine (20%) had facial angiofibromas, tumours primarily occurring in association with tuberous sclerosis. Oedemic buccal mucosa (leucoedema) and gingival overgrowths were more frequent in AGU patients than in controls (p < 0. 001). Of 16 oral mucosal lesions studied histologically, 15 represented fibroepithelial or epithelial hyperplasias and were reactive in nature. Cytoplasmic vacuolisation was evident in four. Immunohistochemically, expression of AGA in AGU patients mucosal lesions did not differ from that seen in corresponding lesions of normal subjects. Thus, the high frequency of mucosal overgrowth in AGU patients does not appear to be directly associated with lysosomal storage or with alterations in the level of AGA expression. 
10353787	0	41	Overgrowth of oral mucosa and facial skin	CompositeMention	D006965
10353787	62	84	aspartylglucosaminuria	SpecificDisease	D054880
10353787	86	108	Aspartylglucosaminuria	SpecificDisease	D054880
10353787	110	113	AGU	SpecificDisease	D054880
10353787	120	146	lysosomal storage disorder	DiseaseClass	D016464
10353787	157	194	deficiency of aspartylglucosaminidase	SpecificDisease	D054880
10353787	234	252	mental retardation	DiseaseClass	D008607
10353787	445	448	AGU	Modifier	D054880
10353787	617	631	facial lesions	DiseaseClass	D013568
10353787	794	821	erythema of the facial skin	SpecificDisease	D017445
10353787	882	902	facial angiofibromas	SpecificDisease	D018322
10353787	904	911	tumours	DiseaseClass	D009369
10353787	952	970	tuberous sclerosis	SpecificDisease	D014402
10353787	972	993	Oedemic buccal mucosa	SpecificDisease	D007967
10353787	995	1005	leucoedema	SpecificDisease	D007967
10353787	1011	1031	gingival overgrowths	SpecificDisease	D019214
10353787	1054	1057	AGU	Modifier	D054880
10353787	1104	1124	oral mucosal lesions	SpecificDisease	D009059
10353787	1164	1206	fibroepithelial or epithelial hyperplasias	CompositeMention	D017573
10353787	1327	1330	AGU	Modifier	D054880
10353787	1340	1355	mucosal lesions	SpecificDisease	D009059
10353787	1459	1477	mucosal overgrowth	SpecificDisease	D009059
10353787	1481	1484	AGU	Modifier	D054880

7550229|t|Molecular characterization of galactosemia (type 1) mutations in Japanese.
7550229|a|We characterized two novel mutations of the galactose-1-phosphate uridyltransferase (GALT) gene in two Japanese patients with GALT deficiency and identified N314D and R333W mutations, previously found in Caucasians. One novel missense mutation was an G-to-A transition in exon 8, resulting in the substitution of arginine by histidine at the codon 231 (R231H). GALT activity of the R231H mutant construct was reduced to 15% of normal controls in a COS cell expression system. The other was a splicing mutation, an A-to-G transition at the 38th nucleotide in exon 3 (318A-- > G), resulting in a 38-bp deletion in the GALT cDNA by activating a cryptic splice acceptor site. In seven Japanese families (14 alleles for classic form and one allele for Duarte variant) with GALT deficiency, the R231H and 318A-- > G mutations were found only on both alleles of the proband. The N314D and R333W mutations were found on one allele each. The Q188R was prevalent in the United States but not in Japanese patients. The N314D mutation was associated with the Duarte variant in Japanese persons, as well as in the United States. We speculate that classic galactosemia mutations appear to differ between Japanese and Caucasian patients. Our limited data set on galactosemia mutations in Japanese suggests that the N314D GALT mutation encoding the Duarte variant arose before Asian and Caucasian people diverged and that classic galactosemia mutations arose and/or accumulated after the divergence of Asian and Caucasian populations.. 
7550229	30	42	galactosemia	Modifier	D005693
7550229	201	216	GALT deficiency	SpecificDisease	D005693
7550229	843	858	GALT deficiency	SpecificDisease	D005693
7550229	1209	1229	classic galactosemia	Modifier	D005693
7550229	1322	1334	galactosemia	Modifier	D005693
7550229	1481	1501	classic galactosemia	Modifier	D005693

1345170|t|Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland.
1345170|a|Linkage disequilibrium mapping in isolated populations provides a powerful tool for fine structure localization of disease genes. Here, Luria and Delbrucks classical methods for analysing bacterial cultures are adapted to the study of human isolated founder populations in order to estimate (i) the recombination fraction between a disease locus and a marker; (ii) the expected degree of allelic homogeneity in a population; and (iii) the mutation rate of marker loci. Using these methods, we report striking linkage disequilibrium for diastrophic dysplasia (DTD) in Finland indicating that the DTD gene should lie within 0. 06 centimorgans (or about 60 kilobases) of the CSF1R gene. Predictions about allelic homogeneity in Finland and mutation rates in simple sequence repeats are confirmed by independent observations. 
1345170	64	85	diastrophic dysplasia	SpecificDisease	C536170
1345170	634	655	diastrophic dysplasia	SpecificDisease	C536170
1345170	657	660	DTD	SpecificDisease	C536170
1345170	693	696	DTD	Modifier	C536170

10615125|t|Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis.
10615125|a|Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21. 2-21 2-21. 3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.
10615125	68	97	familial expansile osteolysis	SpecificDisease	OMIM:174810
10615125	99	128	Familial expansile osteolysis	SpecificDisease	OMIM:174810
10615125	130	133	FEO	SpecificDisease	OMIM:174810
10615125	158	190	autosomal dominant bone disorder	DiseaseClass	D001847
10615125	223	249	increased bone remodelling	SpecificDisease	D001847
10615125	255	273	osteolytic lesions	SpecificDisease	D030981
10615125	451	454	FEO	SpecificDisease	OMIM:174810
10615125	852	855	FEO	SpecificDisease	OMIM:174810
10615125	859	889	familial Paget disease of bone	SpecificDisease	C538098
10615125	891	894	PDB	SpecificDisease	C538098

10196381|t|Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): implications for therapy.
10196381|a|Inherited defects in the peroxisomal ATP-binding cassette (ABC) transporter adrenoleukodystrophy protein (ALDP) lead to the lethal peroxisomal disorder X-linked adrenoleukodystrophy (X-ALD), for which no efficient treatment has been established so far. Three other peroxisomal ABC transporters currently are known  adrenoleukodystrophy-related protein (ALDRP), 70 kDa peroxisomal membrane protein (PMP70) and PMP70- related protein. By using transient and stable overexpression of human cDNAs encoding ALDP and its closest relative ALDRP, we could restore the impaired peroxisomal beta-oxidation in fibroblasts of X-ALD patients. The pathognomonic accumulation of very long chain fatty acids could also be prevented by overexpression of ALDRP in immortalized X-ALD cells. Immunofluorescence analysis demonstrated that the functional replacement of ALDP by ALDRP was not due to stabilization of the mutated ALDP itself. Moreover, we were able to restore the peroxisomal beta-oxidation defect in the liver of ALDP-deficient mice by stimulation of ALDRP and PMP70 gene expression through a dietary treatment with the peroxisome proliferator fenofibrate. These results suggest that a correction of the biochemical defect in X-ALD could be possible by drug-induced overexpression or ectopic expression of ALDRP.. 
10196381	69	108	adrenoleukodystrophy protein deficiency	SpecificDisease	D000326
10196381	110	115	X-ALD	SpecificDisease	D000326
10196381	144	161	Inherited defects	DiseaseClass	D030342
10196381	220	240	adrenoleukodystrophy	Modifier	D000326
10196381	275	295	peroxisomal disorder	DiseaseClass	D018901
10196381	296	325	X-linked adrenoleukodystrophy	SpecificDisease	D000326
10196381	327	332	X-ALD	SpecificDisease	D000326
10196381	758	763	X-ALD	Modifier	D000326
10196381	1364	1369	X-ALD	SpecificDisease	D000326

8317477|t|The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD.
8317477|a|We evaluated the hypothesis that Huntington disease (HD) is influenced by the normal HD allele by comparing transmission patterns of genetically linked markers at the D4S10 locus in the normal parent against age at onset in the affected offspring. Analysis of information from 21 sibships in 14 kindreds showed a significant tendency for sibs who have similar onset ages to share the same D4S10 allele from the normal parent. Affected sibs who inherited different D4S10 alleles from the normal parent tended to have more variable ages at onset. These findings suggest that the expression of HD is modulated by the normal HD allele or by a closely linked locus.. 
8317477	11	29	Huntington disease	Modifier	D006816
8317477	31	33	HD	Modifier	D006816
8317477	96	98	HD	SpecificDisease	D006816
8317477	133	151	Huntington disease	SpecificDisease	D006816
8317477	153	155	HD	SpecificDisease	D006816
8317477	185	187	HD	Modifier	D006816
8317477	691	693	HD	SpecificDisease	D006816
8317477	721	723	HD	Modifier	D006816

10545613|t|Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene.
10545613|a|Most fragile X syndrome patients have expansion of a (CGG) (n) sequence with > 200 repeats (full mutation) in the FMR1 gene responsible for this condition. Hypermethylation of the expanded repeat and of the FMR1 promoter is almost always present and apparently suppresses transcription, resulting in absence of the FMR1 protein. We recently showed that transcriptional reactivation of FMR1 full mutations can be achieved by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC). The level of histone acetylation is another important factor in regulating gene expression; therefore, we treated lymphoblastoid cell lines of non-mosaic full mutation patients with three drugs capable of inducing histone hyperacetylation. We observed a consistent, although modest, reactivation of the FMR1 gene with 4-phenylbutyrate, sodium butyrate and trichostatin A, as shown by RT-PCR. However, we report that combining these drugs with 5-azadC results in a 2- to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus showing a marked synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations.. 
10545613	112	130	fragile X syndrome	Modifier	D005600

1358807|t|Genetic heterogeneity in X-linked amelogenesis imperfecta.
1358807|a|The AMELX gene located at Xp22. 1-p22. 3 encodes for the enamel protein amelogenin and has been implicated as the gene responsible for the inherited dental abnormality X-linked amelogenesis imperfecta (XAI). Three families with XAI have been investigated using polymorphic DNA markers flanking the position of AMELX. Using two-point linkage analysis, linkage was established between XAI and several of these markers in two families, with a combined lod score of 6. 05 for DXS16 at theta = 0. 04 04. This supports the involvement of AMELX, located close to DXS16, in the XAI disease process (AIH1) in those families. Using multipoint linkage analysis, the combined maximum lod score for these two families was 7. 30 for a location of AIH1 at 2 cM distal to DXS16. The support interval around this location extended about 8 cM proximal to DXS92, and the AIH1 location could not be precisely defined by multipoint mapping. Study of recombination events indicated that AIH1 lies in the interval between DXS143 and DXS85. There was significant evidence against linkage to this region in the third family, indicating locus heterogeneity in XAI. Further analysis with markers on the long arm of the X chromosome showed evidence of linkage to DXS144E and F9 with no recombination with either of these markers. Two-point analysis gave a peak lod score at DXS144E with a maximum lod score of 2. 83 at theta = 0, with a peak lod score in multipoint linkage analysis of 2. 84 at theta = 0. The support interval extended 9 cM proximal to DXS144E and 14 cM distal to F9. (ABSTRACT TRUNCATED AT 250 WORDS).
1358807	25	57	X-linked amelogenesis imperfecta	SpecificDisease	C538243
1358807	198	226	inherited dental abnormality	DiseaseClass	D014071
1358807	227	259	X-linked amelogenesis imperfecta	SpecificDisease	C538243
1358807	261	264	XAI	SpecificDisease	C538243
1358807	287	290	XAI	SpecificDisease	C538243
1358807	442	445	XAI	SpecificDisease	C538243
1358807	629	640	XAI disease	SpecificDisease	C538243
1358807	1193	1196	XAI	SpecificDisease	C538243

8304342|t|Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)
8304342|a|The hemochromatosis gene (HFE) maps to 6p21. 3 and is less than 1 cM from the HLA class I genes; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these practical considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. We therefore embarked upon a linkage-disequilibrium analysis of HFE and normal chromosomes from the Brittany population. In the present report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6. 7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6. 7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6. 7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6. 7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. Overall, the establishment of a likely " hemochromatosis critical region " centromeric boundary and the identification of a linkage-disequilibrium zone both significantly contribute to a reduction in the amount of DNA required to be searched for novel coding sequences constituting the HFE defect 
8304342	100	115	hemochromatosis	Modifier	D006432
8304342	131	146	hemochromatosis	Modifier	D006432
8304342	374	389	hemochromatosis	Modifier	D006432
8304342	864	879	hemochromatosis	Modifier	D006432
8304342	902	917	hemochromatosis	Modifier	D006432
8304342	1909	1924	hemochromatosis	Modifier	D006432
8304342	2154	2169	hemochromatosis	Modifier	D006432
8304342	2399	2409	HFE defect	SpecificDisease	D006432

7617034|t|Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria.
7617034|a|Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy of humans, affects over 400 million people. The geographical correlation of its distribution with the historical endemicity of malaria suggests that this disorder has risen in frequency through natural selection by malaria. However, attempts to confirm that G6PD deficiency is protective in case-control studies of malaria have yielded conflicting results. Hence, for this X-linked disorder, it is unclear whether both male hemizygotes and female heterozygotes are protected or, as frequently suggested, only females. Furthermore, how much protection may be afforded is unknown. Here we report that, in two large case-control studies of over 2, 000 African children, the common African form of G6PD deficiency (G6PD A-) is associated with a 46-58% reduction in risk of severe malaria for both female heterozygotes and male hemizygotes. A mathematical model incorporating the measured selective advantage against malaria suggests that a counterbalancing selective disadvantage, associated with this enzyme deficiency, has retarded its rise in frequency in malaria-endemic regions. Although G6PD deficiency is now regarded as a generally benign disorder, in earlier environmental conditions it could have been significantly disadvantageous.. 
7617034	49	64	G6PD deficiency	SpecificDisease	D005955
7617034	99	106	malaria	SpecificDisease	D008288
7617034	108	159	Glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
7617034	177	188	enzymopathy	DiseaseClass	D008661
7617034	316	323	malaria	SpecificDisease	D008288
7617034	404	411	malaria	SpecificDisease	D008288
7617034	447	462	G6PD deficiency	SpecificDisease	D005955
7617034	504	511	malaria	SpecificDisease	D008288
7617034	562	579	X-linked disorder	DiseaseClass	D040181
7617034	883	898	G6PD deficiency	SpecificDisease	D005955
7617034	900	907	G6PD A-	SpecificDisease	D005955
7617034	965	972	malaria	SpecificDisease	D008288
7617034	1101	1108	malaria	SpecificDisease	D008288
7617034	1187	1204	enzyme deficiency	DiseaseClass	D008661
7617034	1244	1251	malaria	Modifier	D008288
7617034	1278	1293	G6PD deficiency	SpecificDisease	D005955

6618488|t|Prader-Willi syndrome and chromosome 15. A clinical discussion of 20 cases.
6618488|a|A chromosome 15 anomaly was observed in 12 of 20 patients, 17 of whom were clinically suspected of having Prader-Willi syndrome (PWS). The clinical features of eight cases with 15q11-12 deletion were very similar to those originally described in PWS. On the other hand, the group of normal karyotype patients is heterogeneous, and their features do not strictly correspond to the clinical definition of PWS. However, the hypothesis that PWS is associated with deletion of 15q11-12 can neither explain the apparently balanced translocations of chromosome 15 nor account for the small supernumerary metacentric chromosomes corresponding to an isochromosome 15 for band 15q11 observed in some cases.. 
6618488	0	21	Prader-Willi syndrome	SpecificDisease	D011218
6618488	78	99	chromosome 15 anomaly	SpecificDisease	D002869
6618488	182	203	Prader-Willi syndrome	SpecificDisease	D011218
6618488	205	208	PWS	SpecificDisease	D011218
6618488	322	325	PWS	SpecificDisease	D011218
6618488	479	482	PWS	SpecificDisease	D011218
6618488	513	516	PWS	SpecificDisease	D011218

1301187|t|Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.
1301187|a|Mutations in the human phenylalanine hydroxylase gene producing phenylketonuria or hyperphenylalaninemia have now been identified in many patients from various ethnic groups. These mutations all exhibit a high degree of association with specific restriction fragment-length polymorphism haplotypes at the PAH locus. About 50 of these mutations are single-base substitutions, including six nonsense mutations and eight splicing mutations, with the remainder being missense mutations. One splicing mutation results in a 3 amino acid in-frame insertion. Two or 3 large deletions, 2 single codon deletions, and 2 single base deletions have been found. Twelve of the missense mutations apparently result from the methylation and subsequent deamination of highly mutagenic CpG dinucleotides. Recurrent mutation has been observed at several of these sites, producing associations with different haplotypes in different populations. About half of all missense mutations have been examined by in vitro expression analysis, and a significant correlation has been observed between residual PAH activity and disease phenotype. Since continuing advances in molecular methodologies have dramatically accelerated the rate in which new mutations are being identified and characterized, this register of mutations will be updated periodically.. 
1301187	19	34	phenylketonuria	SpecificDisease	D010661
1301187	47	69	hyperphenylalaninemias	DiseaseClass	D010661
1301187	208	223	phenylketonuria	SpecificDisease	D010661
1301187	227	248	hyperphenylalaninemia	DiseaseClass	D010661

1483696|t|The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada.
1483696|a|Mutations at the hexosaminidase A (HEXA) gene which cause Tay-Sachs disease (TSD) have elevated frequency in the Ashkenazi Jewish and French-Canadian populations. We report a novel TSD allele in the French-Canadian population associated with the infantile form of the disease. The mutation, a G-- > A transition at the + 1 position of intron 7, abolishes the donor splice site. Cultured human fibroblasts from a compound heterozygote for this transition (and for a deletion mutation) produce no detectable HEXA mRNA. The intron 7 + 1 mutation occurs in the base adjacent to the site of the adult-onset TSD mutation (G805A). In both mutations a restriction site for the endonuclease EcoRII is abolished. Unambiguous diagnosis, therefore, requires allele-specific oligonucleotide hybridization to distinguish between these two mutant alleles. The intron 7 + 1 mutation has been detected in three unrelated families. Obligate heterozygotes for the intron 7 + 1 mutation were born in the Saguenay-Lac-St-Jean region of Quebec. The most recent ancestors common to obligate carriers of this mutation were from the Charlevoix region of the province of Quebec. This mutation thus has a different geographic centre of diffusion and is probably less common than the exon 1 deletion TSD mutation in French Canadians. Neither mutation has been detected in France, the ancestral homeland of French Canada.. 
1483696	52	69	Tay-Sachs disease	Modifier	D013661
1483696	155	172	Tay-Sachs disease	SpecificDisease	D013661
1483696	174	177	TSD	SpecificDisease	D013661
1483696	278	281	TSD	Modifier	D013661
1483696	699	702	TSD	Modifier	D013661
1483696	1369	1372	TSD	Modifier	D013661

10465113|t|Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation.
10465113|a|We have observed over 25 different mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) in association with the recessive disorders achondrogenesis 1B, atelosteogenesis 2, and diastrophic dysplasia. The c862t (R279W) transition is the most common mutation in non-Finnish patients, but in these disorders it is usually combined with other DTDST mutations. We had not seen a case of homozygosity for c862t (R279W) until we analysed DNA from a 36 year old male with tall-normal stature (180 cm) who asked for genetic counselling for suspected multiple epiphyseal dysplasia. He was treated for club foot and hip dysplasia at birth. Skeletal changes consistent with multiple epiphyseal dysplasia, with the peculiar finding of a double layered patella, were recognised during childhood. Cleft palate, swelling of the ear pinna, and hitch hiker thumb were absent. He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders. Counselling was given for a recessive disorder, thereby considerably reducing the probability of affected offspring. Multiple epiphyseal dysplasia is more frequently caused by dominant mutations in the COMP (EDM1, McKusick 132400) and COL9A2 genes (EDM2, McKusick 600204). A few other patients and families with features similar to our proband have been described previously and considered to have autosomal recessive MED (EDM4, McKusick 226900). This observation confirms the existence of this entity and assigns it to the phenotypic spectrum associated with mutations at the DTDST locus.. 
10465113	22	51	multiple epiphyseal dysplasia	SpecificDisease	D010009
10465113	73	82	club foot	SpecificDisease	D003025
10465113	88	110	double layered patella	DiseaseClass	C535504
10465113	191	212	diastrophic dysplasia	Modifier	C536170
10465113	271	290	recessive disorders	DiseaseClass	D030342
10465113	291	309	achondrogenesis 1B	SpecificDisease	C536016
10465113	311	329	atelosteogenesis 2	SpecificDisease	C535395
10465113	335	356	diastrophic dysplasia	SpecificDisease	C536170
10465113	699	728	multiple epiphyseal dysplasia	SpecificDisease	D010009
10465113	749	758	club foot	SpecificDisease	D003025
10465113	763	776	hip dysplasia	SpecificDisease	D006618
10465113	820	849	multiple epiphyseal dysplasia	SpecificDisease	D010009
10465113	882	904	double layered patella	DiseaseClass	C535504
10465113	940	952	Cleft palate	SpecificDisease	D002972
10465113	954	979	swelling of the ear pinna	DiseaseClass	D004427
10465113	985	1002	hitch hiker thumb	DiseaseClass	C536903
10465113	1189	1204	DTDST disorders	SpecificDisease	D030342
10465113	1234	1252	recessive disorder	DiseaseClass	D030342
10465113	1323	1352	Multiple epiphyseal dysplasia	SpecificDisease	D010009
10465113	1414	1418	EDM1	SpecificDisease	OMIM:132400
10465113	1455	1459	EDM2	SpecificDisease	OMIM:600204
10465113	1624	1627	MED	SpecificDisease	D010009
10465113	1629	1633	EDM4	SpecificDisease	OMIM:226900

8098180|t|Myotonic dystrophy: size- and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism.
8098180|a|Myotonic dystrophy (DM) is a progressive neuromuscular disorder which results from elongations of an unstable (CTG) n repeat, located in the 3 untranslated region of the DM gene. A correlation has been demonstrated between the increase in the repeat number of this sequence and the severity of the disease. However, the clinical status of patients cannot be unambiguously ascertained solely on the basis of the number of CTG repeats. Moreover, the exclusive maternal inheritance of the congenital form remains unexplained. Our observation of differently sized repeats in various DM tissues from the same individual may explain why the size of the mutation observed in lymphocytes does not necessarily correlate with the severity and nature of symptoms. Through a molecular and genetic study of 142 families including 418 DM patients, we have investigated the dynamics of the CTG repeat meiotic instability. A positive correlation between the size of the repeat and the intergenerational enlargement was observed similarly through male and female meioses for < or = 0. 5-kb CTG sequences. Beyond 0. 5 kb, the intergenerational variation was more important through female meioses, whereas a tendency to compression was observed almost exclusively in male meioses, for > or = 1. 5-kb fragments. This implies a size- and sex-dependent meiotic instability. Moreover, segregation analysis supports the hypothesis of a maternal as well as a familial predisposition for the occurrence of the congenital form. Finally, this analysis reveals a significant excess of transmitting grandfathers partially accounted for by increased fertility in affected males 
8098180	0	18	Myotonic dystrophy	SpecificDisease	D009223
8098180	104	122	Myotonic dystrophy	SpecificDisease	D009223
8098180	124	126	DM	SpecificDisease	D009223
8098180	145	167	neuromuscular disorder	DiseaseClass	D009468
8098180	274	276	DM	Modifier	D009223
8098180	683	685	DM	Modifier	D009223
8098180	925	927	DM	Modifier	D009223

1517503|t|Fatal pyoderma gangrenosum in association with C7 deficiency.
1517503|a|Although pyoderma gangrenosum (PG) is often associated with systemic diseases, it has not been reported in association with congenital complement deficiencies. We describe an aggressive and ultimately fatal case of PG in a patient with a congenital C7 deficiency. Deficiencies of C7 can be associated with decreased neutrophil chemotaxis, phagocytosis, and opsonization, similar to the immunologic abnormalities described in patients with PG. Our patients decreased complement level, if not directly related to the development of PG, may have contributed to the aggressive nature of her disease.. 
1517503	6	26	pyoderma gangrenosum	SpecificDisease	D017511
1517503	47	60	C7 deficiency	SpecificDisease	OMIM:610102
1517503	71	91	pyoderma gangrenosum	SpecificDisease	D017511
1517503	93	95	PG	SpecificDisease	D017511
1517503	122	139	systemic diseases	DiseaseClass	D034721
1517503	186	220	congenital complement deficiencies	DiseaseClass	D007153
1517503	277	279	PG	SpecificDisease	D017511
1517503	311	324	C7 deficiency	SpecificDisease	OMIM:610102
1517503	326	344	Deficiencies of C7	SpecificDisease	OMIM:610102
1517503	448	473	immunologic abnormalities	DiseaseClass	D007153
1517503	501	503	PG	SpecificDisease	D017511
1517503	592	594	PG	SpecificDisease	D017511

8589715|t|Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy.
8589715|a|Mutations in the STA gene at the Xq28 locus have been found in patients with X-linked Emery-Dreifuss muscular dystrophy (EDMD). This gene encodes a hitherto unknown protein named emerin. To elucidate the subcellular localization of emerin, we raised two antisera against synthetic peptide fragments predicted from emerin cDNA. Using both antisera, we found positive nuclear membrane staining in skeletal, cardiac and smooth muscles in the normal controls and in patients with neuromuscular diseases other than EDMD. In contrast, a deficiency in immunofluorescent staining of skeletal and cardiac muscle from EDMD patients was observed. A 34 kD protein is immunoreactive with the antisera--the protein is equivalent to that predicted for emerin. Together, our findings suggest the specific deficiency of emerin in the nuclear membrane of muscle cells in patients with EDMD.. 
8589715	0	17	Emerin deficiency	SpecificDisease	D020389
8589715	59	92	Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
8589715	171	213	X-linked Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
8589715	215	219	EDMD	SpecificDisease	D020389
8589715	570	592	neuromuscular diseases	DiseaseClass	D009468
8589715	604	608	EDMD	SpecificDisease	D020389
8589715	702	706	EDMD	Modifier	D020389
8589715	883	903	deficiency of emerin	SpecificDisease	D020389
8589715	961	965	EDMD	SpecificDisease	D020389

7652577|t|A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma.
7652577|a|A mutated cyclin-dependent kinase 4 (CDK4) was identified as a tumor-specific antigen recognized by HLA-A2. 1-restricted autologous cytolytic T lymphocytes (CTLs) in a human melanoma. The mutated CDK4 allele was present in autologous cultured melanoma cells and metastasis tissue, but not in the patients lymphocytes. The mutation, an arginine-to-cysteine exchange at residue 24, was part of the CDK4 peptide recognized by CTLs and prevented binding of the CDK4 inhibitor p16INK4a, but not of p21 or of p27KIP1. The same mutation was found in one additional melanoma among 28 melanomas analyzed. These results suggest that mutation of CDK4 can create a tumor-specific antigen and can disrupt the cell-cycle regulation exerted by the tumor suppressor p16INK4a.. 
7652577	82	90	melanoma	SpecificDisease	D008545
7652577	155	160	tumor	Modifier	D009369
7652577	266	274	melanoma	SpecificDisease	D008545
7652577	335	343	melanoma	Modifier	D008545
7652577	650	658	melanoma	SpecificDisease	D008545
7652577	668	677	melanomas	SpecificDisease	D008545
7652577	745	750	tumor	Modifier	D009369
7652577	825	830	tumor	Modifier	D009369

10487710|t|Molecular analysis in familial neurohypophyseal diabetes insipidus: early diagnosis of an asymptomatic carrier.
10487710|a|Familial neurohypophyseal diabetes insipidus (FNDI) is an inherited deficiency of the hormone arginine vasopressin (AVP) and is transmitted as an autosomal dominant trait. In the present study we have analyzed the AVP-neurophysin II (AVP-NPII) gene in a Spanish kindred. Studies were performed on seven members (four clinically affected) of the family. Patients were diagnosed at the Hospital Universitario Gregorio Maranon (Madrid, Spain). The entire coding region of the AVP-NPII gene of all family members was amplified by PCR and sequenced. All affected individuals presented a missense mutation (G1757-- > A) that replaces glycine at position 23 with arginine within the NPII domain. The substitution was confirmed by restriction endonuclease analysis and was present in heterozygosis. Additionally, one of the asymptomatic relatives (a girl 8 months old at the time of study) was identified as carrier of the same mutation and developed the disease 3 months later. The alteration found in the second exon of the gene in this family seems to be responsible for the disease, as all individuals harboring the mutation had been previously diagnosed or have eventually developed FNDI. Identification of the molecular defect underlying FNDI in affected families is a powerful tool for early asymptomatic diagnosis in infants.. 
10487710	22	66	familial neurohypophyseal diabetes insipidus	SpecificDisease	OMIM:125700
10487710	112	156	Familial neurohypophyseal diabetes insipidus	SpecificDisease	OMIM:125700
10487710	158	162	FNDI	SpecificDisease	OMIM:125700
10487710	180	226	deficiency of the hormone arginine vasopressin	DiseaseClass	OMIM:125700
10487710	1292	1296	FNDI	SpecificDisease	OMIM:125700
10487710	1348	1352	FNDI	SpecificDisease	OMIM:125700

3572301|t|Sialophorin, a surface sialoglycoprotein defective in the Wiskott-Aldrich syndrome, is involved in human T lymphocyte proliferation.
3572301|a|The mAb L10 was used to determine the distribution and the function of sialophorin, the heavily glycosylated surface molecule that is deficient/defective in lymphocytes of patients with the X-linked immunodeficiency Wiskott-Aldrich syndrome. Dual-parameter FACS analysis indicated that sialophorin is expressed on CD4 + and CD8 + lymphocytes, on a subpopulation of peripheral blood B lymphocytes, on all thymocytes, and on a subpopulation of bone marrow cells. Functional studies demonstrated that L10 mAb stimulates the proliferation of peripheral blood T lymphocytes as measured by stimulation of [3H] thymidine incorporation. The time course and magnitude of increased [3H] thymidine incorporation by T lymphocytes in response to L10 mAb paralleled that induced by anti-CD3 mAb. Effective stimulation was dependent on the presence of monocytes and the Fc portion of L10 mAb. Stimulation of lymphocytes by L10, like stimulation by anti-CD3 mAb, involves increased expression of 4F2, HLA-DR, and IL-2-R. These observations suggest that sialophorin functions in T cell activation.. 
3572301	58	82	Wiskott-Aldrich syndrome	SpecificDisease	D014923
3572301	323	373	X-linked immunodeficiency Wiskott-Aldrich syndrome	SpecificDisease	D014923

10732811|t|Characterization of the rat spinocerebellar ataxia type 3 gene.
10732811|a|Machado-Joseph disease (MJD) belongs to a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive cerebellar ataxia. The disease-causing mutation has recently been identified as an unstable and expanded (CAG) n trinucleotide repeat in a novel gene of unknown function. In Caucasians, repeat expansions in the MJD1 gene have also been found in patients with the clinically distinct autosomal dominant spinocerebellar ataxia type 3 (SCA3). In order to gain insight into the biology of the MJD1/SCA3 gene we cloned the rat homologue and studied its expression. The rat and human ataxin-3 genes are highly homologous with an overall sequence identity of approximately 88%. However, the C-terminal end of the putative protein differs strongly from the published human sequence. The (CAG) n block in the rat cDNA consists of just three interrupted units suggesting that a long polyglutamine stretch is not essential for the normal function of the ataxin-3 protein in rodents. The expression pattern of the SCA3 gene in various rat and human tissues was investigated by Northern blot analyses. The mature transcript is approximately 6 kb in length. In rat testis, a smaller transcript of 1. 3 kb was identified. Transcription of rsca3 was detected in most rat tissues including brain. Analyzing the expression level of the SCA3 gene in several human brain sections revealed no significant higher mRNA level in regions predominantly affected in MJD. Thus additional molecules and/or regulatory events are necessary to explain the exclusive degeneration of certain brain areas. 
10732811	64	86	Machado-Joseph disease	SpecificDisease	D017827
10732811	88	91	MJD	SpecificDisease	D017827
10732811	156	183	neurodegenerative disorders	DiseaseClass	D019636
10732811	201	230	progressive cerebellar ataxia	SpecificDisease	D002524
10732811	515	544	spinocerebellar ataxia type 3	SpecificDisease	D017827
10732811	546	550	SCA3	SpecificDisease	D017827
10732811	1552	1555	MJD	SpecificDisease	D017827
10732811	1647	1682	degeneration of certain brain areas	DiseaseClass	D001927

7630639|t|The alveolar rhabdomyosarcoma PAX3/FKHR fusion protein is a transcriptional activator.
7630639|a|Chimeric transcription factors, created by gene fusions as the result of chromosomal translocations, have been implicated in the pathogenesis of several pathologically disparate solid tumors. The PAX3/FKHR fusion gene, formed by a t (2; 13) (q35; q14) in alveolar rhabdomyosarcoma, encodes a hybrid protein that contains both PAX3 DNA binding domains, the paired box and homeodomain, linked to the bisected DNA binding domain of FKHR, a member of the forkhead family of transcription factors. Here we report that PAX3 and PAX3/FKHR display similar, but not identical transactivation activities when tested with model Pax recognition sequences. No functional role could be ascribed solely to the residual FKHR binding domain present in the fusion protein, but FKHR was found to contribute a strong carboxyl terminal activation domain replacing the one located in the unrearranged PAX3 gene. We show that the native PAX3/FKHR protein present in tumor cells with this translocation has transcriptional characteristics similar to the in vitro expressed protein. The ability of the PAX3/FKHR hybrid protein to bind DNA in a sequence specific manner and to transactivate the expression of artificial reporter genes suggests that its aberrant expression could subvert the transcriptional programs that normally control the growth, differentiation, and survival of primitive myogenic precursors in vivo.. 
7630639	4	29	alveolar rhabdomyosarcoma	Modifier	D018232
7630639	265	277	solid tumors	DiseaseClass	D009369
7630639	342	367	alveolar rhabdomyosarcoma	SpecificDisease	D018232
7630639	1030	1035	tumor	Modifier	D009369

7581380|t|Myotonia levior is a chloride channel disorder.
7581380|a|The group of dominant non-dystrophic myotonias, comprising disorders characterized by clinically similar forms of myogenic muscle stiffness, is genetically inhomogeneous. Dominant myotonia congenita (Thomsens disease) is linked to CLCN1, the gene encoding the major muscle chloride channel, localized on chromosome 7q35. In contrast, dominant myotonias sensitive to potassium are caused by point mutations in SCN4A on chromosome 17q, the gene for the alpha subunit of the adult skeletal muscle sodium channel. No linkage or molecular genetic data are as yet available on myotonia levior characterized by milder symptoms and later onset of myotonia than in Thomsens disease, and absence of muscle hypertrophy. We report a CLCN1 Gln-552-Arg substitution for a family with dominant inheritance previously diagnosed to have myotonia levior. Thus, this disorder appears as a variant of Thomsens disease due to mutations leading to low clinical expressivity. In addition, we report a novel Ile-290-Met CLCN1 mutation for a typical Thomsen pedigree. In another family previously diagnosed as having Thomsens disease, we unexpectedly found a CLCN1 14 bp deletion known to cause recessive myotonia, and a rare Trp-118-Gly polymorphism.. 
7581380	0	15	Myotonia levior	SpecificDisease	D009224
7581380	21	46	chloride channel disorder	DiseaseClass	OMIM:160800
7581380	61	94	dominant non-dystrophic myotonias	DiseaseClass	C536245
7581380	219	246	Dominant myotonia congenita	SpecificDisease	D009224
7581380	248	264	Thomsens disease	SpecificDisease	D009224
7581380	382	400	dominant myotonias	DiseaseClass	D009224
7581380	619	634	myotonia levior	SpecificDisease	D009224
7581380	687	695	myotonia	DiseaseClass	D009222
7581380	704	720	Thomsens disease	SpecificDisease	D009224
7581380	737	755	muscle hypertrophy	SpecificDisease	C536106
7581380	868	883	myotonia levior	SpecificDisease	D009224
7581380	929	945	Thomsens disease	SpecificDisease	D009224
7581380	1140	1156	Thomsens disease	SpecificDisease	D009224
7581380	1218	1236	recessive myotonia	DiseaseClass	D009224

8282802|t|Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin: cholesterol acyltransferase deficiency and fish-eye disease.
8282802|a|Classic (complete) lecithin  cholesterol acyltransferase (LCAT) deficiency and Fish-eye disease (partial LCAT deficiency) are genetic syndromes associated with markedly decreased plasma levels of high density lipoprotein (HDL) cholesterol but not with an increased risk of atherosclerotic cardiovascular disease. We investigated the metabolism of the HDL apolipoproteins (apo) apoA-I and apoA-II in a total of five patients with LCAT deficiency, one with classic LCAT deficiency and four with Fish-eye disease. Plasma levels of apoA-II were decreased to a proportionately greater extent (23% of normal) than apoA-I (30% of normal). In addition, plasma concentrations of HDL particles containing both apoA-I and apoA-II (LpA-I  A-II) were much lower (18% of normal) than those of particles containing only apoA-I (LpA-I) (51% of normal). The metabolic basis for the low levels of apoA-II and LpA-I  A-II was investigated in all five patients using both exogenous radiotracer and endogenous stable isotope labeling techniques. The mean plasma residence time of apoA-I was decreased at 2. 08 +/- 0. 27 d (controls 4. 74 +/- 0. 65 days); however, the residence time of apoA-II was even shorter at 1. 66 +/- 0. 24 d (controls 5. 25 +/- 0. 61 d). In addition, the catabolism of apoA-I in LpA-I  A-II was substantially faster than that of apoA-I in LpA-I. In summary, genetic syndromes of either complete or partial LCAT deficiency result in low levels of HDL through preferential hypercatabolism of apoA-II and HDL particles containing apoA-II. Because LpA-I has been proposed to be more protective than LpA-I  A-II against atherosclerosis, this selective effect on the metabolism of LpA-I  A-II may provide a potential explanation why patients with classic LCAT deficiency and Fish-eye disease are not at increased risk for premature atherosclerosis despite markedly decreased levels of HDL cholesterol and apoA-I 
8282802	135	173	cholesterol acyltransferase deficiency	SpecificDisease	D007863
8282802	178	194	fish-eye disease	SpecificDisease	D007863
8282802	196	270	Classic (complete) lecithin  cholesterol acyltransferase (LCAT) deficiency	CompositeMention	D007863
8282802	275	291	Fish-eye disease	SpecificDisease	D007863
8282802	293	316	partial LCAT deficiency	SpecificDisease	D007863
8282802	469	507	atherosclerotic cardiovascular disease	SpecificDisease	D050197
8282802	625	640	LCAT deficiency	SpecificDisease	D007863
8282802	651	674	classic LCAT deficiency	SpecificDisease	D007863
8282802	689	705	Fish-eye disease	SpecificDisease	D007863
8282802	1585	1620	complete or partial LCAT deficiency	CompositeMention	D007863
8282802	1814	1829	atherosclerosis	SpecificDisease	D050197
8282802	1940	1963	classic LCAT deficiency	SpecificDisease	D007863
8282802	1968	1984	Fish-eye disease	SpecificDisease	D007863
8282802	2025	2040	atherosclerosis	SpecificDisease	D050197

10598803|t|The identical 5' splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect.
10598803|a|Inherited mutations of the APC gene predispose carriers to multiple adenomatous polyps of the colon and rectum and to colorectal cancer. Mutations located at the extreme 5 end of the APC gene, however, are associated with a less severe disease known as attenuated adenomatous polyposis coli (AAPC). Many individuals with AAPC develop relatively few colorectal polyps but are still at high risk for colorectal cancer. We report here the identification of a 5 APC germline mutation in five separately ascertained AAPC families from Newfoundland, Canada. This disease-causing mutation is a single basepair change (G to A) in the splice-acceptor region of APC intron 3 that creates a mutant RNA without exon 4 of APC. The observation of the same APC mutation in five families from the same geographic area demonstrates a founder effect. Furthermore, the identification of this germline mutation strengthens the correlation between the 5 location of an APC disease-causing mutation and the attenuated polyposis phenotype.. 
10598803	55	69	attenuated APC	Modifier	C538265
10598803	155	158	APC	Modifier	D011125
10598803	196	238	adenomatous polyps of the colon and rectum	CompositeMention	D011125
10598803	246	263	colorectal cancer	SpecificDisease	D015179
10598803	311	314	APC	Modifier	D011125
10598803	381	418	attenuated adenomatous polyposis coli	SpecificDisease	C538265
10598803	420	424	AAPC	SpecificDisease	C538265
10598803	449	453	AAPC	SpecificDisease	C538265
10598803	477	494	colorectal polyps	SpecificDisease	D003111
10598803	526	543	colorectal cancer	SpecificDisease	D015179
10598803	586	589	APC	Modifier	D011125
10598803	639	643	AAPC	Modifier	C538265
10598803	780	783	APC	Modifier	D011125
10598803	870	873	APC	Modifier	D011125
10598803	1076	1079	APC	Modifier	D011125
10598803	1113	1133	attenuated polyposis	Modifier	C538265

1973404|t|Linkage of aspartylglucosaminuria (AGU) to marker loci on the long arm of chromosome 4.
1973404|a|Aspartylglucosaminuria (AGU) is caused by deficient activity of the enzyme aspartylglucosaminidase (AGA). The structural gene for AGA has been assigned to the region 4q21-qter of chromosome 4. We have studied the map position of the AGU locus in relation to other marker loci on the long arm of chromosome 4 using linkage analyses. Restriction fragment length polymorphism alleles for the ADH2, ADH3, EGF, FG alpha and FG beta loci and blood group antigens for the MNS locus were determined in a panel of 12 Finnish AGU families. The heterozygous family members were identified by reduced activity of AGA in lymphocytes. Linkage studies were performed using both pairwise and multipoint analyses. Loose linkage of the AGU locus to the FG and MNS loci was observed (z = 1. 16, z = 1. 39, respectively). Multipoint analysis to the fixed map [ADH- (0. 03) -EGF- (0. 35) -FG- (0. 11) -MNS] suggests that the location of the AGU locus is 0. 05-0. 30 recombination units distal to MNS (z = 3. 03). The order cen-ADH-EGF-FG-MNS-AGU is 35 times more likely than the next best order cen-ADH-EGF-AGU-FG-MNS. 
1973404	11	33	aspartylglucosaminuria	SpecificDisease	D054880
1973404	35	38	AGU	SpecificDisease	D054880
1973404	88	110	Aspartylglucosaminuria	SpecificDisease	D054880
1973404	112	115	AGU	SpecificDisease	D054880
1973404	604	607	AGU	Modifier	D054880
1973404	806	809	AGU	Modifier	D054880

1671851|t|Linkage analysis in X-linked adrenoleukodystrophy and application in post- and prenatal diagnosis.
1671851|a|We have performed linkage analysis with the DNA markers DXS52 and the clotting factor VIII gene (F8C), in several large families with X-linked adrenoleukodystrophy (ALD). The tight linkage to DXS52 could be extended giving a maximal LOD score of 22. 5 at 1 cM. F8C was also tightly linked to ALD with a maximal LOD score of 7. 8 without recombination. Multipoint linkage analysis with the markers DXS304, DXS52, and F8C indicated that both the gene for ALD and for F8C are distal to DXS52. In four patients with ALD, no major structural rearrangement in the Xqter region was observed; in particular, there were no abnormalities in the vision blindness genes. DNA analysis appeared to be of use in determination of the carrier status of females at risk, for the determination of the origin of the mutation in a particular family, and for prenatal diagnosis.
1671851	20	49	X-linked adrenoleukodystrophy	SpecificDisease	D000326
1671851	233	262	X-linked adrenoleukodystrophy	SpecificDisease	D000326
1671851	264	267	ALD	SpecificDisease	D000326
1671851	391	394	ALD	SpecificDisease	D000326
1671851	552	555	ALD	SpecificDisease	D000326
1671851	611	614	ALD	SpecificDisease	D000326
1671851	713	756	abnormalities in the vision blindness genes	DiseaseClass	D003117

10090890|t|Multicentric origin of hemochromatosis gene (HFE) mutations.
10090890|a|Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, > 80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1% -2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies > 5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends </= 6 Mb, suggesting that this mutation has arisen during the past 2, 000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending </= 700 kb. Here we report the finding of the H63D and C282Y mutations on new haplotypes. In Sri Lanka we have found H63D on three new haplotypes and have found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island. These results suggest that the HFE gene has been the subject of selection pressure. These selection pressures could be due to infectious diseases, environmental conditions,  or other genetic disorders such as anemia.
10090890	23	38	hemochromatosis	Modifier	D006432
10090890	61	84	Genetic hemochromatosis	SpecificDisease	D006432
10090890	86	88	GH	SpecificDisease	D006432
10090890	193	195	GH	Modifier	D006432
10090890	351	353	GH	Modifier	D006432
10090890	1467	1486	infectious diseases	DiseaseClass	D003141
10090890	1524	1541	genetic disorders	DiseaseClass	D030342
10090890	1550	1556	anemia	DiseaseClass	D000740

3563511|t|Identification and localization of mutations at the Lesch-Nyhan locus by ribonuclease A cleavage.
3563511|a|Many mutations leading to human disease are the result of single DNA base pair changes that cannot be identified by Southern analysis. This has prompted the development of alternative assays for point mutation detection. The recently described ribonuclease A cleavage procedure, with a polyuridylic acid-paper affinity chromatography step, has been used to identify the mutational lesions in the hypoxanthine phosphoribosyltransferase (HPRT) messenger RNAs of patients with Lesch-Nyhan syndrome. Distinctive ribonuclease A cleavage patterns were identified in messenger RNA from 5 of 14 Lesch-Nyhan patients who were chosen because no HPRT Southern or Northern blotting pattern changes had been found. This approach now allows HPRT mutation detection in 50 percent of the cases of Lesch-Nyhan syndrome. The polyuridylic acid-paper affinity procedure provides a general method for analysis of low abundance messenger RNAs.. 
3563511	52	63	Lesch-Nyhan	Modifier	D007926
3563511	572	592	Lesch-Nyhan syndrome	SpecificDisease	D007926
3563511	685	696	Lesch-Nyhan	Modifier	D007926
3563511	879	899	Lesch-Nyhan syndrome	SpecificDisease	D007926

10364520|t|MEFV-Gene analysis in armenian patients with Familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications.
10364520|a|Familial Mediterranean fever (FMF) is a recessively inherited disorder that is common in patients of Armenian ancestry. To date, its diagnosis, which can be made only retrospectively, is one of exclusion, based entirely on nonspecific clinical signs that result from serosal inflammation and that may lead to unnecessary surgery. Renal amyloidosis, prevented by colchicine, is the most severe complication of FMF, a disorder associated with mutations in the MEFV gene. To evaluate the diagnostic and prognostic value of MEFV-gene analysis, we investigated 90 Armenian FMF patients from 77 unrelated families that were not selected through genetic-linkage analysis. Eight mutations, one of which (R408Q) is new, were found to account for 93% of the 163 independent FMF alleles, with both FMF alleles identified in 89% of the patients. In several instances, family studies provided molecular evidence for pseudodominant transmission and incomplete penetrance of the disease phenotype. The M694V homozygous genotype was found to be associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes (P =. 0002 and P =. 006, respectively). The demonstration of both the diagnostic and prognostic value of MEFV analysis and particular modes of inheritance should lead to new ways for management of FMF-including genetic counseling and therapeutic decisions in affected families.
10364520	45	73	Familial Mediterranean fever	SpecificDisease	D010505
10364520	195	223	Familial Mediterranean fever	SpecificDisease	D010505
10364520	225	228	FMF	SpecificDisease	D010505
10364520	235	265	recessively inherited disorder	DiseaseClass	D030342
10364520	462	482	serosal inflammation	SpecificDisease	D007249
10364520	525	542	Renal amyloidosis	SpecificDisease	C538249
10364520	604	607	FMF	SpecificDisease	D010505
10364520	763	766	FMF	Modifier	D010505
10364520	959	962	FMF	Modifier	D010505
10364520	982	985	FMF	Modifier	D010505
10364520	1263	1280	renal amyloidosis	SpecificDisease	C538249
10364520	1285	1294	arthritis	SpecificDisease	D001168

7568002|t|Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies.
7568002|a|The Huntington disease (HD) phenotype is associated with expansion of a trinucleotide repeat in the IT15 gene, which is predicted to encode a 348-kDa protein named huntington. We used polyclonal and monoclonal anti-fusion protein antibodies to identify native huntingtin in rat, monkey, and human. Western blots revealed a protein with the expected molecular weight which is present in the soluble fraction of rat and monkey brain tissues and lymphoblastoid cells from control cases. In lymphoblastoid cell lines from juvenile-onset heterozygote HD cases, both normal and mutant huntingtin are expressed, and increasing repeat expansion leads to lower levels of the mutant protein. Immunocytochemistry indicates that huntingtin is located in neurons throughout the brain, with the highest levels evident in larger neurons. In the human striatum, huntingtin is enriched in a patch-like distribution, potentially corresponding to the first areas affected in HD. Subcellular localization of huntingtin is consistent with a cytosolic protein primarily found in somatodendritic regions. Huntingtin appears to particularly associate with microtubules, although some is also associated with synaptic vesicles. On the basis of the localization of huntingtin in association with microtubules, we speculate that the mutation impairs the cytoskeletal anchoring or transport of mitochondria, vesicles, or other organelles or molecules.. 
7568002	132	150	Huntington disease	Modifier	D006816
7568002	152	154	HD	Modifier	D006816
7568002	674	676	HD	Modifier	D006816
7568002	1084	1086	HD	SpecificDisease	D006816

1319838|t|Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients.
1319838|a|Recently we have isolated the adenomatous polyposis coli (APC) gene which causes familial adenomatous polyposis (FAP), and its germ-line mutations in a substantial number of FAP patients have been identified. On the basis of this information, we compared the location of germ-line mutations in the APC gene in 22 unrelated patients (12 of whom have been reported previously) with the number of colorectal polyps developed in FAP patients; 17 were sparse types and five were profuse types. All but one of the mutations were considered to cause truncation of the gene product by frame-shift due to deletion (14 cases) or nonsense mutation (seven cases). The location of the germ-line mutations seems to correlate with the two clinical types; germ-line mutations in five FAP patients with profuse polyps were observed between codon 1250 and codon 1464, whereas mutations in 17 FAP patients with fewer polyps were observed in the other regions of the APC gene. The result suggests that the number of colorectal polyps in FAP patients may be associated with a difference in the stability or biological function of the truncated APC protein.. 
1319838	63	66	APC	Modifier	D011125
1319838	90	107	colorectal polyps	SpecificDisease	D003111
1319838	111	141	familial adenomatous polyposis	Modifier	D011125
1319838	182	208	adenomatous polyposis coli	Modifier	D011125
1319838	210	213	APC	Modifier	D011125
1319838	233	263	familial adenomatous polyposis	SpecificDisease	D011125
1319838	265	268	FAP	SpecificDisease	D011125
1319838	326	329	FAP	Modifier	D011125
1319838	450	453	APC	Modifier	D011125
1319838	546	563	colorectal polyps	SpecificDisease	D003111
1319838	577	580	FAP	Modifier	D011125
1319838	920	923	FAP	Modifier	D011125
1319838	946	952	polyps	DiseaseClass	D011127
1319838	1026	1029	FAP	Modifier	D011125
1319838	1050	1056	polyps	DiseaseClass	D011127
1319838	1099	1102	APC	Modifier	D011125
1319838	1148	1165	colorectal polyps	SpecificDisease	D003111
1319838	1169	1172	FAP	Modifier	D011125
1319838	1275	1278	APC	Modifier	D011125

10480348|t|Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations.
10480348|a|The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD/BMD) shows a marked reduction in b-wave amplitude. Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations upon the phenotype  mice with 5 defects of dystrophin have normal ERGs, those with defects in the central region have a normal b-wave amplitude associated with prolonged implicit times for both the b-wave and oscillatory potentials, and mice with 3 defects have a phenotype similar to that seen in  DMD/BMD patients. The mouse studies suggest a key role for the carboxyl terminal dystrophin isoform, Dp260, in retinal electrophysiology. We have undertaken a systematic evaluation of DMD/BMD patients through clinical examination and review of the literature in order to determine whether the position-specific effects of mutations noted in the mouse are present in man. We have found that, in man, a wider variation of DMD defects correlate with reductions in the b-wave amplitude. Individuals with normal ERGs have mutations predominantly located 5 of the transcript initiation site of Dp260. Our results suggest that the most important determinant in the ERG b-wave phenotype is the mutation position, rather than muscle disease severity. Forty-six per cent of patients with mutations 5 of the Dp260 transcript start site have abnormal ERGs, as opposed to 94% with more distal mutations. The human genotype-phenotype correlations are consistent with a role for Dp260 in normal retinal electrophysiology and may also reflect the expression of other C-terminal dystrophin isoforms and their contributions to retinal signal transmission.. 
10480348	0	34	Duchenne/Becker muscular dystrophy	CompositeMention	D020388|C537666
10480348	178	216	Duchenne and Becker muscular dystrophy	CompositeMention	D020388|C537666
10480348	218	221	DMD	SpecificDisease	D020388
10480348	222	225	BMD	SpecificDisease	C537666
10480348	320	323	DMD	SpecificDisease	D020388
10480348	671	674	DMD	Modifier	D020388
10480348	675	678	BMD	Modifier	C537666
10480348	855	858	DMD	Modifier	D020388
10480348	859	862	BMD	Modifier	C537666
10480348	1091	1102	DMD defects	DiseaseClass	D020388
10480348	1388	1402	muscle disease	Modifier	D009135

1610789|t|Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase.
1610789|a|We report here the molecular characterization of two galactosemia mutations, L74P and F171S, and one polymorphism, S135L, in human galactose-1-phosphate uridyltransferase (GALT). Both galactosemia mutations result in reduced enzymatic activity when reconstructed in the cDNA and overexpressed. The polymorphism, in contrast, has near normal activity. Both mutations affect evolutionarily conserved residues, suggesting that they are functionally important, while the polymorphism occurs in a nonconserved domain which is presumably not critical for enzymatic function. The F171S mutation is close to the putative active-site nucleophile. Our data further support the notion of molecular heterogeneity of galactosemia and suggest that galactosemia mutations and GALT polymorphisms may be useful tools in highlighting different functional domains in human GALT.. 
1610789	34	46	galactosemia	Modifier	D005693
1610789	227	239	galactosemia	Modifier	D005693
1610789	358	370	galactosemia	Modifier	D005693
1610789	878	890	galactosemia	SpecificDisease	D005693
1610789	908	920	galactosemia	Modifier	D005693

10777718|t|Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations.
10777718|a|Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder, results from the deficient activity of acid beta-glucosidase (GBA). Type 1 disease is panethnic but is more prevalent in individuals of Ashkenazi Jewish (AJ) descent. Of the causative GBA mutations, N370S is particularly frequent in the AJ population, (q approximately. 03), whereas the 84GG insertion (q approximately. 003) occurs exclusively in the Ashkenazim. To investigate the genetic history of these mutations in the AJ population, short tandem repeat (STR) markers were used to map a 9. 3-cM region containing the GBA locus and to genotype 261 AJ N370S chromosomes, 60 European non-Jewish N370S chromosomes, and 62 AJ 84GG chromosomes. A highly conserved haplotype at four markers flanking GBA (PKLR, D1S1595, D1S2721, and D1S2777) was observed on both the AJ chromosomes and the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common to both populations. Of note, the presence of different divergent haplotypes suggested the occurrence of de novo, recurrent N370S mutations. In contrast, a different conserved haplotype at these markers was identified on the 84GG chromosomes, which was unique to the AJ population. On the basis of the linkage disequilibrium (LD) delta values, the non-Jewish European N370S chromosomes had greater haplotype diversity and less LD at the markers flanking the conserved haplotype than did the AJ N370S chromosomes. This finding is consistent with the presence of the N370S mutation in the non-Jewish European population prior to the founding of the AJ population. Coalescence analyses for the N370S and 84GG mutations estimated similar coalescence times, of 48 and 55.5 generations ago, respectively. The results of these studies are consistent with a significant bottleneck occurring in the AJ population during the first millennium, when the population became established in Europe. 
10777718	0	15	Gaucher disease	SpecificDisease	D005776
10777718	108	123	Gaucher disease	SpecificDisease	D005776
10777718	125	127	GD	SpecificDisease	D005776
10777718	150	176	lysosomal storage disorder	DiseaseClass	D016464

8209890|t|Investigation of thermoregulatory characteristics in patients with Prader-Willi syndrome.
8209890|a|A survey instrument is used to assess temperature regulation characteristics in children with Prader-Willi syndrome (PWS) compared to 3 control groups  sibs of PWS patients (SIB), neurodevelopmentally handicapped children (ND), and age and gender matched well children (WC). Significant differences were found between PWS patients, SIB controls, and WC controls in the prevalence of febrile convulsions, fever-associated symptoms, and temperature less than 94 degrees F. No differences were noted in any variable between the PWS patients and the ND controls, suggesting that these abnormalities are not unique to PWS, but can occur in any neurodevelopmentally handicapped individual, further suggesting these do not necessarily reflect syndrome-specific hypothalamic abnormalities.. 
8209890	67	88	Prader-Willi syndrome	SpecificDisease	D011218
8209890	184	205	Prader-Willi syndrome	SpecificDisease	D011218
8209890	207	210	PWS	SpecificDisease	D011218
8209890	250	253	PWS	Modifier	D011218
8209890	270	302	neurodevelopmentally handicapped	Modifier	D009422
8209890	408	411	PWS	Modifier	D011218
8209890	615	618	PWS	Modifier	D011218
8209890	703	706	PWS	SpecificDisease	D011218
8209890	729	761	neurodevelopmentally handicapped	Modifier	D009422
8209890	844	870	hypothalamic abnormalities	DiseaseClass	D007027

7298854|t|Abnormal high density lipoproteins in cerebrotendinous xanthomatosis.
7298854|a|The plasma lipoprotein profiles and high density lipoproteins (HDL) were characterized in patients with the genetic disease cerebrotendinous xanthomatosis (CTX). Abnormalities in the HDL may contribute to their increased atherogenesis and excessive deposits of tissue sterols in the presence of low or low-normal concentrations of plasma cholesterol (165 +/- 25 mg/dl) and low density lipoproteins (LDL). The mean HDL-cholesterol concentration in the CTX plasmas was 14. 5 +/- 3. 2 mg/dl, about one-third the normal value. The low HDL-cholesterol reflects a low concentration and an abnormal lipid composition of the plasma HDL. Relative to normal HDL, the cholesteryl esters are low, free cholesterol and phospholipids essentially normal, and triglycerides increased. The ratio of apoprotein (apo) to total cholesterol in the HDL of CTX was two to three times greater than normal. In the CTX HDL, the ratio of apoAI to apoAII was high, the proportion of apoC low, and a normally minor form of apoAI increased relative to other forms. The HDL in electron micrographs appeared normal morphologically and in particle size. The abnormalities in lipoprotein distribution profile and composition of the plasma HDL result from metabolic defects that are not understood but may be linked to the genetic defect in bile acid synthesis in CTX. As a consequence, it is probable that the normal functions of the HDL, possibly including modulation of LDL-cholesterol uptake and the removal of excess cholesterol from peripheral tissues, are perturbed significantly in this disease.
7298854	38	68	cerebrotendinous xanthomatosis	SpecificDisease	D019294
7298854	178	193	genetic disease	DiseaseClass	D030342
7298854	194	224	cerebrotendinous xanthomatosis	SpecificDisease	D019294
7298854	226	229	CTX	SpecificDisease	D019294
7298854	232	256	Abnormalities in the HDL	DiseaseClass	D052456
7298854	521	524	CTX	Modifier	D019294
7298854	904	907	CTX	SpecificDisease	D019294
7298854	959	962	CTX	Modifier	D019294
7298854	1358	1372	genetic defect	DiseaseClass	D030342
7298854	1399	1402	CTX	SpecificDisease	D019294

10330348|t|Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.
10330348|a|Mutations resulting in defective splicing constitute a significant proportion (30/62 [48%]) of a new series of mutations in the ATM gene in patients with ataxia-telangiectasia (AT) that were detected by the protein-truncation assay followed by sequence analysis of genomic DNA. Fewer than half of the splicing mutations involved the canonical AG splice-acceptor site or GT splice-donor site. A higher percentage of mutations occurred at less stringently conserved sites, including silent mutations of the last nucleotide of exons, mutations in nucleotides other than the conserved AG and GT in the consensus splice sites, and creation of splice-acceptor or splice-donor sites in either introns or exons. These splicing mutations led to a variety of consequences, including exon skipping and, to a lesser degree, intron retention, activation of cryptic splice sites, or creation of new splice sites. In addition, 5 of 12 nonsense mutations and 1 missense mutation were associated with deletion in the cDNA of the exons in which the mutations occurred. No ATM protein was detected by western blotting in any AT cell line in which splicing mutations were identified. Several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA were also observed, suggesting caution in the interpretation of exon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations.. 
10330348	24	45	ataxia-telangiectasia	Modifier	D001260
10330348	250	271	ataxia-telangiectasia	SpecificDisease	D001260
10330348	273	275	AT	SpecificDisease	D001260
10330348	1202	1204	AT	Modifier	D001260

10593994|t|Mutations of the cathepsin C gene are responsible for Papillon-Lefevre syndrome.
10593994|a|Papillon-Lefevre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar hyperkeratosis and severe early onset periodontitis that results in the premature loss of the primary and secondary dentitions. A major gene locus for PLS has been mapped to a 2. 8 cM interval on chromosome 11q14. Correlation of physical and genetic maps of this interval indicate it includes at least 40 ESTs and six known genes including the lysosomal protease cathepsin C gene (CTSC). The CTSC message is expressed at high levels in a variety of immune cells including polymorphonuclear leucocytes, macrophages, and their precursors. By RT-PCR, we found CTSC is also expressed in epithelial regions commonly affected by PLS, including the palms, soles, knees, and oral keratinised gingiva. The 4. 7 kb CTSC gene consists of two exons. Sequence analysis of CTSC from subjects affected with PLS from five consanguineous Turkish families identified four different mutations. An exon 1 nonsense mutation (856C-- > T) introduces a premature stop codon at amino acid 286. Three exon 2 mutations were identified, including a single nucleotide deletion (2692delA) of codon 349 introducing a frameshift and premature termination codon, a 2 bp deletion (2673-2674delCT) that results in introduction of a stop codon at amino acid 343, and a G-- > A substitution in codon 429 (2931G-- > A) introducing a premature termination codon. All PLS patients were homozygous for cathepsin C mutations inherited from a common ancestor. Parents and sibs heterozygous for cathepsin C mutations do not show either the palmoplantar hyperkeratosis or severe early onset periodontitis characteristic of PLS. A more complete understanding of the functional physiology of cathepsin C carries significant implications for understanding normal and abnormal skin development and periodontal disease susceptibility 
10593994	54	79	Papillon-Lefevre syndrome	SpecificDisease	D010214
10593994	81	106	Papillon-Lefevre syndrome	SpecificDisease	D010214
10593994	108	111	PLS	SpecificDisease	D010214
10593994	119	147	autosomal recessive disorder	DiseaseClass	D030342
10593994	165	192	palmoplantar hyperkeratosis	SpecificDisease	D007645
10593994	216	229	periodontitis	SpecificDisease	D010518
10593994	329	332	PLS	SpecificDisease	D010214
10593994	801	804	PLS	SpecificDisease	D010214
10593994	970	973	PLS	SpecificDisease	D010214
10593994	1506	1509	PLS	Modifier	D010214
10593994	1674	1701	palmoplantar hyperkeratosis	SpecificDisease	D007645
10593994	1724	1737	periodontitis	SpecificDisease	D010518
10593994	1756	1759	PLS	SpecificDisease	D010214
10593994	1927	1946	periodontal disease	Modifier	D010510

2910902|t|Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome.
2910902|a|Complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) causes the Lesch-Nyhan syndrome. Previous characterization of a mutant form of HPRT, HPRTYale, from a subject with the Lesch-Nyhan syndrome revealed normal mRNA and protein concentrations, no residual catalytic activity, and cathodal migration upon PAGE. We have cloned and sequenced HPRTYale cDNA. The nucleotide sequence of full-length HPRTYale cDNA revealed a single nucleotide substitution compared with normal HPRT cDNA  G----C at nucleotide position 211. This transversion predicts substitution of arginine for glycine at amino acid position 71, explaining the cathodal migration of HPRTYale. Chou-Fasman secondary structure analysis predicts a change in the probability of beta-turn formation in the region containing the mutation. Inclusion of the bulky arginine side chain in place of glycine probably disrupts protein folding as well. Cloning mutant forms of cDNA allows identification of specific mutations, provides insight into mutational mechanisms, and facilitates structure-function analysis of mutant proteins.. 
2910902	131	151	Lesch-Nyhan syndrome	SpecificDisease	D007926
2910902	162	222	deficiency of hypoxanthine-guanine phosphoribosyltransferase	SpecificDisease	D007926
2910902	241	261	Lesch-Nyhan syndrome	SpecificDisease	D007926
2910902	349	369	Lesch-Nyhan syndrome	SpecificDisease	D007926

2927388|t|Molecular detection of chromosomal translocations that disrupt the putative retinoblastoma susceptibility locus.
2927388|a|A candidate DNA sequence with many of the properties predicted for the retinoblastoma susceptibility (RB1) locus has been cloned (S. H. Friend, R. Bernards, S. Rogelj, R. A. Weinberg, J. M. Rapaport, D. M. Albert, and T. P. Dryja, Nature [London] 323  643-645, 1986). The large size of this gene (ca. 200 kilobases [kb]) and its multiple dispersed exons (Wiggs et al., N. Engl. J. Med. 318  151-157, 1988) complicate molecular screening strategies important in prenatal and presymptomatic diagnosis and in carrier detection. Here we used field inversion gel electrophoresis (FIGE) to construct a restriction map of approximately 1, 000 kb of DNA surrounding the RB1 locus and to detect the translocation breakpoints in three retinoblastoma patients. DNA probes from either the 5 or 3 end of the gene were used to detect a 250-kb EagI restriction fragment in DNA from unaffected individuals. Both probes identified an additional hybridizing fragment in the DNA from each patient, permitting the breakpoints in all three to be mapped within the cloned RB1 gene. Analysis of the breakpoint in one translocation cell line allowed the RB1 gene to be oriented with its 5 end toward the centromere. The 5 end of the gene also appeared to be associated with a clustering of sites for several infrequently cleaving restriction enzymes, indicating the presence of an HpaII tiny fragment island. The detection and mapping of the translocation breakpoints of all three retinoblastoma patients to within the putative RB1 gene substantiated the authenticity of this candidate sequence and demonstrated the utility of FIGE in detecting chromosomal rearrangements affecting this locus. 
2927388	76	90	retinoblastoma	Modifier	D012175
2927388	184	198	retinoblastoma	Modifier	D012175
2927388	838	852	retinoblastoma	Modifier	D012175
2927388	1570	1584	retinoblastoma	Modifier	D012175

1338906|t|Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome.
1338906|a|The Denys-Drash syndrome is characterised by a typical nephropathy, genital abnormalities and also predisposes to the development of Wilms tumor. These patients eventually go into end stage renal failure. A candidate Wilms tumor gene, WT1, from the 11p13 chromosome region has recently been cloned. We have analysed the DNA sequence in constitutional cells from eight patients and have shown heterozygous mutations in six of them. Four of the mutations were in exon 9, all resulting in missense mutations. Three were at nucleotide position 1180 resulting in an arg > trp amino acid change. The other was at position 1186 converting an asp > asn in the predicted resultant protein. One patient had a missense mutation in exon 8, converting an arg > his. A single base pair insertion at nucleotide position 821 in exon 6 resulted in the generation of a premature stop codon in the last patient. We were unable to find a mutation in one patient despite complete sequencing of the genomic sequence of the gene. The last patient carried a constitutional deletion of the 11p13 region and no additional mutation was found. There was no obvious correlation between the type of mutation and phenotypic expression. These results further demonstrate that the WT1 gene is important in both the development of the kidney and the genito-urinary system.. 
1338906	58	78	Denys-Drash syndrome	SpecificDisease	D030321
1338906	84	104	Denys-Drash syndrome	SpecificDisease	D030321
1338906	135	146	nephropathy	DiseaseClass	D007674
1338906	148	169	genital abnormalities	DiseaseClass	D014564
1338906	213	224	Wilms tumor	SpecificDisease	D009396
1338906	270	283	renal failure	SpecificDisease	D051437
1338906	297	308	Wilms tumor	Modifier	D009396

8198124|t|Four novel PEPD alleles causing prolidase deficiency.
8198124|a|Mutations at the PEPD locus cause prolidase deficiency (McKusick 170100), a rare autosomal recessive disorder characterized by iminodipeptiduria, skin ulcers, mental retardation, and recurrent infections. Four PEPD mutations from five severely affected individuals were characterized by analysis of reverse-transcribed, PCR-amplified (RT-PCR) cDNA. We used SSCP analysis on four overlapping cDNA fragments covering the entire coding region of the PEPD gene and detected abnormal SSCP bands for the fragment spanning all or part of exons 13-15 in three of the probands. Direct sequencing of the mutant cDNAs showed a G-- > A, 1342 substitution (G448R) in two patients and a 3-bp deletion (delta E452 or delta E453) in another. In the other two probands the amplified products were of reduced size. Direct sequencing of these mutant cDNAs revealed a deletion of exon 5 in one patient and of exon 7 in the other. Intronic sequences flanking exons 5 and 7 were identified using inverse PCR followed by direct sequencing. Conventional PCR and direct sequencing then established the intron-exon borders of the mutant genomic DNA revealing two splice acceptor mutations  a G-- > C substitution at position -1 of intron 4 and an A-- > G substitution at position -2 of intron 6. Our results indicate that the severe form of prolidase deficiency is caused by multiple PEPD alleles. In this report we attempt to begin the process of describing these alleles and cataloging their phenotypic expression.. 
8198124	32	52	prolidase deficiency	SpecificDisease	D056732
8198124	88	108	prolidase deficiency	SpecificDisease	D056732
8198124	135	163	autosomal recessive disorder	DiseaseClass	D030342
8198124	181	198	iminodipeptiduria	SpecificDisease	D000592
8198124	200	211	skin ulcers	SpecificDisease	D012883
8198124	213	231	mental retardation	DiseaseClass	D008607
8198124	1369	1389	prolidase deficiency	SpecificDisease	D056732

2817003|t|Translocation t(5;11)(q13.1;p13) associated with familial isolated aniridia.
2817003|a|A father and daughter with isolated aniridia were observed to have an apparently balanced, reciprocal translocation involving chromosomes 5 and 11 [t (5; 11) (q13. 1; p13)]. No other clinical characteristics often associated with the deletion of 11p13 were observed in this family. This finding, in association with 3 other instances of single breaks at 11p13 and aniridia, supports the assignment of AN2 to 11p13. 
2817003	58	75	isolated aniridia	SpecificDisease	D015783
2817003	104	121	isolated aniridia	SpecificDisease	D015783
2817003	441	449	aniridia	SpecificDisease	D015783

10382909|t|Genotype-phenotype analysis in X-linked Emery-Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype.
10382909|a|Direct sequencing of the emerin gene in 22 families with Emery-Dreifuss muscular dystrophy (EMD) revealed mutations in 21 (95%), confirming that emerin mutations can be identified in the majority of families with X-linked EMD. Most emerin mutations result in absence of the protein. In this study three mutations (a missense mutation Pro183Thr and two in-frame deletions removing residues 95-99 and 236-241, respectively) were unusual in being associated with expression of mutant protein. The phenotype in these families was compared in detail with the clinical features in cases with typical null mutations. For the in-frame deletions there were no significant differences. In the family with the missense mutation the phenotype was milder. Age at onset was later for first symptoms and for development of ankle contractures and muscle weakness. These findings have diagnostic implications as well as pointing to functionally important regions of the emerin protein.. 
10382909	31	73	X-linked Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10382909	209	242	Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10382909	244	247	EMD	SpecificDisease	D020389
10382909	365	377	X-linked EMD	SpecificDisease	D020389
10382909	960	978	ankle contractures	DiseaseClass	D003286
10382909	983	998	muscle weakness	DiseaseClass	D018908

10947987|t|Asef, a link between the tumor suppressor APC and G-protein signaling.
10947987|a|The adenomatous polyposis coli gene (APC) is mutated in familial adenomatous polyposis and in sporadic colorectal tumors. Here the APC gene product is shown to bind through its armadillo repeat domain to a Rac-specific guanine nucleotide exchange factor (GEF), termed Asef. Endogenous APC colocalized with Asef in mouse colon epithelial cells and neuronal cells. Furthermore, APC enhanced the GEF activity of Asef and stimulated Asef-mediated cell flattening, membrane ruffling, and lamellipodia formation in MDCK cells. These results suggest that the APC-Asef complex may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function.. 
10947987	25	30	tumor	Modifier	D009369
10947987	75	101	adenomatous polyposis coli	Modifier	D011125
10947987	127	157	familial adenomatous polyposis	SpecificDisease	D011125
10947987	174	191	colorectal tumors	SpecificDisease	D015179
10947987	202	205	APC	Modifier	D011125

3600794|t|Localization of the region homologous to the Duchenne muscular dystrophy locus on the mouse X chromosome.
3600794|a|Recent progress has resulted in part of the gene mutated in Duchenne and the milder Becker muscular dystrophies being cloned and has suggested that the gene itself extends over 1, 000 to 2, 000 kilobases (kb). To study how mutations in this gene affect muscle development and integrity, it would be of interest to have available a mouse model of the human disease. The mouse mdx mutation affects muscle and confers a mild dystrophic syndrome, but it is not clear whether this mutation is equivalent to Duchenne/Becker muscular dystrophy in man. Here we describe the use of two sequences from the human Duchenne muscular dystrophy (DMD) gene that cross-hybridize to mouse X-linked sequences to localize the gene homologous to DMD in the mouse. Both sequences map to the region of 10 centimorgan lying between the Tabby (Ta) and St14-1 (DxPas8) loci, close to the phosphorylase b kinase locus (Phk). By analogy with the human X-chromosome, we conclude that the region in the mouse around the G6pd and St14-1 loci may contain two genes corresponding to distinct human myopathies  Emery Dreifuss muscular dystrophy which is known to be closely linked to St14-1 in man and the DMD homologue described here.. 
3600794	45	72	Duchenne muscular dystrophy	Modifier	D020388
3600794	166	217	Duchenne and the milder Becker muscular dystrophies	CompositeMention	D020388|C537666
3600794	528	547	dystrophic syndrome	SpecificDisease	D009136
3600794	608	642	Duchenne/Becker muscular dystrophy	CompositeMention	D020388|C537666
3600794	708	735	Duchenne muscular dystrophy	Modifier	D020388
3600794	737	740	DMD	Modifier	D020388
3600794	831	834	DMD	SpecificDisease	D020388
3600794	1171	1181	myopathies	DiseaseClass	D009135
3600794	1183	1216	Emery Dreifuss muscular dystrophy	SpecificDisease	D020389
3600794	1278	1281	DMD	Modifier	D020388

1301937|t|Molecular basis of hexosaminidase A deficiency and pseudodeficiency in the Berks County Pennsylvania Dutch.
1301937|a|Following the birth of two infants with Tay-Sachs disease (TSD), a non-Jewish, Pennsylvania Dutch kindred was screened for TSD carriers using the biochemical assay. A high frequency of individuals who appeared to be TSD heterozygotes was detected (Kelly et al., 1975). Clinical and biochemical evidence suggested that the increased carrier frequency was due to at least two altered alleles for the hexosaminidase A alpha-subunit. We now report two mutant alleles in this Pennsylvania Dutch kindred, and one polymorphism. One allele, reported originally in a French TSD patient (Akli et al., 1991), is a GT-- > AT transition at the donor splice-site of intron 9. The second, a C-- > T transition at nucleotide 739 (Arg247Trp), has been shown by Triggs-Raine et al. (1992) to be a clinically benign " pseudodeficient " allele associated with reduced enzyme activity against artificial substrate. Finally, a polymorphism [G-- > A (759)], which leaves valine at codon 253 unchanged, is described .
1301937	19	46	hexosaminidase A deficiency	SpecificDisease	D013661
1301937	148	165	Tay-Sachs disease	SpecificDisease	D013661
1301937	167	170	TSD	SpecificDisease	D013661
1301937	231	234	TSD	Modifier	D013661
1301937	324	327	TSD	Modifier	D013661
1301937	673	676	TSD	Modifier	D013661

3856322|t|Gene transfer and expression of human phenylalanine hydroxylase.
3856322|a|Phenylketonuria (PKU) is caused by a genetic deficiency of the enzyme phenylalanine hydroxylase (PAH). A full-length complementary DNA clone of human PAH was inserted into a eukaryotic expression vector and transferred into mouse NIH3T3 cells which do not normally express PAH. The transformed mouse cells expressed PAH messenger RNA, immunoreactive protein, and enzymatic activity that are characteristic of the normal human liver products, demonstrating that a single gene contains all of the necessary genetic information to code for functional PAH. These results support the use of the human PAH probe in prenatal diagnosis and detection of carriers, to provide new opportunities for the biochemical characterization of normal and mutant enzymes, and in the investigation of alternative genetic therapies for PKU.. 
3856322	65	80	Phenylketonuria	SpecificDisease	D010661
3856322	82	85	PKU	SpecificDisease	D010661
3856322	110	160	deficiency of the enzyme phenylalanine hydroxylase	SpecificDisease	OMIM:261600
3856322	878	881	PKU	SpecificDisease	D010661

8302543|t|Macular dystrophy associated with mutations at codon 172 in the human retinal degeneration slow gene.
8302543|a|BACKGROUND  Recently, mutations in the retinal degeneration slow (rds) gene which codes for peripherin-rds have been implicated as a cause of autosomal dominant retinitis pigmentosa. Because this gene is expressed in both rods and cones, mutations in the rds gene might be expected to cause degeneration affecting either the scotopic or photopic systems. Mutations at codon 172 of the rds gene have been identified in three families with autosomal dominantly inherited, progressive macular dystrophy. METHODS  Affected individuals underwent ophthalmic examination, scotopic perimetry, dark adaptometry, measurement of color-contrast sensitivity, and electroretinography to characterize the photoreceptor dysfunction. RESULTS  In all but one affected member, symptoms of progressive central visual loss developed in the third or fourth decade of life accompanied by central scotoma and well-demarcated atrophy of the retinal pigment epithelium and choriocapillaris of the macula. In general, cone and rod thresholds were elevated, and color-contrast sensitivity was absent in the central visual field. Peripherally, the scotopic sensitivities were normal, as was the recovery from bleach. Cone electroretinograms were diminished in amplitude, and delayed in all affected adults except one. Rod electroretinograms were normal or near normal in amplitude, and had normal implicit times. Affected asymptomatic children had macular changes, abnormal color-contrast sensitivity, and reduced pattern and cone electroretinograms. CONCLUSION  These results indicate that mutations in the rds gene can be expressed as a macular dystrophy, with evidence of primary cone dysfunction and preservation of peripheral rod function.. 
8302543	0	17	Macular dystrophy	SpecificDisease	D008268
8302543	70	90	retinal degeneration	Modifier	D012162
8302543	141	161	retinal degeneration	Modifier	D012162
8302543	244	283	autosomal dominant retinitis pigmentosa	SpecificDisease	D012174
8302543	584	601	macular dystrophy	SpecificDisease	D008268
8302543	892	903	visual loss	SpecificDisease	C531604
8302543	967	982	central scotoma	SpecificDisease	D012607
8302543	1003	1044	atrophy of the retinal pigment epithelium	SpecificDisease	C536309
8302543	1049	1079	choriocapillaris of the macula	SpecificDisease	D008268
8302543	1712	1729	macular dystrophy	SpecificDisease	D008268
8302543	1756	1772	cone dysfunction	DiseaseClass	OMIM:180020

23402|t|Glucose 6-phosphate dehydrogenase variants: Gd (+) Alexandra associated with neonatal jaundice and Gd (-) Camperdown in a young man with lamellar cataracts.
23402|a|Two male subjects are described, with unusual clinical presentations and with hitherto undescribed G6PD variants. The first, of Italian extraction, suffered from severe neonatal jaundice following maternal ingestion of fresh broad beans (Vicia fava) both prenatally and postnatally  the expression of the enzymatic defect was much more severe in the neonatal period than on retesting in adolescence, when biochemical characterization showed unique features which justify designation as a new variant Gd (+) Alexandra. The second patient, a boy of Maltese extraction who was found to have bilateral lamellar cataracts at the age of 4 years, was identified as G6PD deficient only as a result of a survey of children of Mediterranean origin with unexplained cataract formation; he has approximately 15% of normal enzyme activity, with another unique combination of biochemical characteristics which has led to its designation as Gd (-) Camperdown. Although this association may be coincidental, it prompts further attention to the possibility that under certain circumstances G6PD deficiency may favor cataract formation. The two cases illustrate the value of characterization of the mutant enzyme whenever unexpected clinical or laboratory results are obtained.. 
23402	77	94	neonatal jaundice	SpecificDisease	D007567
23402	137	155	lamellar cataracts	SpecificDisease	C535342|OMIM:116800
23402	326	343	neonatal jaundice	SpecificDisease	D007567
23402	745	773	bilateral lamellar cataracts	SpecificDisease	C535342|OMIM:116800
23402	815	829	G6PD deficient	SpecificDisease	D005955
23402	912	920	cataract	Modifier	D002386
23402	1230	1245	G6PD deficiency	SpecificDisease	D005955
23402	1256	1264	cataract	Modifier	D002386

2989709|t|DNA restriction fragments associated with alpha 1-antitrypsin indicate a single origin for deficiency allele PI Z.
2989709|a|The alpha 1-protease inhibitor, or alpha-antitrypsin (AAT), a major plasma inhibitor of leukocyte elastase and bacterial proteases, is encoded at the PI locus on chromosome 14 (14q24. 3-q32. 1). A deficiency of AAT in individuals homozygous for the PI Z allele occurs in about 1 in 2, 000-8, 000 caucasians and is associated with an increased risk of early adult onset emphysema and liver disease in childhood. We have now used DNA polymorphisms associated with the AAT gene to investigate the origin of the PI Z allele. Using two genomic probes extending into the 5 and 3 flanking regions, respectively, we have identified eight polymorphic restriction sites. Extensive linkage disequilibrium occurs throughout the probed region with the PI Z allele, but not with normal PI M alleles. The Z allele occurs mainly with one haplotype, indicating a single, relatively recent, origin in caucasians 
2989709	312	329	deficiency of AAT	SpecificDisease	C531610
2989709	484	493	emphysema	DiseaseClass	D004646
2989709	498	511	liver disease	DiseaseClass	D008107

10976074|t|Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat.
10976074|a|Myotonic dystrophy (DM), the most common form of muscular dystrophy in adult humans, results from expansion of a CTG repeat in the 3 untranslated region of the DMPK gene. The mutant DMPK messenger RNA (mRNA) contains an expanded CUG repeat and is retained in the nucleus. We have expressed an untranslated CUG repeat in an unrelated mRNA in transgenic mice. Mice that expressed expanded CUG repeats developed myotonia and myopathy, whereas mice expressing a nonexpanded repeat did not. Thus, transcripts with expanded CUG repeats are sufficient to generate a DM phenotype. This result supports a role for RNA gain of function in disease pathogenesis.. 
10976074	0	18	Myotonic dystrophy	SpecificDisease	D009223
10976074	73	91	Myotonic dystrophy	SpecificDisease	D009223
10976074	93	95	DM	SpecificDisease	D009223
10976074	122	140	muscular dystrophy	SpecificDisease	D009136
10976074	482	490	myotonia	DiseaseClass	D009222
10976074	495	503	myopathy	DiseaseClass	D009135
10976074	632	634	DM	Modifier	D009223

10797418|t|Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting.
10797418|a|The Prader-Willi syndrome (PWS) critical region on 15q11-q13 is subject to imprinting. PWS becomes apparent when genes on the paternally inherited chromosome are not expressed. Familial PWS is rare. We report on a family in which a male and a female paternal first cousin both have PWS with cytogenetically normal karyotypes. Fluorescence in situ hybridization (FISH) analysis shows a submicroscopic deletion of SNRPN, but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3. The cousins fathers and two paternal aunts have the same deletion and are clinically normal. The grandmother of the cousins is deceased and not available for study, and their grandfather is not deleted for SNRPN. DNA methylation analysis of D15S63 is consistent with an abnormality of the imprinting center associated with PWS. " Grandmatrilineal " inheritance occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In this case, PWS does not become evident as long as the deletion is passed through the matrilineal line. This represents a unique inheritance pattern due to imprinting.. 
10797418	40	61	Prader-Willi syndrome	SpecificDisease	D011218
10797418	136	157	Prader-Willi syndrome	SpecificDisease	D011218
10797418	159	162	PWS	SpecificDisease	D011218
10797418	219	222	PWS	SpecificDisease	D011218
10797418	309	321	Familial PWS	SpecificDisease	D011218
10797418	414	417	PWS	SpecificDisease	D011218
10797418	946	949	PWS	SpecificDisease	D011218
10797418	1137	1140	PWS	SpecificDisease	D011218

10915770|t|Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the homologous murine imprinting phenotype.
10915770|a|Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11-q13. Affected individuals exhibit neonatal hypotonia, developmental delay and childhood-onset obesity. Necdin, a protein implicated in the terminal differentiation of neurons, is the only PWS candidate gene to reduce viability when disrupted in a mouse model. In this study, we have characterized MAGEL2 (also known as NDNL1), a gene with 51% amino acid sequence similarity to necdin and located 41 kb distal to NDN in the PWS deletion region. MAGEL2 is expressed predominantly in brain, the primary tissue affected in PWS and in several fetal tissues as shown by northern blot analysis. MAGEL2 is imprinted with monoallelic expression in control brain, and paternal-only expression in the central nervous system as demonstrated by its lack of expression in brain from a PWS-affected individual. The orthologous mouse gene (Magel2) is located within 150 kb of NDN , is imprinted with paternal-only expression and is expressed predominantly in late developmental stages and adult brain as shown by northern blotting, RT-PCR and whole-mount RNA in situ hybridization. Magel2 distribution partially overlaps that of NDN , with strong expression being detected in the central nervous system in mid-gestation mouse embryos by in situ hybridization. We hypothesize that, although loss of necdin expression may be important in the neonatal presentation of PWS, loss of MAGEL2 may be critical to abnormalities in brain development and dysmorphic features in individuals with PWS.. 
10915770	54	75	Prader-willi syndrome	SpecificDisease	D011218
10915770	124	145	Prader-Willi syndrome	SpecificDisease	D011218
10915770	147	150	PWS	SpecificDisease	D011218
10915770	261	279	neonatal hypotonia	SpecificDisease	D009123
10915770	281	300	developmental delay	DiseaseClass	D002658
10915770	305	328	childhood-onset obesity	DiseaseClass	D009765
10915770	415	418	PWS	Modifier	D011218
10915770	650	653	PWS	Modifier	D011218
10915770	746	749	PWS	SpecificDisease	D011218
10915770	998	1001	PWS	Modifier	D011218
10915770	1576	1579	PWS	SpecificDisease	D011218
10915770	1615	1649	abnormalities in brain development	DiseaseClass	D002658
10915770	1654	1673	dysmorphic features	DiseaseClass	D057215
10915770	1694	1697	PWS	SpecificDisease	D011218

1968617|t|A single origin of phenylketonuria in Yemenite Jews.
1968617|a|Phenylketonuria (PKU) is a metabolic disease caused by recessive mutations of the gene encoding the hepatic enzyme phenylalanine hydroxylase (PAH). The incidence of PKU varies widely across different geographic areas, and is highest (about 1 in 5, 000 live births) in Ireland and western Scotland, and among Yemenite Jews. A limited number of point mutations account for most of the PKU cases in the European population. Here we report that a single molecular defect--a deletion spanning the third exon of the PAH gene--is responsible for all the PKU cases among the Yemenite Jews. Examination of a random sample of Yemenite Jews using a molecular probe that detects the carriers of this deletion indicated a high frequency of the defective gene in this community. Although the deleted PAH gene was traced to 25 different locations throughout Yemen, family histories and official documents of the Yemenite Jewish community showed that the common ancestor of all the carriers of this genetic defect lived in Sana, the capital of Yemen, before the eighteenth century.. 
1968617	19	34	phenylketonuria	SpecificDisease	D010661
1968617	53	68	Phenylketonuria	SpecificDisease	D010661
1968617	70	73	PKU	SpecificDisease	D010661
1968617	80	97	metabolic disease	DiseaseClass	D008659
1968617	218	221	PKU	SpecificDisease	D010661
1968617	436	439	PKU	Modifier	D010661
1968617	600	603	PKU	Modifier	D010661
1968617	1036	1050	genetic defect	DiseaseClass	D030342

7909252|t|High resolution genetic analysis suggests one ancestral predisposing haplotype for the origin of the myotonic dystrophy mutation.
7909252|a|The mutation causing myotonic dystrophy (DM) has been identified as an amplification of an unstable trinucleotide (CTG) n repeat in over 99% of the global DM population. It is in complete linkage disequilibrium with an Alu element polymorphism within the DM kinase gene, suggesting that DM is a consequence of one or few ancestral mutations. A recent analysis utilizing this polymorphism as well as a flanking dinucleotide marker, suggested that similar to Fragile X syndrome, DM exhibited a founder effect (Imbert et al., 1993 Nature Genet. 4, 72-76). In contrast, the low reproductive fitness of individuals with congenital DM (the endpoint of genetic anticipation in myotonic dystrophy) suggests a higher rate of new mutations. We present a high resolution genetic analysis of the DM locus using PCR based assays of nine polymorphisms, spanning a physical distance of 30 kb, within and immediately flanking the DM kinase gene. The persistent complete allelic association of the DM mutation with all these polymorphisms provides further support to previous observations and suggests more strongly that the DM mutation occurred on the background of a particular haplotype in which the (CTG) n repeat became inherently unstable and therefore predisposed to amplification. 
7909252	101	119	myotonic dystrophy	Modifier	D009223
7909252	151	169	myotonic dystrophy	SpecificDisease	D009223
7909252	171	173	DM	SpecificDisease	D009223
7909252	285	287	DM	Modifier	D009223
7909252	385	387	DM	Modifier	D009223
7909252	417	419	DM	SpecificDisease	D009223
7909252	587	605	Fragile X syndrome	SpecificDisease	D005600
7909252	607	609	DM	SpecificDisease	D009223
7909252	756	758	DM	SpecificDisease	D009223
7909252	800	818	myotonic dystrophy	SpecificDisease	D009223
7909252	914	916	DM	Modifier	D009223
7909252	1044	1046	DM	Modifier	D009223
7909252	1111	1113	DM	Modifier	D009223
7909252	1238	1240	DM	Modifier	D009223

1322637|t|Identification and rapid detection of three Tay-Sachs mutations in the Moroccan Jewish population.
1322637|a|Infantile Tay-Sachs disease (TSD) is caused by mutations in the HEXA gene that result in the complete absence of beta-hexosaminidase A activity. It is well known that an elevated frequency of TSD mutations exists among Ashkenazi Jews. More recently it has become apparent that elevated carrier frequencies for TSD also occur in several other ethnic groups, including Moroccan Jews, a subgroup of Sephardic Jews. Elsewhere we reported an in-frame deletion of one of the two adjacent phenylalanine codons at position 304 or 305 (delta F304/305) in one HEXA allele of a Moroccan Jewish TSD patient and in three obligate carriers from six unrelated Moroccan Jewish families. We have now identified two additional mutations within exon 5 of the HEXA gene that account for the remaining TSD alleles in the patient and carriers. One of the mutations is a novel C-to-G transversion, resulting in a replacement of Tyr180 by a stop codon. The other mutation is a G-to-A transition resulting in an Arg170-to-Gln substitution. This mutation is at a CpG site in a Japanese infant with Tay-Sachs disease and was described elsewhere. Analysis of nine obligate carriers from seven unrelated families showed that four harbor the delta F304/305 mutation, two the Arg170----Gln mutation, and one the Tyr180----Stop mutation. We also have developed rapid, nonradioactive assays for the detection of each mutation, which should be helpful for carrier screening.. 
1322637	44	53	Tay-Sachs	Modifier	D013661
1322637	109	126	Tay-Sachs disease	SpecificDisease	D013661
1322637	128	131	TSD	SpecificDisease	D013661
1322637	291	294	TSD	Modifier	D013661
1322637	409	412	TSD	SpecificDisease	D013661
1322637	682	685	TSD	Modifier	D013661
1322637	880	883	TSD	Modifier	D013661
1322637	1171	1188	Tay-Sachs disease	SpecificDisease	D013661

7490097|t|Mapping of the mouse homologue of the Wilson disease gene to mouse chromosome 8.
7490097|a|ATP7B, the gene altered in Wilson disease (WD) patients, lies in a block of homology shared between human chromosome 13q14 and the central region of mouse chromosome 14. However, we have mapped the murine homologue of ATP7B (Atp7b) to mouse chromosome 8 by somatic cell hybrid analysis. Analysis of 80 interspecific backcross offspring was used to position Atp7b close to D8Mit3 and another ATPase locus, Atp4b, on mouse chromosome 8. ATP4B lies in 13q34 and is separated from ATP7B by several loci whose mouse homologues map to mouse chromosome 14. The assignment of Atp7b to mouse chromosome 8 identifies a previously unrecognized region of homology between this chromosome and human chromosome 13. This assignment suggests a possible location for the toxic milk mutation in the mouse, which has been proposed as a homologue of WD.. 
7490097	38	52	Wilson disease	Modifier	D006527
7490097	108	122	Wilson disease	Modifier	D006527
7490097	124	126	WD	Modifier	D006527
7490097	911	913	WD	SpecificDisease	D006527

8116611|t|Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy.
8116611|a|In myotonic dystrophy (DM), the size of a CTG repeat in the DM kinase gene generally increases in successive generations with clinical evidence of anticipation. However, there have also been cases with an intergenerational contraction of the repeat. We examined 1, 489 DM parent-offspring pairs, of which 95 (6. 4%) showed such contractions in peripheral blood leukocytes (PBL). In 56 of the 95 pairs, clinical data allowed an analysis of their anticipation status. It is surprising that anticipation occurred in 27 (48%) of these 56 pairs, while none clearly showed a later onset of DM in the symptomatic offspring. The contraction occurred in 76 (10%) of 753 paternal transmissions and in 19 (3%) of 736 maternal transmissions. Anticipation was observed more frequently in maternal (85%) than in paternal (37%) transmissions (P <. 001). The parental repeat size correlated with the size of intergenerational contraction (r2 =. 50, P < <. 001), and the slope of linear regression was steeper in paternal (-. 62) than in maternal (-. 30) transmissions (P < <. 001). Sixteen DM parents had multiple DM offspring with the CTG repeat contractions. This frequency was higher than the frequency expected from the probability of the repeat contractions (6. 4%) and the size of DM sib population (1. 54 DM offspring per DM parent, in 968 DM parents). We conclude that (1) intergenerational contractions of the CTG repeat in leukocyte DNA frequently accompanies apparent anticipation, especially when DM is maternally transmitted, and (2) the paternal origin of the repeat and the presence of the repeat contraction in a sibling increase the probability of the CTG repeat contraction 
8116611	71	89	myotonic dystrophy	SpecificDisease	D009223
8116611	94	112	myotonic dystrophy	SpecificDisease	D009223
8116611	114	116	DM	SpecificDisease	D009223
8116611	151	153	DM	Modifier	D009223
8116611	360	362	DM	Modifier	D009223
8116611	675	677	DM	SpecificDisease	D009223
8116611	1165	1167	DM	Modifier	D009223
8116611	1189	1191	DM	Modifier	D009223
8116611	1362	1364	DM	Modifier	D009223
8116611	1387	1389	DM	Modifier	D009223
8116611	1404	1406	DM	Modifier	D009223
8116611	1422	1424	DM	Modifier	D009223
8116611	1584	1586	DM	SpecificDisease	D009223

10571950|t|Splice-site mutation in the PDS gene may result in intrafamilial variability for deafness in Pendred syndrome.
10571950|a|Pendred syndrome is a recessive inherited disorder that consists of developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter). This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS) has been mapped to chromosome 7q22-q31, and encodes a chloride-iodide transport protein. We performed mutation analysis of individual exons of the PDS gene in one Spanish family that shows intrafamilial variability of the deafness phenotype (two patients with profound and one with moderate-severe deafness). We identified a new splice-site mutation affecting intron 4 of the PDS gene, at nucleotide position 639 + 7. RNA analysis from lymphocytes of the affected patients showed that mutation 639 + 7A-- > G generates a new donor splice site, leading to an mRNA with an insertion of six nucleotides from intron 4 of PDS. Since the newly created donor splice site is likely to compete with the normal one, variations of the levels of normal and aberrant transcripts of the PDS gene in the cochlea may explain the variability in the deafness presentation.. 
10571950	28	31	PDS	Modifier	C536648
10571950	81	89	deafness	SpecificDisease	D003638
10571950	93	109	Pendred syndrome	SpecificDisease	C536648
10571950	111	127	Pendred syndrome	SpecificDisease	C536648
10571950	133	161	recessive inherited disorder	DiseaseClass	D030342
10571950	179	221	developmental abnormalities of the cochlea	DiseaseClass	D015834
10571950	223	249	sensorineural hearing loss	SpecificDisease	D006319
10571950	255	282	diffuse thyroid enlargement	SpecificDisease	D013959
10571950	284	290	goiter	SpecificDisease	D006042
10571950	345	364	hereditary deafness	SpecificDisease	D030342+D003638
10571950	384	387	PDS	SpecificDisease	C536648
10571950	536	539	PDS	Modifier	C536648
10571950	611	619	deafness	Modifier	D003638
10571950	687	695	deafness	SpecificDisease	D003638
10571950	765	768	PDS	Modifier	C536648
10571950	1162	1165	PDS	Modifier	C536648
10571950	1221	1229	deafness	Modifier	D003638

10802668|t|Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts.
10802668|a|Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, mental retardation and ocular cataracts. The genetic defect in DM is a CTG repeat expansion located in the 3 untranslated region of DMPK and 5 of a homeodomain-encoding gene, SIX5 (formerly DMAHP; refs 2-5). There are three mechanisms by which CTG expansion can result in DM. First, repeat expansion may alter the processing or transport of the mutant DMPK mRNA and consequently reduce DMPK levels. Second, CTG expansion may establish a region of heterochromatin 3 of the repeat sequence and decrease SIX5 transcription. Third, toxic effects of the repeat expansion may be intrinsic to the repeated elements at the level of DNA or RNA (refs 10, 11). Previous studies have demonstrated that a dose-dependent loss of Dm15 (the mouse DMPK homologue) in mice produces a partial DM phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders. To test the role of Six5 loss in DM, we have analysed a strain of mice in which Six5 was deleted. Our results demonstrate that the rate and severity of cataract formation is inversely related to Six5 dosage and is temporally progressive. Six5 +/- and Six5-/- mice show increased steady-state levels of the Na +/K + -ATPase alpha-1 subunit and decreased Dm15 mRNA levels. Thus, altered ion homeostasis within the lens may contribute to cataract formation. As ocular cataracts are a characteristic feature of DM, these results demonstrate that decreased SIX5 transcription is important in the aetiology of DM. Our data support the hypothesis that DM is a contiguous gene syndrome associated with the partial loss of both DMPK and SIX5.. 
10802668	64	73	cataracts	SpecificDisease	D002386
10802668	75	93	Myotonic dystrophy	SpecificDisease	D009223
10802668	95	97	DM	SpecificDisease	D009223
10802668	105	131	autosomal dominant disorde	DiseaseClass	D030342
10802668	159	173	muscle wasting	SpecificDisease	D009133
10802668	175	183	myotonia	DiseaseClass	D009222
10802668	185	203	cardiac arrhythmia	DiseaseClass	D001145
10802668	205	222	hyperinsulinaemia	SpecificDisease	D006946
10802668	224	242	mental retardation	DiseaseClass	D008607
10802668	254	263	cataracts	SpecificDisease	D002386
10802668	269	283	genetic defect	DiseaseClass	D030342
10802668	287	289	DM	SpecificDisease	D009223
10802668	496	498	DM	SpecificDisease	D009223
10802668	998	1000	DM	Modifier	D009223
10802668	1079	1107	cardiac conduction disorders	DiseaseClass	D001145
10802668	1142	1144	DM	SpecificDisease	D009223
10802668	1261	1269	cataract	Modifier	D002386
10802668	1544	1552	cataract	Modifier	D002386
10802668	1574	1583	cataracts	SpecificDisease	D002386
10802668	1616	1618	DM	SpecificDisease	D009223
10802668	1713	1715	DM	SpecificDisease	D009223
10802668	1754	1756	DM	SpecificDisease	D009223

10484765|t|Cis and trans effects of the myotonic dystrophy (DM) mutation in a cell culture model.
10484765|a|The mutation causing myotonic dystrophy (DM) has been identified as a CTG expansion in the 3-untranslated region (3-UTR) of the DM protein kinase gene (DMPK), but the mechanism (s) of pathogenesis remain unknown. Studies using DM patient materials have often produced confusing results. Therefore, to study the effects of the DM mutation in a controlled environment, we have established a cell culture model system using C2C12 mouse myoblasts. By expressing chimeric reporter constructs containing a reporter gene fused to a human DMPK 3-UTR, we identified both cis and trans effects that are mediated by the DM mutation. Our data show that a mutant DMPK 3-UTR, with as few as 57 CTGs, had a negative cis effect on protein expression and resulted in the aggregation of reporter transcripts into discrete nuclear foci. We determined by deletion analysis that an expanded (CTG) (n) tract alone was sufficient to mediate these cis effects. Furthermore, in contrast to the normal DMPK 3-UTR mRNA, a mutant DMPK 3-UTR mRNA with (CUG) (200) selectively inhibited myogenic differentiation of C2C12 myoblasts. Genetic analysis and the Cre- loxP system were used to clearly demonstrate that the myoblast fusion defect could be rescued by eliminating the expression of the mutant DMPK 3-UTR transcript. Characterization of spontaneous deletion events mapped the inhibitory effect to the (CTG) (n) expansion and/or the 3 end of the DMPK 3-UTR. These results provide evidence that the DM mutation acts in cis to reduce protein production (consistent with DMPK haploinsufficiency) and in trans as a riboregulator to inhibit myogenesis.. 
10484765	29	47	myotonic dystrophy	Modifier	D009223
10484765	49	51	DM	Modifier	D009223
10484765	108	126	myotonic dystrophy	SpecificDisease	D009223
10484765	128	130	DM	SpecificDisease	D009223
10484765	215	217	DM	Modifier	D009223
10484765	314	316	DM	Modifier	D009223
10484765	413	415	DM	Modifier	D009223
10484765	696	698	DM	Modifier	D009223
10484765	1560	1562	DM	Modifier	D009223
10484765	1630	1653	DMPK haploinsufficiency	SpecificDisease	D058495

8071955|t|Intelligence quotient profile in myotonic dystrophy, intergenerational deficit, and correlation with CTG amplification.
8071955|a|An abbreviated Wechsler Adult Intelligence Scale Revised (WAIS-R) was used to assess verbal and arithmetical cognitive performance in 55 subjects with myotonic dystrophy (DM), covering all grades of disease severity, and 31 controls at 50% risk of inheriting DM. Scaled scores from the assessment were converted into an intelligence quotient (IQ) estimation on each person. Significant IQ differences were found between  (1) all 55 DM subjects (mean 90. 2, SD 16. 1) and 31 controls (102. 6, SD 9. 4), with no sex differences in either group; (2) 15 affected parents (99. 3, SD 12. 2) and their affected children (88. 1, SD 17. 2), where significance was dependent on parental sex being female; and (3) 15 pairs of affected sibs (89. 6, SD 13. 2) and their normal sibs (100. 2, SD 7. 6). IQ steadily declined as (1) the age of onset of signs and symptoms decreased, and (2) the CTG expansion size increased. The correlation appeared to be more linear with age of onset. The correlation of IQ difference and CTG expansion difference in both the DM parent-child pairs and normal sib-affected sib pairs was poor, indicating that CTG expansion is not a reliable predictor of IQ either in individual persons or families. Further analysis of cognitive function in DM is required to clarify specific deficits characteristic of this patient group 
8071955	33	51	myotonic dystrophy	SpecificDisease	D009223
8071955	271	289	myotonic dystrophy	SpecificDisease	D009223
8071955	291	293	DM	SpecificDisease	D009223
8071955	379	381	DM	SpecificDisease	D009223
8071955	552	554	DM	Modifier	D009223
8071955	1164	1166	DM	Modifier	D009223
8071955	1378	1380	DM	SpecificDisease	D009223

1361318|t|Complement factor 2 deficiency: a clinical and serological family study.
1361318|a|Inherited complement deficiencies are associated with a variety of connective tissue diseases. A family with inherited deficiency of complement factor 2 (C2) is described in which two family members with homozygous C2 deficiency developed cutaneous vasculitis and sicca syndrome. The other family members had heterozygous C2 deficiency and each member had the HLA-A25, B18, DR2 (w15) haplotype. The mother had seropositive rheumatoid arthritis. Further studies showed the presence of cryoglobulins, antibodies against endothelial cells, and anticardiolipin antibodies.. 
1361318	0	30	Complement factor 2 deficiency	SpecificDisease	OMIM:217000
1361318	73	106	Inherited complement deficiencies	DiseaseClass	D007153
1361318	182	225	inherited deficiency of complement factor 2	SpecificDisease	OMIM:217000
1361318	288	301	C2 deficiency	SpecificDisease	OMIM:217000
1361318	312	332	cutaneous vasculitis	SpecificDisease	D018366
1361318	337	351	sicca syndrome	SpecificDisease	D012859
1361318	395	408	C2 deficiency	SpecificDisease	OMIM:217000
1361318	483	516	seropositive rheumatoid arthritis	SpecificDisease	D001172

1352883|t|Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype.
1352883|a|The retinoblastoma-predisposition gene, RB1, segregates as an autosomal dominant trait with high (90%) penetrance. Certain families, however, show an unusual low-penetrance phenotype with many individuals being unaffected, unilaterally affected, or with evidence of spontaneously regressed tumors. We have used single-strand conformation polymorphism analysis and PCR sequencing to study two such families. Mutations were found in exon 20 of RB1 in both cases. In one family a C----T transition in codon 661 converts an arginine (CGG) to a tryptophan (TGG) codon. In this family, incomplete penetrance and mild phenotypic expression were observed in virtually all patients, possibly indicating that single amino acid changes may modify protein structure/function such that tumorigenesis is not inevitable. In the second family the mutation in codon 675 is a G----T transversion that converts a glutamine (GAA) to a stop (TAA) codon. However, this mutation also occurs near a potential cryptic splice acceptor site, raising the possibility of alternative splicing resulting in a less severely disrupted protein.. 
1352883	122	136	retinoblastoma	Modifier	D012175
1352883	152	166	retinoblastoma	Modifier	D012175
1352883	438	444	tumors	DiseaseClass	D009369

10502833|t|Identification of a novel R21X mutation in the liver-type arginase gene (ARG1) in four Portuguese patients with argininemia.
10502833|a|Argininemia is a rare autossomal recessive disorder caused by deficiency in the cytosolic liver-type arginase enzyme (L-arginine urea-hydrolase; E. C. 3. 5. 3. 1). In order to investigate the molecular basis for argininemia in four unrelated Portuguese patients (two from northern Portugal and two from Madeira Island) we performed a DNA sequence analysis of all the exons and exon/intron boundaries of the liver-type arginase gene (ARG1). All patients were found to be homozygous for a newly identified C - > T transition in codon 21 (exon 2) substituting arginine for a premature stop codon (R21X  CGA to TGA) and generating a NlaIII restriction site. Restriction digestion following PCR amplification of ARG1 exon 2 confirmed the presence of the mutation.
10502833	112	123	argininemia	SpecificDisease	D020162
10502833	125	136	Argininemia	SpecificDisease	D020162
10502833	147	176	autossomal recessive disorder	DiseaseClass	D030342
10502833	187	241	deficiency in the cytosolic liver-type arginase enzyme	DiseaseClass	D020162
10502833	337	348	argininemia	SpecificDisease	D020162

10930571|t|A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome).
10930571|a|Aarskog-Scott Syndrome (AAS) is an X-linked disorder characterised by short stature and multiple facial, limb and genital abnormalities. A gene, FGD1, altered in a patient with AAS phenotype, has been identified and found to encode a protein with homology to Rho/Rac guanine nucleotide exchange factors (Rho/Rac GEF). However, since this original report on identification of a mutated FGD1 gene in an AAS patient, no additional mutations in the FGD1 gene have been described. We analysed 13 independent patients with clinical diagnosis of AAS. One patient presented a mutation that results in a nucleotide change in exon 10 of the FGD1 gene (G2559 > A) substituting a Gln for Arg in position 610. The mutation was found to segregate with the AAS phenotype in affected males and carrier females in the family of this patient. Interestingly, Arg-610 is located within one of the two pleckstrin homology (PH) domains of the FGD1 gene and it corresponds to a highly conserved residue which has been involved in InsP binding in PH domains of other proteins. The same residue is often mutated in the Brutons tyrosine kinase (Btk) gene in patients with an X-linked agammaglobulinemia. The Arg610Gln mutation represents the first case of a mutation in the PH domain of the FGD1 gene and additional evidence that mutations in PH domains can be associated to human diseases.. 
10930571	93	115	faciogenital dysplasia	SpecificDisease	C535331
10930571	117	139	Aarskog-Scott syndrome	SpecificDisease	C535331
10930571	142	164	Aarskog-Scott Syndrome	SpecificDisease	C535331
10930571	166	169	AAS	SpecificDisease	C535331
10930571	177	194	X-linked disorder	DiseaseClass	D040181
10930571	212	225	short stature	DiseaseClass	D006130
10930571	239	277	facial, limb and genital abnormalities	CompositeMention	D019465|D017880|D014564
10930571	319	322	AAS	Modifier	C535331
10930571	543	546	AAS	Modifier	C535331
10930571	681	684	AAS	SpecificDisease	C535331
10930571	884	887	AAS	Modifier	C535331
10930571	1291	1318	X-linked agammaglobulinemia	SpecificDisease	OMIM:300755

2055114|t|Localization of histidase to human chromosome region 12q22----q24.1 and mouse chromosome region 10C2----D1.
2055114|a|The human gene for histidase (histidine ammonia-lyase; HAL), the enzyme deficient in histidinemia, was assigned to human chromosome 12 by Southern blot analysis of human X mouse somatic cell hybrid DNA. The gene was sublocalized to region 12q22----q24. 1 by in situ hybridization, using a human histidase cDNA. The homologous locus in the mouse (Hal) was mapped to region 10C2----D1 by in situ hybridization, using a cell line from a mouse homozygous for a 1. 10 Robertsonian translocation. These assignments extend the conserved syntenic region between human chromosome 12 and mouse chromosome 10 that includes the genes for phenylalanine hydroxylase, gamma interferon, peptidase, and citrate synthase. The localization of histidase to mouse chromosome 10 suggests that the histidase regulatory locus (Hsd) and the histidinemia mutation (his), which are both known to be on chromosome 10, may be alleles of the histidase structural gene locus.
2055114	193	205	histidinemia	SpecificDisease	C538320

10364521|t|Noninvasive test for fragile X syndrome, using hair root analysis.
10364521|a|Identification of the FMR1 gene and the repeat-amplification mechanism causing fragile X syndrome led to development of reliable DNA-based diagnostic methods, including Southern blot hybridization and PCR. Both methods are performed on DNA isolated from peripheral blood cells and measure the repeat size in FMR1. Using an immunocytochemical technique on blood smears, we recently developed a novel test for identification of patients with fragile X syndrome. This method, also called " antibody test, " uses monoclonal antibodies against the FMR1 gene product (FMRP) and is based on absence of FMRP in patients cells. Here we describe a new diagnostic test to identify male patients with fragile X syndrome, on the basis of lack of FMRP in their hair roots. Expression of FMRP in hair roots was studied by use of an FMRP-specific antibody test, and the percentage of FMRP-expressing hair roots in controls and in male fragile X patients was determined. Control individuals showed clear expression of FMRP in nearly every hair root, whereas male fragile X patients lacked expression of FMRP in almost all their hair roots. Mentally retarded female patients with a full mutation showed FMRP expression in only some of their hair roots (< 55%), and no overlap with normal female controls was observed. The advantages of this test are (1) plucking of hair follicles does no appreciable harm to the mentally retarded patient, (2) hairs can be sent in a simple envelope to a diagnostic center, and (3) the result of the test is available within 5 h of plucking. In addition, this test enabled us to identify two fragile X patients who did not show the full mutation by analysis of DNA isolated from blood cells.. 
10364521	21	39	fragile X syndrome	SpecificDisease	D005600
10364521	146	164	fragile X syndrome	SpecificDisease	D005600
10364521	507	525	fragile X syndrome	SpecificDisease	D005600
10364521	756	774	fragile X syndrome	SpecificDisease	D005600
10364521	986	995	fragile X	Modifier	D005600
10364521	1113	1122	fragile X	Modifier	D005600
10364521	1190	1207	Mentally retarded	Modifier	D008607
10364521	1462	1479	mentally retarded	Modifier	D008607
10364521	1674	1683	fragile X	Modifier	D005600

1384324|t|Pelizaeus-Merzbacher disease: detection of mutations Thr181----Pro and Leu223----Pro in the proteolipid protein gene, and prenatal diagnosis.
1384324|a|A family with an apparent history of X-linked Pelizaeus-Merzbacher disease presented for genetic counseling, requesting carrier detection and prenatal diagnosis. RFLP analysis using the proteolipid protein (PLP) gene probe was uninformative in this family. A prenatal diagnosis on a chorionic villus sample (CVS) was carried out using single-strand conformation polymorphism (SSCP) analysis of a variant in exon 4 of the PLP gene. The fetus was predicted to be unaffected. Sequencing of the exon from the CVS, the predicted-carrier mother, and the obligate-carrier grandmother revealed an A-to-C change at nucleotide 541 in the two women but not in the fetus. As this change results in a Thr-to-Pro change at amino acid 181 in a region of the gene predicted to be part of a transmembrane segment, it was concluded that this was the mutation causing the disease in this family. In addition, in a second family, an exon 5 variant band pattern on SSCP analysis was shown by sequencing to be due to a T-to-C change at nucleotide 668. This results in a Leu-to-Pro change in a carrier mother and in her two affected sons. These results provide further examples of mutations in PLP that cause Pelizaeus-Merzbacher disease and illustrate the value of SSCP in genetic analysis.. 
1384324	0	28	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
1384324	188	216	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
1384324	1328	1356	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080

2404853|t|A normal male with an inherited deletion of one exon within the DMD gene.
2404853|a|We describe two brothers with identical inherited deletions of one single exon within the middle of the DMD gene; one brother has Becker muscular dystrophy diagnosed at 11 years of age, whereas the older brother is normal at 18. These results have implications for genetic counselling and prenatal diagnosis in families with Becker muscular dystrophy.. 
2404853	64	67	DMD	Modifier	D020388
2404853	178	181	DMD	Modifier	D020388
2404853	204	229	Becker muscular dystrophy	SpecificDisease	C537666
2404853	399	424	Becker muscular dystrophy	SpecificDisease	C537666

10406661|t|Small deletions in the type II collagen triple helix produce kniest dysplasia.
10406661|a|Kniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia. All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene. We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia. Sequencing of the index patients genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia  a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case. The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype.. 
10406661	61	77	kniest dysplasia	SpecificDisease	C537207
10406661	79	95	Kniest dysplasia	SpecificDisease	C537207
10406661	119	141	type II collagenopathy	DiseaseClass	C535964
10406661	183	197	kyphoscoliosis	DiseaseClass	OMIM:610170
10406661	199	217	midface hypoplasia	SpecificDisease	OMIM:300194
10406661	226	232	myopia	DiseaseClass	D009216
10406661	238	250	hearing loss	DiseaseClass	D034381
10406661	405	421	Kniest dysplasia	SpecificDisease	C537207
10406661	772	788	Kniest dysplasia	SpecificDisease	C537207
10406661	899	915	Kniest dysplasia	SpecificDisease	C537207
10406661	1325	1341	Kniest dysplasia	SpecificDisease	C537207
10406661	1511	1527	Kniest dysplasia	Modifier	C537207

8071957|t|Adenomatous polyposis coli and a cytogenetic deletion of chromosome 5 resulting from a maternal intrachromosomal insertion.
8071957|a|We present the clinical and laboratory findings in an institutionalised adult patient originally referred for autism. A high risk of colorectal cancer was predicted when an interstitial deletion of the long arm of chromosome 5, del (5) (q15q22. 3), was detected in her lymphocytes and deletion of the MCC and APC genes confirmed by molecular analysis. Adenomatous polyposis coli and carcinoma of the rectum were subsequently diagnosed in the patient. She was profoundly mentally retarded, autistic, and had minor dysmorphic features consistent with those of previous patients with similar deletions. The deletion arose as a result of recombination within the small insertion loop formed at meiosis by the direct insertion (dir ins (5) (q22. 3q14. 2q15)) found in the patients mother. This family further confirms the cytogenetic mapping of both MCC and APC genes to 5q22 and comparison with other recent cases suggests that both genes and their closely linked markers lie within the 5q22. 1 subband 
8071957	0	26	Adenomatous polyposis coli	SpecificDisease	D011125
8071957	234	240	autism	SpecificDisease	D001321
8071957	257	274	colorectal cancer	SpecificDisease	D015179
8071957	433	436	APC	Modifier	D011125
8071957	476	502	Adenomatous polyposis coli	SpecificDisease	D011125
8071957	507	530	carcinoma of the rectum	SpecificDisease	D012004
8071957	594	611	mentally retarded	Modifier	D008607
8071957	613	621	autistic	Modifier	D001321
8071957	637	656	dysmorphic features	SpecificDisease	D000013
8071957	977	980	APC	Modifier	D011125

1338904|t|Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene.
1338904|a|We examined somatic mutations of the adenomatous polyposis coli (APC) gene in 63 colorectal tumors (16 adenomas and 47 carcinomas) developed in familial adenomatous polyposis (FAP) and non-FAP patients. In addition to loss of heterozygosity (LOH) at the APC locus in 30 tumors, 43 other somatic mutations were detected. Twenty-one of them were point mutations; 16 nonsense and two missense mutations, and three occurred in introns at the splicing site. Twenty-two tumors had frameshift mutations due to deletion or insertion; nineteen of them were deletions of one to 31 bp and three were a 1-bp insertion. One tumor had a 1-bp deletion in an intron near the splicing site. Hence, 41 (95%) of 43 mutations resulted in truncation of the APC protein. Over 60% of the somatic mutations in the APC gene were clustered within a small region of exon 15, designated as MCR (mutation cluster region), which accounted for less than 10% of the coding region. Combining these data and the results of LOH, more than 80% of tumors (14 adenomas and 39 carcinomas) had at least one mutation in the APC gene, of which more than 60% (9 adenomas and 23 carcinomas) had two mutations. These results strongly suggest that somatic mutations of the APC gene are associated with development of a great majority of colorectal tumors.. 
1338904	25	28	APC	Modifier	D011125
1338904	37	54	colorectal tumors	DiseaseClass	D015179
1338904	87	90	APC	Modifier	D011125
1338904	134	160	adenomatous polyposis coli	Modifier	D011125
1338904	162	165	APC	Modifier	D011125
1338904	178	195	colorectal tumors	DiseaseClass	D015179
1338904	200	208	adenomas	DiseaseClass	D000236
1338904	216	226	carcinomas	DiseaseClass	D009369
1338904	241	271	familial adenomatous polyposis	Modifier	D011125
1338904	273	276	FAP	Modifier	D011125
1338904	351	354	APC	Modifier	D011125
1338904	367	373	tumors	DiseaseClass	D009369
1338904	561	567	tumors	DiseaseClass	D009369
1338904	708	713	tumor	DiseaseClass	D009369
1338904	833	836	APC	Modifier	D011125
1338904	887	890	APC	Modifier	D011125
1338904	1108	1114	tumors	DiseaseClass	D009369
1338904	1119	1127	adenomas	DiseaseClass	D000236
1338904	1135	1145	carcinomas	DiseaseClass	D009369
1338904	1180	1183	APC	Modifier	D011125
1338904	1216	1224	adenomas	DiseaseClass	D000236
1338904	1232	1242	carcinomas	DiseaseClass	D009369
1338904	1324	1327	APC	Modifier	D011125
1338904	1388	1405	colorectal tumors	DiseaseClass	D015179

3362213|t|Identification of an altered splice site in Ashkenazi Tay-Sachs disease.
3362213|a|Tay-Sachs disease is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, beta-N-acetylhexosaminidase A (ref. 1). A relatively high frequency of carriers (1/27) of a lethal, infantile form of the disease is found in the Ashkenazi Jewish population, but it is not yet evident whether this has resulted from a founder effect and random genetic drift or from a selective advantage of heterozygotes. We have identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient. This change, the substitution of a C for G in the first nucleotide of intron 12 is expected to result in defective splicing of the messenger RNA. A test for the mutant allele based on amplification of DNA by the polymerase chain rection and cleavage of a DdeI restriction site generated by the mutation revealed that this case and two other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for two different mutations. The occurrence of multiple mutant alleles warrants further examination of the selective advantage hypothesis.. 
3362213	54	71	Tay-Sachs disease	SpecificDisease	D013661
3362213	73	90	Tay-Sachs disease	SpecificDisease	D013661
3362213	97	133	autosomal recessive genetic disorder	DiseaseClass	D030342
3362213	1046	1063	Tay-Sachs disease	SpecificDisease	D013661

10484772|t|Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis.
10484772|a|Coats disease is characterized by abnormal retinal vascular development (so-called retinal telangiectasis) which results in massive intraretinal and subretinal lipid accumulation (exudative retinal detachment). The classical form of Coats disease is almost invariably isolated, unilateral and seen in males. A female with a unilateral variant of Coats disease gave birth to a son affected by Norrie disease. Both carried a missense mutation within the NDP gene on chromosome Xp11. 2 2. Subsequently analysis of the retinas of nine enucleated eyes from males with Coats disease demonstrated in one a somatic mutation in the NDP gene which was not present within non-retinal tissue. We suggest that Coats telangiectasis is secondary to somatic mutation in the NDP gene which results in a deficiency of norrin (the protein product of the NDP gene) within the developing retina. This supports recent observations that the protein is critical for normal retinal vasculogenesis. 
10484772	0	14	Coats' disease	SpecificDisease	D058456
10484772	30	63	unilateral retinal telangiectasis	SpecificDisease	D058456
10484772	152	165	Coats disease	SpecificDisease	D058456
10484772	186	223	abnormal retinal vascular development	DiseaseClass	D058456
10484772	235	257	retinal telangiectasis	SpecificDisease	D058456
10484772	284	330	intraretinal and subretinal lipid accumulation	CompositeMention	D006949
10484772	332	360	exudative retinal detachment	DiseaseClass	D012163
10484772	385	398	Coats disease	SpecificDisease	D058456
10484772	498	511	Coats disease	SpecificDisease	D058456
10484772	544	558	Norrie disease	SpecificDisease	C537849
10484772	715	728	Coats disease	SpecificDisease	D058456
10484772	849	869	Coats telangiectasis	SpecificDisease	D058456
10484772	938	958	deficiency of norrin	DiseaseClass	C537849

1357962|t|Trisomy 15 with loss of the paternal 15 as a cause of Prader-Willi syndrome due to maternal disomy.
1357962|a|Uniparental disomy has recently been recognized to cause human disorders, including Prader-Willi syndrome (PWS). We describe a particularly instructive case which raises important issues concerning the mechanisms producing uniparental disomy and whose evaluation provides evidence that trisomy may precede uniparental disomy in a fetus. Chorionic villus sampling performed for advanced maternal age revealed trisomy 15 in all direct and cultured cells, though the fetus appeared normal. Chromosome analysis of amniocytes obtained at 15 wk was normal in over 100 cells studied. The child was hypotonic at birth, and high-resolution banding failed to reveal the deletion of 15q11-13, a deletion which is found in 50% -70% of patients with PWS. Over time, typical features of PWS developed. Molecular genetic analysis using probes for chromosome 15 revealed maternal disomy. Maternal nondisjunction with fertilization of a disomic egg by a normal sperm, followed by loss of the paternal 15, is a likely cause of confined placental mosaicism and uniparental disomy in this case of PWS, and advanced maternal age may be a predisposing factor.. 
1357962	0	10	Trisomy 15	SpecificDisease	C538037
1357962	54	75	Prader-Willi syndrome	SpecificDisease	D011218
1357962	83	98	maternal disomy	SpecificDisease	D024182
1357962	100	118	Uniparental disomy	SpecificDisease	D024182
1357962	184	205	Prader-Willi syndrome	SpecificDisease	D011218
1357962	207	210	PWS	SpecificDisease	D011218
1357962	323	341	uniparental disomy	SpecificDisease	D024182
1357962	406	424	uniparental disomy	SpecificDisease	D024182
1357962	508	518	trisomy 15	SpecificDisease	C538037
1357962	691	700	hypotonic	SpecificDisease	D009123
1357962	837	840	PWS	SpecificDisease	D011218
1357962	873	876	PWS	SpecificDisease	D011218
1357962	1142	1160	uniparental disomy	SpecificDisease	D024182
1357962	1177	1180	PWS	SpecificDisease	D011218

492335|t|Genetic defect in secretion of complement C5 in mice.
492335|a|A genetic deficiency of the fifth (C5) component of complement1-3, a serum glycoprotein of molecular weight (MW) 220, 000 (ref. 4), has been found in 39% of inbred strains of mice3. Sera of deficient mice lack detectable C5 activity and protein2, 3. In addition deficient mice produce antibody to mouse C5 when injected with sera from C5 sufficient (normal) strains. Levy et al. 5 showed that somatic cell hybrids between C5 deficient (B10. D2/old line) macrophages and either C5 sufficient (B10. D2/new line) mouse kidney or chicken erythroblasts secreted haemolytically active mouse C5 in vitro. Several possible molecular mechanisms to account for the findings were considered, but insufficient direct data were available to choose among them. We recently reported that mouse (CD. 1 strain) peritoneal cells in culture synthesise and secrete a single chain precursor, pro-C5 (MW approximately 210, 000), of the two-chain (alpha chain, 125, 000 and beta chain 83, 000 MW) C5 protein6. Radiolabelled precursor C5 was contained within the cells and was secreted into the tissue culture media. Using similar methods, we now find that C5 deficiency in each of five different mouse strains (AKR, SWR, DBA/2J8 A/HeJ and B10. D2/old line) is due to a failure in secretion of C5 protein and not to a failure in biosynthesis of pro-C5 
492335	8	44	defect in secretion of complement C5	SpecificDisease	OMIM:609536
492335	64	119	deficiency of the fifth (C5) component of complement1-3	SpecificDisease	OMIM:609536
492335	1187	1200	C5 deficiency	SpecificDisease	OMIM:609536

8528199|t|WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia.
8528199|a|The WASP gene has been recently cloned from Xp11. 23 and shown to be mutated in three patients with the Wiskott-Aldrich syndrome (WAS). We have developed a screening protocol for identifying WASP gene alterations in genomic DNA and have identified a spectrum of novel mutations in 12 additional unrelated families. These missense, nonsense and frameshift mutations involve eight of the 12 exons of the gene. Two mutations creating premature termination codons were associated with lack of detectable mRNA on Northern blots. Four amino acid substitutions, Leu27Phe, Thr48Ile, Val75Met and Arg477Lys, were found in patients with congenital thrombocytopenia and no clinically evident immune defect indicating that the WASP gene is the site for mutations in X-linked thrombocytopenia as well as in WAS. A T-cell line from a WAS patient contained two independent DNA alterations, a constitutional frameshift mutation, also present in peripheral blood leukocytes from the patient, and compensatory splice site mutation unique to the cell line. The distribution of eight missense mutations provides valuable information on amino acids which are essential for normal protein function, and suggests that sites in the first two exons are hot-spots for mutation. 
8528199	23	47	Wiskott-Aldrich syndrome	SpecificDisease	D014923
8528199	52	77	X-linked thrombocytopenia	SpecificDisease	OMIM:313900
8528199	183	207	Wiskott-Aldrich syndrome	SpecificDisease	D014923
8528199	209	212	WAS	SpecificDisease	D014923
8528199	706	733	congenital thrombocytopenia	SpecificDisease	OMIM:313900
8528199	833	858	X-linked thrombocytopenia	SpecificDisease	OMIM:313900
8528199	873	876	WAS	SpecificDisease	D014923
8528199	899	902	WAS	Modifier	D014923

1307253|t|Detection of a nonsense mutation in the dystrophin gene by multiple SSCP.
1307253|a|A combination of multiplex PCR with the single strand conformation polymorphism (SSCP) technique was employed to screen for point mutations in the human dystrophin gene. Co-amplification of 11 exons from genomic DNA of Duchenne and Becker muscular dystrophy (DMD/BMD) patients with no deletion or duplication was performed and the samples subjected to multiple SSCP analysis. We report the case of a nonsense mutation in a Duchenne patient identified by this approach. The mutation introduces a termination codon within exon 8 of the dystrophin gene. It is predicted to cause a very premature translational termination accounting for the severe phenotype observed. The patient inherited this mutation from his mother. In addition the analysis revealed 5 polymorphisms useful for internal control.. 
1307253	293	331	Duchenne and Becker muscular dystrophy	Modifier	D020388|C537666
1307253	333	336	DMD	Modifier	D020388
1307253	337	340	BMD	Modifier	C537666
1307253	497	505	Duchenne	Modifier	D020388

8346255|t|Molecular mechanisms of oncogenic mutations in tumors from patients with bilateral and unilateral retinoblastoma.
8346255|a|The RB1 gene from 12 human retinoblastoma tumors has been analyzed exon-by-exon with the single-strand conformation polymorphism technique. Mutations were found in all tumors, and one-third of the tumors had independent mutations in both alleles neither of which were found in the germ line, confirming their true sporadic nature. In the remaining two-thirds of the tumors only one mutation was found, consistent with the loss-of-heterozygosity theory of tumorigenesis. Point mutations, the majority of which were C-- > T transitions, were the most common abnormality and usually resulted in the conversion of an arginine codon to a stop codon. Small deletions were the second most common abnormality and most often created a downstream stop codon as the result of a reading frameshift. Deletions and point mutations also affected splice junctions. Direct repeats were present at the breakpoint junctions in the majority of deletions, supporting a slipped-mispairing mechanism. Point mutations generally produced DNA sequences which resulted in perfect homology with endogenous sequences which lay within 14 bp.. 
8346255	47	53	tumors	DiseaseClass	D009369
8346255	73	112	bilateral and unilateral retinoblastoma	CompositeMention	D012175
8346255	141	162	retinoblastoma tumors	SpecificDisease	D012175
8346255	282	288	tumors	DiseaseClass	D009369
8346255	311	317	tumors	DiseaseClass	D009369
8346255	480	486	tumors	DiseaseClass	D009369

7951315|t|PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects.
7951315|a|The human eye malformation aniridia results from haploinsufficiency of PAX6, a paired box DNA-binding protein. To study this dosage effect, we characterized two PAX6 mutations in a family segregating aniridia and a milder syndrome consisting of congenital cataracts and late onset corneal dystrophy. The nonsense mutations, at codons 103 and 353, truncate PAX6 within the N-terminal paired and C-terminal PST domains, respectively. The wild-type PST domain activates transcription autonomously and the mutant form has partial activity. A compound heterozygote had severe craniofacial and central nervous system defects and no eyes. The pattern of malformations is similar to that in homozygous Sey mice and suggests a critical role for PAX6 in controlling the migration and differentiation of specific neuronal progenitor cells in the brain.. 
7951315	41	61	congenital cataracts	SpecificDisease	D002386
7951315	63	71	aniridia	SpecificDisease	D015783
7951315	73	85	anophthalmia	SpecificDisease	D000853
7951315	90	120	central nervous system defects	DiseaseClass	D009421
7951315	149	157	aniridia	SpecificDisease	D015783
7951315	171	197	haploinsufficiency of PAX6	SpecificDisease	OMIM:106210
7951315	322	330	aniridia	SpecificDisease	D015783
7951315	367	387	congenital cataracts	SpecificDisease	D002386
7951315	403	420	corneal dystrophy	SpecificDisease	D003317
7951315	693	740	craniofacial and central nervous system defects	CompositeMention	D019465|D009421
7951315	745	752	no eyes	DiseaseClass	D000853

409732|t|Hereditary C7 deficiency. Diagnosis and HLA studies in a French-Canadian family.
409732|a|The serum of a 44-yr-old woman of French-Canadian descent having a B-27 positive ankylosing spondylitis was deficient in the seventh component of complement (C7) as determined by hemolytic and immunochemical methods. No inhibitor against C7 was detected, and the levels of all other complement components were normal. No deficiency in the opsonic activity of the serum was found, and the results of basic coagulation studies of the plasma were normal. On investigation of the patients family, two sisters were found to have the same deficiency but were otherwise in good health. The seven other siblings were heterozygous for C7 deficiency, while the paternal aunt had a normal C7 level. In the third generation, six children of the three homozygous sisters and five children of heterozygotes were available for testing. Studies of the HLA antigens in all the 22 subjects and in three spouses indicated no close linkage between the CM deficienty and the HLA system. In addition, the simultaneous occurrence of two hereditary complement deficiencies (C2 and C7) was discovered in one family of this remarkable kindred.. 
409732	0	24	Hereditary C7 deficiency	SpecificDisease	OMIM:610102
409732	162	184	ankylosing spondylitis	SpecificDisease	D013167
409732	189	237	deficient in the seventh component of complement	SpecificDisease	OMIM:610102
409732	707	720	C7 deficiency	SpecificDisease	OMIM:610102
409732	1013	1026	CM deficienty	SpecificDisease	OMIM:610102
409732	1106	1141	complement deficiencies (C2 and C7)	CompositeMention	OMIM:610102|OMIM:217000

10598815|t|Alstrom syndrome: further evidence for linkage to human chromosome 2p13.
10598815|a|Alstrom syndrome is a rare autosomal recessive disorder characterized by retinal degeneration, sensorineural hearing loss, early-onset obesity, and non-insulin-dependent diabetes mellitus. The gene for Alstrom syndrome (ALMS1) has been previously localized to human chromosome 2p13 by homozygosity mapping in two distinct isolated populations - French Acadian and North African. Pair-wise analyses resulted in maximum lod (logarithm of the odds ratio) scores of 3. 84 and 2. 9, respectively. To confirm these findings, a large linkage study was performed in twelve additional families segregating for Alstrom syndrome. A maximum two-point lod score of 7. 13 (theta = 0. 00) for marker D2S2110 and a maximum cumulative multipoint lod score of 9. 16 for marker D2S2110 were observed, further supporting linkage to chromosome 2p13. No evidence of genetic heterogeneity was observed in these families. Meiotic recombination events have localized the critical region containing ALMS1 to a 6. 1-cM interval flanked by markers D2S327 and D2S286. A fine resolution radiation hybrid map of 31 genes and markers has been constructed.
10598815	0	16	Alstrom syndrome	SpecificDisease	D056769
10598815	73	89	Alstrom syndrome	SpecificDisease	D056769
10598815	100	128	autosomal recessive disorder	DiseaseClass	D030342
10598815	146	166	retinal degeneration	SpecificDisease	D012162
10598815	168	194	sensorineural hearing loss	SpecificDisease	D006319
10598815	208	215	obesity	SpecificDisease	D009765
10598815	221	260	non-insulin-dependent diabetes mellitus	SpecificDisease	D003924
10598815	275	291	Alstrom syndrome	SpecificDisease	D056769
10598815	674	690	Alstrom syndrome	SpecificDisease	D056769

2575071|t|Haplotype and multipoint linkage analysis in Finnish choroideremia families.
2575071|a|Multipoint linkage analysis of choroideremia (TCD) and seven X chromosomal restriction fragment length polymorphisms (RFLPs) was carried out in 18 Finnish TCD families. The data place TCD distal to PGK and DXS72, very close to DXYS1 and DXYS5 (Zmax = 24 at theta = 0) and proximal to DXYS4 and DXYS12. This agrees with the data obtained from other linkage studies and from physical mapping. All the TCD males and carrier females studied have the same DXYS1 allele in coupling with TCD. In Northeastern Finland, 66/69 chromosomes carrying TCD had the same haplotype at loci DXS72, DXYS1, DXYS4, and DXYS12. The same haplotype is seen in only 15/99 chromosomes not carrying TCD. Moreover, in 71/104 non-TCD chromosomes, the haplotype at six marker loci is different from those seen in any of the 76 TCD chromosomes. This supports the previously described hypothesis that the large Northern Finnish choroideremia pedigrees, comprising a total of over 80 living patients representing more than a fifth of all TCD patients described worldwide, carry the same mutation. These linkage and haplotype data provide improved opportunities for prenatal diagnosis based on RFLP studies.. 
2575071	53	66	choroideremia	Modifier	D015794
2575071	108	121	choroideremia	SpecificDisease	D015794
2575071	123	126	TCD	SpecificDisease	D015794
2575071	232	235	TCD	Modifier	D015794
2575071	261	264	TCD	SpecificDisease	D015794
2575071	476	479	TCD	Modifier	D015794
2575071	558	561	TCD	SpecificDisease	D015794
2575071	615	618	TCD	SpecificDisease	D015794
2575071	749	752	TCD	SpecificDisease	D015794
2575071	874	877	TCD	Modifier	D015794
2575071	973	986	choroideremia	Modifier	D015794
2575071	1082	1085	TCD	Modifier	D015794

2253938|t|Genetic heterogeneity at the glucose-6-phosphate dehydrogenase locus in southern Italy: a study on a population from the Matera district.
2253938|a|Glucose-6-phosphate dehydrogenase (G6PD) has been analyzed by gel electrophoresis and by quantitative assay in an unselected sample of 1524 schoolboys from the province of Matera (Lucania) in southern Italy. We have identified 43 subjects with a G6PD variant. Of these, 31 had severe G6PD deficiency, nine had mild to moderate deficiency, and three had a non-deficient electrophoretic variant. The overall rate of G6PD deficiency was 2. 6%. The frequency of G6PD deficiency, ranging from 7. 2% on the Ionian Coast to zero on the eastern side of the Lucanian Apennines, appears to be inversely related to the distance of each town examined from the Ionian Coast, suggesting that this geographic distribution may reflect, at least in part, gene flow from Greek settlers. Biochemical characterization has shown that most of the G6PD deficiency in this population is accounted for by G6PD Mediterranean. In addition, we have found several examples of two other known polymorphic variants (G6PD Cagliari and G6PD A-); three new polymorphic variants, G6PD Metaponto (class III), G6PD Montalbano (class III), and G6PD Pisticci (class IV); and two sporadic variants, G6PD Tursi (class III) and G6PD Ferrandina (class II). These data provide further evidence for the marked genetic heterogeneity of G6PD deficiency within a relatively narrow geographic area and they prove the presence in the Italian peninsula of a gene (GdA-) regarded as characteristically African.
2253938	422	437	G6PD deficiency	SpecificDisease	D005955
2253938	552	567	G6PD deficiency	SpecificDisease	D005955
2253938	596	611	G6PD deficiency	SpecificDisease	D005955
2253938	963	978	G6PD deficiency	SpecificDisease	D005955
2253938	1428	1443	G6PD deficiency	SpecificDisease	D005955

10411929|t|Defective CTLA-4 cycling pathway in Chediak-Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation.
10411929|a|Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, also known as CD152) has been shown to play a major role in the regulation of T cell activation. Its membrane expression is highly regulated by endocytosis and trafficking through the secretory lysosome pathway. Chediak-Higashi syndrome (CHS) is an inherited disorder caused by mutations in the lysosomal trafficking regulator gene, LYST. It results in defective membrane targeting of the proteins present in secretory lysosomes, and it is associated with a variety of features, including a lymphoproliferative syndrome with hemophagocytosis. The murine equivalent of CHS, beige mice, present similar characteristics but do not develop the lymphoproliferative syndrome. We show herein that CTLA-4 is present in enlarged, abnormal vesicles in CHS T cells and is not properly expressed at the cell surface after T cell activation, whereas its surface expression is not impaired. It is therefore proposed that the defective surface expression of CTLA-4 by CHS T cells is involved in the generation of lymphoproliferative disease. This observation may provide insight into the role of CTLA-4 in humans.. 
10411929	36	60	Chediak-Higashi syndrome	SpecificDisease	D002609
10411929	393	417	Chediak-Higashi syndrome	SpecificDisease	D002609
10411929	419	422	CHS	SpecificDisease	D002609
10411929	430	448	inherited disorder	DiseaseClass	D030342
10411929	672	700	lymphoproliferative syndrome	SpecificDisease	D008232
10411929	706	722	hemophagocytosis	DiseaseClass	D051359
10411929	749	752	CHS	SpecificDisease	D002609
10411929	821	849	lymphoproliferative syndrome	SpecificDisease	D008232
10411929	923	926	CHS	Modifier	D002609
10411929	1134	1137	CHS	Modifier	D002609
10411929	1179	1206	lymphoproliferative disease	SpecificDisease	D008232

10398436|t|Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma.
10398436|a|Hepatoblastoma is a rare malignant tumor of the liver that occurs in children at an average age of 2 to 3 years. Epidemiologic studies have shown an increased frequency of this tumor type in families affected by adenomatous polyposis coli. In addition to the epidemiologic data, molecular genetic studies suggest that inactivation of the APC tumor suppressor may be involved in hepatoblastoma tumorigenesis. A major function of APC is the downregulation of beta-catenin, a transcription-activating protein with oncogenic potential. In an ongoing immunohistochemical study of beta-catenin expression in sporadic cases of tumor types that are associated with adenomatous polyposis coli, we observed increased beta-catenin levels in the cytoplasm and in the nuclei of three investigated hepatoblastomas. Sequencing of exon 3 of the beta-catenin gene (CTNNB1) revealed an activating mutation in one of the tumor samples. Our data indicate for the first time that beta-catenin accumulation may play a role in the development of hepatoblastoma and that activating mutations of the beta-catenin gene may substitute biallelic APC inactivation in this tumor type. Genes Chromosomes Cancer 25  399-402, 1999.. 
10398436	61	75	hepatoblastoma	SpecificDisease	D018197
10398436	77	91	Hepatoblastoma	SpecificDisease	D018197
10398436	102	130	malignant tumor of the liver	DiseaseClass	D008113+D018198
10398436	254	259	tumor	Modifier	D009369
10398436	289	315	adenomatous polyposis coli	SpecificDisease	D011125
10398436	415	424	APC tumor	Modifier	D011125
10398436	455	469	hepatoblastoma	Modifier	D018197
10398436	697	702	tumor	Modifier	D009369
10398436	734	760	adenomatous polyposis coli	SpecificDisease	D011125
10398436	861	876	hepatoblastomas	SpecificDisease	D018197
10398436	979	984	tumor	Modifier	D009369
10398436	1100	1114	hepatoblastoma	SpecificDisease	D018197
10398436	1220	1225	tumor	Modifier	D009369

1833974|t|Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.
1833974|a|The rapid identification of mutations causing Tay-Sachs disease requires the capacity to readily screen the regions of the HEXA gene most likely to be affected by mutation. We have sequenced the portions of the introns flanking each of the 14 HEXA exons in order to specify oligonucleotide primers for the PCR-dependent amplification of each exon and splice-junction sequence. The amplified products were analyzed, by electrophoresis in nondenaturing polyacrylamide gels, for the presence of either heteroduplexes, derived from the annealing of normal and mutant DNA strands, or single-strand conformational polymorphisms (SSCP), derived from the renaturation of single-stranded DNA. Five novel mutations from Tay-Sachs disease patients were detected  a 5-bp deletion of TCTCC in IVS-9; a 2-bp deletion of TG in exon 5; G78 to A, giving a stop codon in exon 1; G533 to T in exon 5, producing the third amino acid substitution detected at this site; and G to C at position 1 of IVS-2, expected to produce abnormal splicing. In addition, two mutations, (G1496 to A in exon 13 and a 4-bp insertion in exon 11) that have previously been reported were identified.. 
1833974	88	105	Tay-Sachs disease	SpecificDisease	D013661
1833974	153	170	Tay-Sachs disease	SpecificDisease	D013661
1833974	817	834	Tay-Sachs disease	Modifier	D013661

10742101|t|In vivo modulation of Hmgic reduces obesity.
10742101|a|The HMGI family of proteins consists of three members, HMGIC, HMGI and HMGI (Y), that function as architectural factors and are essential components of the enhancesome. HMGIC is predominantly expressed in proliferating, undifferentiated mesenchymal cells and is not detected in adult tissues. It is disrupted and misexpressed in a number of mesenchymal tumour cell types, including fat-cell tumours (lipomas). In addition Hmgic-/- mice have a deficiency in fat tissue. To study its role in adipogenesis and obesity, we examined Hmgic expression in the adipose tissue of adult, obese mice. Mice with a partial or complete deficiency of Hmgic resisted diet-induced obesity. Disruption of Hmgic caused a reduction in the obesity induced by leptin deficiency (Lepob/Lepob) in a gene-dose-dependent manner. Our studies implicate a role for HMGIC in fat-cell proliferation, indicating that it may be an adipose-specific target for the treatment of obesity.. 
10742101	36	43	obesity	SpecificDisease	D009765
10742101	386	404	mesenchymal tumour	Modifier	D008637
10742101	427	443	fat-cell tumours	DiseaseClass	D018205
10742101	445	452	lipomas	DiseaseClass	D008067
10742101	552	559	obesity	SpecificDisease	D009765
10742101	622	627	obese	Modifier	D009765
10742101	646	685	partial or complete deficiency of Hmgic	CompositeMention	OMIM:600698
10742101	708	715	obesity	SpecificDisease	D009765
10742101	763	770	obesity	SpecificDisease	D009765
10742101	782	799	leptin deficiency	SpecificDisease	OMIM:164160
10742101	987	994	obesity	SpecificDisease	D009765

10210128|t|Prenatal diagnosis by FISH in a family with Pelizaeus-Merzbacher disease caused by duplication of PLP gene.
10210128|a|A diagnosis of Pelizaeus-Merzbacher disease (MIM 312080) was made in a young boy. No mutation in the coding region of the proteolipid protein (PLP) gene had been found. The boys maternal aunt came for prenatal diagnosis when 16 + weeks pregnant and carrying a male fetus. Samples were tested for duplication of the PLP gene, by interphase FISH, in lymphocyte preparations from the proband, his aunt and an amniotic fluid cell preparation from the fetus. The proband was found to carry the duplication, thus confirming the diagnosis of Pelizaeus Merzbacher disease, but neither the aunt nor the fetus carried a duplication.. 
10210128	44	72	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
10210128	123	151	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
10210128	643	671	Pelizaeus Merzbacher disease	SpecificDisease	OMIM:312080

1056013|t|Somatic rearrangement of chromosome 14 in human lymphocytes.
1056013|a|Ataxia-telangiectasia is a rare genetic disorder associated with immune deficiency, chromosome instability, and a predisposition to lymphoid malignancy. We have detected chromosomally anomalous clones of lymphocytes in eight patients with this disorder. Chromosome banding disclosed that the clones are consistently marked by structural rearrangement of the long arm (q) of chromosome 14. A translocation involving 14q was found in clones obtained from seven of the eight patients whereas a ring 14 chromosome was found in a clone obtained from the other. These findings as well as data obtained by others for patients with ataxia-telangiectasia suggest that structural rearrangement of 14q is the initial chromosomal change in lymphocyte clones of patients with this disorder. Chromosomes of lymphocytes from one of the patients were studied before and after the onset of chronic lymphocytic leukemia. Before leukemia was diagnosed, the patient had a lymphocyte clone with a 14q translocation. This clone appears to have given rise to the leukemic cells. We hypothesize that structural rearrangement of 14q is directly related to abnormal growth of lymphocytes and that it may be a step toward the development of lymphoid malignancies. Increasing evidence, provided by others, for the nonrandom involvement of 14q in African-type Burkitts lymphoma and other lymphoid neoplasms further strengthens this hypothesis.. 
1056013	61	82	Ataxia-telangiectasia	SpecificDisease	D001260
1056013	93	109	genetic disorder	DiseaseClass	D030342
1056013	126	143	immune deficiency	DiseaseClass	D007153
1056013	145	167	chromosome instability	DiseaseClass	D043171
1056013	193	212	lymphoid malignancy	SpecificDisease	D008223
1056013	685	706	ataxia-telangiectasia	SpecificDisease	D001260
1056013	934	962	chronic lymphocytic leukemia	SpecificDisease	D015451
1056013	971	979	leukemia	DiseaseClass	D007938
1056013	1101	1109	leukemic	Modifier	D007938
1056013	1275	1296	lymphoid malignancies	SpecificDisease	D008223
1056013	1392	1409	Burkitts lymphoma	SpecificDisease	D002051
1056013	1420	1438	lymphoid neoplasms	DiseaseClass	D008223

1301200|t|Two missense mutations causing mild hyperphenylalaninemia associated with DNA haplotype 12.
1301200|a|The genetic defects responsible for most phenylketonuria (PKU) and hyperphenylalaninemia (HPA) cases are located in the phenylalanine hydroxylase (PAH) gene. Approximately 50-60 mutations have been reported in Caucasians and are reflected in a wide range of clinical severities. Most mutations are linked to specific haplotypes, as defined by eight polymorphic restriction sites in the PAH gene. We hypothesized that there is at least one mild mutation linked to haplotype 12 in the Swedish PKU/HPA population, since 7 of 8 patients carrying haplotype 12 had mild HPA. Sequence analysis revealed a C-to-G transversion at the second base of codon 322, resulting in a substitution of glycine for alanine, in four mutant haplotype 12 genes, and a G-to-A transition at the second base of codon 408, resulting in a substitution of glutamine for arginine, in another three mutant haplotype 12 genes. These mutations segregated with mutant haplotype 12 alleles in nuclear families but were not present on normal or other mutant alleles. Both mutations were tested in a eukaryotic expression system in which enzyme activities of different mutant PAH enzymes reflect the relative severities of the mutations, although these in vitro activities cannot be translated directly into in vivo hepatic activities. The A322G mutant PAH had about 75% and the R408Q mutant PAH about 55% of the wild-type PAH enzyme activity. These in vitro activities are the highest reported for mutant PAH enzymes produced in the same expression system. (ABSTRACT TRUNCATED AT 250 WORDS). 
1301200	36	57	hyperphenylalaninemia	DiseaseClass	D010661
1301200	96	111	genetic defects	DiseaseClass	D030342
1301200	133	148	phenylketonuria	SpecificDisease	D010661
1301200	150	153	PKU	SpecificDisease	D010661
1301200	159	180	hyperphenylalaninemia	DiseaseClass	D010661
1301200	182	185	HPA	DiseaseClass	D010661
1301200	583	586	PKU	Modifier	D010661
1301200	587	590	HPA	Modifier	D010661
1301200	656	659	HPA	DiseaseClass	D010661

7959759|t|Genomic organization of the adrenoleukodystrophy gene.
7959759|a|Adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder, is a severe neurodegenerative disease associated with an impairment of very long chain fatty acids beta-oxidation. We have recently identified by positional cloning the gene responsible for ALD, located in Xq28. It encodes a new member of the " ABC " superfamily of membrane-associated transporters that shows, in particular, significant homology to the 70-kDa peroxisomal membrane protein (PMP70). We report here a detailed characterization of the ALD gene structure. It extends over 21 kb and consists of 10 exons. To facilitate the detection of mutations in ALD patients, we have determined the intronic sequences flanking the exons as well as the sequence of the 3 untranslated region and of the immediate 5 promoter region. Sequences present in distal exons cross-hybridize strongly to additional sequences in the human genome. The ALD gene has been positioned on a pulsed-field map between DXS15 and the L1CAM gene, about 650 kb upstream from the color pigment genes. The frequent occurrence of color vision anomalies observed in patients with adrenomyeloneuropathy (the adult onset form of ALD) thus does not represent a contiguous gene syndrome but a secondary manifestation of ALD.. 
7959759	28	48	adrenoleukodystrophy	Modifier	D000326
7959759	55	75	Adrenoleukodystrophy	SpecificDisease	D000326
7959759	77	80	ALD	SpecificDisease	D000326
7959759	101	121	peroxisomal disorder	DiseaseClass	D018901
7959759	135	160	neurodegenerative disease	DiseaseClass	D019636
7959759	180	236	impairment of very long chain fatty acids beta-oxidation	DiseaseClass	OMIM:300100
7959759	313	316	ALD	SpecificDisease	D000326
7959759	572	575	ALD	Modifier	D000326
7959759	684	687	ALD	Modifier	D000326
7959759	960	963	ALD	Modifier	D000326
7959759	1173	1194	adrenomyeloneuropathy	SpecificDisease	D000326
7959759	1220	1223	ALD	SpecificDisease	D000326
7959759	1251	1275	contiguous gene syndrome	DiseaseClass	D025063
7959759	1309	1312	ALD	SpecificDisease	D000326

10220405|t|BRCA1 interacts with components of the histone deacetylase complex.
10220405|a|Germ-line mutations in the BRCA1 tumor-suppressor gene are associated with an increased susceptibility to breast and ovarian cancer. BRCA1 contains a carboxyl-terminal domain (BRCT) that is shared with several other proteins involved in maintaining genome integrity. In an effort to understand the function of BRCA1, we sought to isolate proteins that interact with the BRCT domain. Purified BRCT polypeptide was used as a probe to screen a human placenta cDNA expression library by Far Western analysis. Here we report that BRCA1 interacts in vivo and in vitro with the Rb-binding proteins, RbAp46 and RbAp48, as well as with Rb. Moreover, the BRCT domain associates with the histone deacetylases HDAC1 and HDAC2. These results demonstrate that BRCA1 interacts with components of the histone deacetylase complex, and therefore may explain the involvement of BRCA1 in multiple processes such as transcription, DNA repair, and recombination.. 
10220405	174	199	breast and ovarian cancer	CompositeMention	D061325

1279971|t|Deletion of the KIT and PDGFRA genes in a patient with piebaldism.
1279971|a|We have previously shown that human piebaldism results from mutations of the KIT gene, which encodes the receptor for the mast/stem cell growth factor and is located in chromosome segment 4q12. Using DNA of a patient with piebaldism, mental retardation, and multiple congenital anomalies associated with a 46, XY, del (4) (q12q21. 1) karyotype, we carried out quantitative Southern blot hybridization analyses of the KIT gene and the adjacent PDGFRA (platelet-derived growth factor receptor alpha subunit) genes. The patient was hemizygous for both the KIT and PDGFRA genes, indicating that both of these genes are included within the deleted region. Therefore, deletion of the KIT and PDGFRA genes may account for the piebald phenotype in this patient. 
1279971	55	65	piebaldism	SpecificDisease	D016116
1279971	103	113	piebaldism	SpecificDisease	D016116
1279971	289	299	piebaldism	SpecificDisease	D016116
1279971	301	319	mental retardation	DiseaseClass	D008607
1279971	325	354	multiple congenital anomalies	DiseaseClass	D000013
1279971	786	793	piebald	Modifier	D016116

3198117|t|Glucose-6-phosphate dehydrogenase variants and their frequency in Guangdong, China.
3198117|a|Erythrocyte glucose-6-phosphate dehydrogenase (G6PD) was characterized in blood samples obtained from 97 randomly selected males with enzyme deficiency from various regions of Guangdong Province, China. Nine new variants (Gd Kaiping, Gd Boluo, Gd Huiyang, Gd Gaomin, Gd Qing-Baijiang, Gd Gaozhou, Gd Huazhou, Gd Nanhai, and Gd Guangzhou) were identified. Of the 31 variants found in this province, Gd Kaiping, Gd Taiwan-Hakka, Gd Haad Yai, Gd Haad Yai-like and Gd Huiyang occurred most frequently. The frequency of each variant was calculated. The results demonstrated that the genetic heterogeneity of G6PD deficiency was high in this area.. 
3198117	218	235	enzyme deficiency	DiseaseClass	D008661
3198117	687	702	G6PD deficiency	SpecificDisease	D005955

10369860|t|A common molecular basis for rearrangement disorders on chromosome 22q11.
10369860|a|The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors. Three congenital anomaly disorders, cat-eye syndrome, der () syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11. VCFS/DGS is the most common syndrome associated with 22q11 rearrangements. In order to determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS patients were defined by haplotype analysis. Most VCFS/DGS patients have a similar 3 Mb deletion, some have a nested distal deletion breakpoint resulting in a 1. 5 Mb deletion and a few rare patients have unique deletions or translocations. The high prevalence of the disorder in the population and the fact that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements. To investigate this hypothesis, we developed hamster-human somatic hybrid cell lines from VCFS/DGS patients with all three classes of deletions and we now show that the breakpoints occur within similar low copy repeats, termed LCR22s. To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients. We present models to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders. We identified five additional copies of the LCR22 on 22q11 that may mediate other rearrangements leading to disease. 
10369860	29	52	rearrangement disorders	DiseaseClass	D002869
10369860	160	188	congenital anomaly disorders	DiseaseClass	D000013
10369860	193	209	malignant tumors	DiseaseClass	D018198
10369860	217	245	congenital anomaly disorders	DiseaseClass	D000013
10369860	247	263	cat-eye syndrome	SpecificDisease	C535918|OMIM:115470
10369860	265	280	der () syndrome	SpecificDisease	C535733
10369860	285	312	velo-cardio-facial syndrome	SpecificDisease	D004062
10369860	313	330	DiGeorge syndrome	SpecificDisease	D004062
10369860	332	336	VCFS	SpecificDisease	D004062
10369860	337	340	DGS	SpecificDisease	D004062
10369860	438	442	VCFS	SpecificDisease	D004062
10369860	443	446	DGS	SpecificDisease	D004062
10369860	660	664	VCFS	Modifier	D004062
10369860	665	668	DGS	Modifier	D004062
10369860	719	723	VCFS	Modifier	D004062
10369860	724	727	DGS	Modifier	D004062
10369860	1204	1208	VCFS	Modifier	D004062
10369860	1209	1212	DGS	Modifier	D004062
10369860	1486	1490	VCFS	Modifier	D004062
10369860	1491	1494	DGS	Modifier	D004062
10369860	1675	1703	congenital anomaly disorders	DiseaseClass	D000013

1424237|t|Typical and partial cat eye syndrome: identification of the marker chromosome by FISH.
1424237|a|Three children are reported with typical cat eye syndrome (CES) and three more children with partial CES because of absence of coloboma, in which the supernumerary marker chromosome was studied by FISH. Using a genomic library, and also a centromeric and particularly a cosmid probe of 22q11, partial tetrasomy was shown in all cases.. 
1424237	20	36	cat eye syndrome	SpecificDisease	C535918|OMIM:115470
1424237	128	144	cat eye syndrome	SpecificDisease	C535918|OMIM:115470
1424237	146	149	CES	SpecificDisease	C535918|OMIM:115470
1424237	188	191	CES	SpecificDisease	C535918|OMIM:115470
1424237	388	397	tetrasomy	DiseaseClass	D058670

1313112|t|An intrachromosomal insertion causing 5q22 deletion and familial adenomatous polyposis coli in two generations.
1313112|a|We report familial adenomatous polyposis coli (FAPC) with epidermoid cysts, osteomata, and areas of congenital hypertrophy of the retinal pigment epithelium (CHRPEs) in a male patient and his maternal aunt, both of whom suffered a mild to moderate degree of mental handicap. Both had an interstitial deletion of the long arm of chromosome 5 (del (5) (q22q23. 2)). Two other normal family members had the underlying direct insertion of chromosome 5 (dir ins (5) (q31. 3q22q23 3q22q23. 2)). Molecular genetic and fluorescent hybridisation studies have shown that loci D5S37 and D5S98 are outside the deletion whereas loci detected by probes EF5. 44 and YN5. 48 are lost. As expected, the molecular analyses indicate loss of one allele at the MCC and APC loci. The APC gene is located within band 5q22. Familial direct insertions should be considered as a cause of recurrent microdeletion syndromes.
1313112	56	91	familial adenomatous polyposis coli	SpecificDisease	D011125
1313112	122	157	familial adenomatous polyposis coli	SpecificDisease	D011125
1313112	159	163	FAPC	SpecificDisease	D011125
1313112	170	186	epidermoid cysts	SpecificDisease	D004814
1313112	188	197	osteomata	SpecificDisease	D010016
1313112	212	268	congenital hypertrophy of the retinal pigment epithelium	SpecificDisease	D012164
1313112	270	276	CHRPEs	SpecificDisease	D012164
1313112	370	385	mental handicap	DiseaseClass	D008607
1313112	860	863	APC	Modifier	D011125
1313112	874	877	APC	Modifier	D011125

1303170|t|Cloning of the Huntington disease region in yeast artificial chromosomes.
1303170|a|The gene responsible for Huntington disease has been localized to a 2. 5 million base pair (Mb) region between the loci D4S10 and D4S168 on the short arm of chromosome 4. As part of a strategy to clone the HD gene on the basis of its chromosomal location, we isolated genomic DNA from the HD region as a set of overlapping yeast artificial chromosome (YAC) clones. Twenty-eight YAC clones were identified by screening human YAC libraries with twelve PCR-based sequence-tagged sites (STSs) from the region. We assembled the YAC clones into overlapping sets by hybridizing them to a large number of DNA probes from the HD region, including the STSs. In addition, we isolated the ends of the human DNA inserts of most of the YAC clones to assist in the construction of the contig. Although almost half of the YACs appear to contain chimeric inserts and several contain internal deletions or other rearrangements, we were able to obtain over 2. 2 Mb of the HD region in YACs, including one continuous segment of 2. 0 Mb covering the region that most likely contains the HD gene. Ten of the twenty eight YAC clones comprise a minimal set spanning the 2. 2 Mb. These clones provide reagents for the complete characterization of this region of the genome and for the eventual isolation of the HD gene. 
1303170	15	33	Huntington disease	Modifier	D006816
1303170	99	117	Huntington disease	SpecificDisease	D006816
1303170	280	282	HD	Modifier	D006816
1303170	363	365	HD	Modifier	D006816
1303170	691	693	HD	Modifier	D006816
1303170	1027	1029	HD	Modifier	D006816
1303170	1140	1142	HD	Modifier	D006816
1303170	1360	1362	HD	Modifier	D006816

8113388|t|Three novel mutations in five unrelated subjects with hereditary protein S deficiency type I.
8113388|a|A panel of eight unrelated subjects with inherited type I protein S deficiency was screened for mutations in the PROS1 gene. In five subjects an abnormality was found but mutations were not detected in the remaining three subjects. Two subjects shared a G-- > A transition at position + 5 of the donor splice site consensus sequence of intron 10. Also in two subjects an A-- > T transversion was detected in the stopcodon of the PROS1 gene; this transversion predicts a protein S molecule that is extended by 14 amino acids. The fifth subject was found to possess two sequence abnormalities. One allele carried a G-- > A transition near the donor splice junction of intron 2, but this abnormality is probably neutral, since it was inherited from the parent with normal protein S antigen levels. In the other allele a single T insertion in codon -25 was found. Analysis of platelet RNA showed that only the mRNA with the A-- > T mutation in the stopcodon is present in amounts comparable to wildtype RNA. mRNA from the alleles with the other two mutations was either undetectable or present in greatly reduced amounts. The latter indicates that a mRNA based approach is not feasible for the genetic analysis of protein S deficiency type I.. 
8113388	65	92	protein S deficiency type I	SpecificDisease	D018455
8113388	145	172	type I protein S deficiency	SpecificDisease	D018455
8113388	1304	1331	protein S deficiency type I	SpecificDisease	D018455

3029599|t|A potential animal model for Lesch-Nyhan syndrome through introduction of HPRT mutations into mice.
3029599|a|The human Lesch-Nyhan syndrome is a rare neurological and behavioural disorder, affecting only males, which is caused by an inherited deficiency in the level of activity of the purine salvage enzyme hypoxanthine-guanosine phosphoribosyl transferase (HPRT). How the resulting alterations in purine metabolism lead to the severe symptoms characteristic of Lesch-Nyhan patients is still not understood. No mutations at the Hprt locus leading to loss of activity have been described in laboratory animals. To derive an animal model for the Lesch-Nyhan syndrome, we have used cultured mouse embryonic stem cells, mutagenized by retroviral insertion and selected for loss of HPRT activity, to construct chimaeric mice. Two clonal lines carrying different mutant Hprt alleles have given rise to germ cells in chimaeras, allowing the derivation of strains of mutant mice having the same biochemical defect as Lesch-Nyhan patients. Male mice carrying the mutant alleles are viable and analysis of their cells shows a total lack of HPRT activity.. 
3029599	29	49	Lesch-Nyhan syndrome	SpecificDisease	D007926
3029599	110	130	Lesch-Nyhan syndrome	SpecificDisease	D007926
3029599	141	178	neurological and behavioural disorder	DiseaseClass	D009422|D001523
3029599	224	244	inherited deficiency	DiseaseClass	D030342
3029599	454	465	Lesch-Nyhan	Modifier	D007926
3029599	636	656	Lesch-Nyhan syndrome	SpecificDisease	D007926
3029599	1001	1012	Lesch-Nyhan	Modifier	D007926

2316519|t|Duplicational mutation at the Duchenne muscular dystrophy locus: its frequency, distribution, origin, and phenotypegenotype correlation.
2316519|a|Partial gene deletion is the major cause of mutation leading to Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Partial gene duplication has also been recognized in a few cases. We have conducted a survey for duplication in 72 unrelated nondeletion patients, analyzed by Southern blot hybridization with clones representing the entire DMD cDNA. With careful quantitative analysis of hybridization band intensity, 10 cases were found to carry a duplication of part of the gene, a frequency of 14% for nondeletion cases (10/72), or 6% for all cases (10/181). The extent of these duplications has been characterized according to the published exon-containing HindIII fragment map, and in six of the 10 duplications a novel restriction fragment that spanned the duplication junction was detected. The resulting translational reading frame of mRNA has been predicted for nine duplications. A shift of the reading frame was predicted in four of the six DMD cases and in one of the two intermediate cases, while the reading frame remained uninterrupted in both BMD cases. RFLP and quantitative Southern blot analyses revealed a grandpaternal origin of duplication in four families and grandmaternal origin in one family. In all five families, the duplication was found to originate from a single X chromosome. Unequal sister-chromatid exchange is proposed to be the mechanism for the formation of these duplications.. 
2316519	30	57	Duchenne muscular dystrophy	Modifier	D020388
2316519	201	228	Duchenne muscular dystrophy	SpecificDisease	D020388
2316519	230	233	DMD	SpecificDisease	D020388
2316519	239	264	Becker muscular dystrophy	SpecificDisease	C537666
2316519	266	269	BMD	SpecificDisease	C537666
2316519	495	498	DMD	Modifier	D020388
2316519	1107	1110	DMD	Modifier	D020388
2316519	1214	1217	BMD	Modifier	C537666

6087154|t|Molecular evidence for new mutation at the hprt locus in Lesch-Nyhan patients.
6087154|a|Hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC2. 4. 2. 8), which functions in the metabolic salvage of purines, is encoded by an X-linked gene in man. Partial HPRT deficiencies are associated with gouty arthritis, while absence of activity results in Lesch-Nyhan syndrome (L-N). L-N patients fail to reproduce and the heterozygous state appears to confer no selective advantage. Thus, Haldanes principle predicts that new mutations at the hprt locus must occur frequently in order for L-N syndrome to be maintained in the population. This constant introduction of new mutations would be expected to result in a heterogeneous collection of genetic lesions, some of which may be novel. As we report here, the mutations in the hprt gene of seven L-N patients, selected from an initial survey of 28 patients, have been characterized and all were found to be distinctly different, as predicted. The origin of one unusual mutation has been identified by analysis of DNA from four generations of family members. Further molecular analysis of the origin of new mutations at the hprt locus should aid in resolving the issue of an apparent difference in the frequency of hprt mutations in males and females 
6087154	57	68	Lesch-Nyhan	Modifier	D007926
6087154	248	265	HPRT deficiencies	DiseaseClass	OMIM:300323
6087154	286	301	gouty arthritis	SpecificDisease	D015210
6087154	340	360	Lesch-Nyhan syndrome	SpecificDisease	D007926
6087154	362	365	L-N	SpecificDisease	D007926
6087154	368	371	L-N	Modifier	D007926
6087154	574	586	L-N syndrome	SpecificDisease	D007926
6087154	728	743	genetic lesions	DiseaseClass	D020022
6087154	832	835	L-N	Modifier	D007926

3600793|t|The mapping of a cDNA from the human X-linked Duchenne muscular dystrophy gene to the mouse X chromosome.
3600793|a|The recent discovery of sequences at the site of the Duchenne muscular dystrophy (DMD) gene in humans has opened up the possibility of a detailed molecular analysis of the genes in humans and in related mammalian species. Until relatively recently, there was no obvious mouse model of this genetic disease for the development of therapeutic strategies. The identification of a mouse X-linked mutant showing muscular dystrophy, mdx, has provided a candidate mouse genetic homologue to the DMD locus; the relatively mild pathological features of mdx suggest it may have more in common with mutations of the Becker muscular dystrophy type at the same human locus, however. But the close genetic linkage of mdx to G6PD and Hprt on the mouse X chromosome, coupled with its comparatively mild pathology, have suggested that the mdx mutation may instead correspond to Emery Dreifuss muscular dystrophy which itself is closely linked to DNA markers at Xq28-qter in the region of G6PD on the human X chromosome. Using an interspecific mouse domesticus/spretus cross, segregating for a variety of markers on the mouse X chromosome, we have positioned on the mouse X chromosome sequences homologous to a DMD cDNA clone. These sequences map provocatively close to the mdx mutation and unexpectedly distant from sparse fur, spf, the mouse homologue of OTC (ornithine transcarbamylase) which is closely linked to DMD on the human X chromosome.. 
3600793	37	73	X-linked Duchenne muscular dystrophy	Modifier	D020388
3600793	159	186	Duchenne muscular dystrophy	Modifier	D020388
3600793	188	191	DMD	Modifier	D020388
3600793	396	411	genetic disease	DiseaseClass	D030342
3600793	513	531	muscular dystrophy	SpecificDisease	D009136
3600793	594	597	DMD	Modifier	D020388
3600793	711	736	Becker muscular dystrophy	Modifier	C537666
3600793	967	1000	Emery Dreifuss muscular dystrophy	SpecificDisease	D020389
3600793	1299	1302	DMD	Modifier	D020388
3600793	1505	1508	DMD	SpecificDisease	D020388

10094559|t|Identification of the mutation in the alkaptonuria mouse model.
10094559|a|Alkaptonuria (aku), an inborn error of metabolism caused by the loss of homogentisate 1, 2-dioxygenase (HGD), has been described in a mouse model created by ethylnitrosourea mutagenesis but the mutation in these mice has not previously been identified. We used RT-PCR to amplify the Hgd cDNA from Hgd (aku)/Hgd (aku) mice. Two products shorter than the wild-type product were amplified. Restriction mapping and DNA sequencing were then used to identify the Hgd (aku) mouse mutation, found to be a single base change in a splice donor consensus sequence, causing exon skipping and frame-shifted products. This base change allowed us to create a non-radioactive genotyping assay for this allele. 
10094559	38	50	alkaptonuria	Modifier	D000474
10094559	64	76	Alkaptonuria	SpecificDisease	D000474
10094559	78	81	aku	SpecificDisease	D000474
10094559	87	113	inborn error of metabolism	DiseaseClass	D008661

1347968|t|Common sequence motifs at the rearrangement sites of a constitutional X/autosome translocation and associated deletion.
1347968|a|Reciprocal chromosome translocations are common de novo rearrangements that occur randomly throughout the human genome. To learn about causative mechanisms, we have cloned and sequenced the breakpoints of a cytologically balanced constitutional reciprocal translocation, t (X; 4) (p21. 2; q31. 22), present in a girl with Duchenne muscular dystrophy (DMD). Physical mapping of the derivative chromosomes, after their separation in somatic cell hybrids, reveals that the translocation disrupts the DMD gene in Xp21 within the 18-kb intron 16. Restriction mapping and sequencing of clones that span both translocation breakpoints as well as the corresponding normal regions indicate the loss of approximately 5 kb in the formation of the derivative X chromosome, with 4-6 bp deleted from chromosome 4. RFLP and Southern analyses indicate that the de novo translocation is a paternal origin and that the fathers X chromosome contains the DNA that is deleted in the derivative X. Most likely, deletion and translation arose simultaneously from a complex rearrangement event that involves three chromosomal breakpoints. Short regions of sequence homology were present at the three sites. A 5-bp sequence, GGAAT, found exactly at the translocation breakpoints on both normal chromosomes X and 4, has been preserved only on the der (4) chromosome. It is likely that the X-derived sequence GGAATCA has been lost in the formation of the der (X) chromosome, as it matches an inverted GAATCA sequence present on the opposite strand exactly at the other end of the deleted 5-kb fragment. 
1347968	442	469	Duchenne muscular dystrophy	SpecificDisease	D020388
1347968	471	474	DMD	SpecificDisease	D020388
1347968	617	620	DMD	Modifier	D020388

10874302|t|The human factor IX gene as germline mutagen test: samples from Mainland China have the putatively endogenous pattern of mutation.
10874302|a|Germline mutations are the major source of genetic variation that allows a species to evolve over time but at the cost of Mendelian disease and genetic predisposition to multifactorial diseases. Previous analyses have revealed that the pattern of germline mutations in the factor IX gene (F9) is similar among a variety of ethnically and geographically diverse populations and compatible with the ancient pattern that has shaped the mammalian genome. Here, we compare the pattern of germline mutation in a population of hemophilia B patients from Mainland China (n = 66) to that in U. S. Caucasians, Blacks, and Mexican Hispanics and stratify by disease severity and ethnicity. The similar pattern of germline mutation in all ethnic groups studied to date provides additional data compatible with the inference that endogenous processes predominate in germline mutations. 
10874302	253	270	Mendelian disease	DiseaseClass	D030342
10874302	301	324	multifactorial diseases	DiseaseClass	D004194
10874302	651	663	hemophilia B	Modifier	D002836

3591825|t|Phenotype heterogeneity among hemizygotes in a family biochemically screened for adrenoleukodystrophy.
3591825|a|We report on two clinically, neurologically normal relatives of a boy affected by adrenoleukodystrophy (ALD); they were found repeatedly to have the biochemical defect of an ALD hemizygote. The assay consisted in the determination of very-long-chain fatty acids in lyophilized and reconstituted plasma. While no evidence of neurologic disease (leukodystrophy or myeloneuropathy) was present in these hemizygotes, adrenocortical insufficiency provoking compensatory high ACTH release was found in both. These findings should be taken into consideration when counseling families in which cases with clinically expressed ALD are represented in several generations.. 
3591825	81	101	adrenoleukodystrophy	SpecificDisease	D000326
3591825	185	205	adrenoleukodystrophy	SpecificDisease	D000326
3591825	207	210	ALD	SpecificDisease	D000326
3591825	277	280	ALD	Modifier	D000326
3591825	427	445	neurologic disease	DiseaseClass	D009422
3591825	447	461	leukodystrophy	SpecificDisease	D007966
3591825	465	480	myeloneuropathy	SpecificDisease	D009422
3591825	516	544	adrenocortical insufficiency	DiseaseClass	D000224
3591825	721	724	ALD	SpecificDisease	D000326

10721669|t|Novel mutations of the ATP7B gene in Japanese patients with Wilson disease.
10721669|a|Wilson disease (WD) is an autosomal recessive disorder characterized by copper accumulation in the liver, brain, kidneys, and corneas, and culminating in copper toxication in these organs. In this study, we analyzed mutations of the responsible gene, ATP7B, in four Japanese patients with WD. By direct sequencing, we identified five mutations, of which two were novel, and 16 polymorphisms, of which 6 were novel. The mutations 2871delC and 2513delA shift the reading frame so that truncated abnormal protein is expected. In contrast to these mutations found in patients with hepatic-type of early onset, the mutations A874V, R778L, and 3892delGTC were either missense mutations or in frame 1-amino acid deletion, and occurred in the patients with hepato-neurologic type of late onset. The mutations 2871delC and R778L have been previously reported in a relatively large number of Japanese patients. In particular, R778L is known to be more prevalent in Asian countries than in other countries of the world. Our data are compatible with the hypothesis that the mutations tend to occur in a population-specific manner. Therefore, the accumulation of the types of mutations in Japanese patients with WD will facilitate the fast and effective genetic diagnosis of WD in Japanese patients.. 
10721669	60	74	Wilson disease	SpecificDisease	D006527
10721669	76	90	Wilson disease	SpecificDisease	D006527
10721669	92	94	WD	SpecificDisease	D006527
10721669	102	130	autosomal recessive disorder	DiseaseClass	D030342
10721669	365	367	WD	SpecificDisease	D006527
10721669	1275	1277	WD	SpecificDisease	D006527
10721669	1338	1340	WD	SpecificDisease	D006527

7759106|t|Structural analysis of the 5' region of mouse and human Huntington disease genes reveals conservation of putative promoter region and di- and trinucleotide polymorphisms.
7759106|a|We have previously cloned and characterized the murine homologue of the Huntington disease (HD) gene and shown that it maps to mouse chromosome 5 within a region of conserved synteny with human chromosome 4p16. 3 3. Here we present a detailed comparison of the sequence of the putative promoter and the organization of the 5 genomic region of the murine (Hdh) and human HD genes encompassing the first five exons. We show that in this region these two genes share identical exon boundaries, but have different-size introns. Two dinucleotide (CT) and one trinucleotide intronic polymorphism in Hdh and an intronic CA polymorphism in the HD gene were identified. Comparison of 940-bp sequence 5 to the putative translation start site reveals a highly conserved region (78. 8% nucleotide identity) between Hdh and the HD gene from nucleotide -56 to -206 (of Hdh). Neither Hdh nor the HD gene have typical TATA or CCAAT elements, but both show one putative AP2 binding site and numerous potential Sp1 binding sites. The high sequence identity between Hdh and the HD gene for approximately 200 bp 5 to the putative translation start site indicates that these sequences may play a role in regulating expression of the Huntington disease gene 
7759106	56	74	Huntington disease	Modifier	D006816
7759106	243	261	Huntington disease	Modifier	D006816
7759106	263	265	HD	Modifier	D006816
7759106	541	543	HD	Modifier	D006816
7759106	807	809	HD	Modifier	D006816
7759106	986	988	HD	Modifier	D006816
7759106	1052	1054	HD	Modifier	D006816
7759106	1230	1232	HD	Modifier	D006816
7759106	1383	1401	Huntington disease	Modifier	D006816

6103091|t|Complement deficiency and nephritis. A report of a family.
6103091|a|A family is described in which three children had homozygous deficiency of C3 and in which both parents and two other children were heterozygous for the C3 null gene. One child with heterozygous C3 deficiency was found to have membranoproliferative glomerulonephritis; proteinuria and/or microscopical haematuria was present in all three homozygous C3-deficient children. All children with homozygous or heterozygous C3 deficiency were, to a varying degree, susceptible to infection. The only child of the family with normal complement had no increased risk of infection and no renal disease. This family study provides further support for the proposal that C3 deficiency predisposes to nephritis.. 
6103091	0	21	Complement deficiency	SpecificDisease	D007153
6103091	26	35	nephritis	SpecificDisease	D009393
6103091	120	136	deficiency of C3	SpecificDisease	OMIM:613779
6103091	254	267	C3 deficiency	SpecificDisease	OMIM:613779
6103091	308	326	glomerulonephritis	SpecificDisease	D005921
6103091	328	339	proteinuria	SpecificDisease	D011507
6103091	361	371	haematuria	SpecificDisease	D006417
6103091	408	420	C3-deficient	Modifier	OMIM:613779
6103091	476	489	C3 deficiency	SpecificDisease	OMIM:613779
6103091	637	650	renal disease	DiseaseClass	D007674
6103091	717	730	C3 deficiency	SpecificDisease	OMIM:613779
6103091	746	755	nephritis	SpecificDisease	D009393

1222588|t|Cytogenetic investigations in families with ataxia-telangiectasia.
1222588|a|Chromosomal studies were performed on peripheral blood lymphocytes and cultured skin fibroblasts from five Israeli-Moroccan families with ataxia-telangiectasia. A total of 24 individuals, including seven propositi, was investigated. Among the probands, significantly elevated rates of chromosome damage were observed in both blood and skin. Skin fibroblasts of affected individuals showed several orders of magnitude more chromosome breakage than lymphocytes. Increased rates of chromosome damage were also observed in the fibroblasts of some phenotypically normal family members (obligate heterozygotes and sibs) when compared to normal controls. An apparent abnormal clone of cells, possessing a large acrocentric marker chromosome (14q +), was observed in varying proportions among cells of all the propositi (2-5% of lymphocytes; 1-9% of fibroblasts).. 
1222588	44	65	ataxia-telangiectasia	SpecificDisease	D001260
1222588	205	226	ataxia-telangiectasia	SpecificDisease	D001260

7991123|t|Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in The Netherlands: a survey of 30 kindreds.
7991123|a|X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal beta-oxidation associated with accumulation of saturated very long-chain fatty acids, which results in central and peripheral demyelination and in impaired function of adrenal cortex and testes. The phenotypic expression is highly variable, childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN) being the main variants. We explored the 30 Dutch kindreds well known to the Dutch X-ALD/AMN Study Group and phenotyped 77 male patients  35 (46%) had AMN and 24 (31%) CCALD or adolescent cerebral ALD (AdolCALD). These percentages differ significantly from previous reports, in which 25 to 28% of the patients developed AMN and 53 to 57% CCALD or AdolCALD. Our findings indicate that--at least in the Netherlands--AMN may be the most frequent phenotype of X-ALD.. 
7991123	20	41	adrenomyeloneuropathy	Modifier	D000326
7991123	55	84	X-linked adrenoleukodystrophy	SpecificDisease	D000326
7991123	130	159	X-linked adrenoleukodystrophy	SpecificDisease	D000326
7991123	161	166	X-ALD	SpecificDisease	D000326
7991123	174	192	inherited disorder	DiseaseClass	D030342
7991123	334	347	demyelination	DiseaseClass	D003711
7991123	355	401	impaired function of adrenal cortex and testes	CompositeMention	D000303
7991123	449	471	childhood cerebral ALD	SpecificDisease	D000326
7991123	473	478	CCALD	SpecificDisease	D000326
7991123	484	505	adrenomyeloneuropathy	SpecificDisease	D000326
7991123	507	510	AMN	SpecificDisease	D000326
7991123	595	600	X-ALD	Modifier	D000326
7991123	601	604	AMN	Modifier	D000326
7991123	663	666	AMN	SpecificDisease	D000326
7991123	680	685	CCALD	SpecificDisease	D000326
7991123	689	712	adolescent cerebral ALD	SpecificDisease	D000326
7991123	714	722	AdolCALD	SpecificDisease	D000326
7991123	832	835	AMN	SpecificDisease	D000326
7991123	850	855	CCALD	SpecificDisease	D000326
7991123	859	867	AdolCALD	SpecificDisease	D000326
7991123	926	929	AMN	SpecificDisease	D000326
7991123	968	973	X-ALD	SpecificDisease	D000326

7550230|t|Three novel aniridia mutations in the human PAX6 gene.
7550230|a|Aniridia (iris hypoplasia) is an autosomal dominant congenital disorder of the eye. Mutations in the human aniridia (PAX6) gene have now been identified in many patients from various ethnic groups. In the study reported here we describe PAX6 mutations in one sporadic and five familial cases with aniridia. Of the four different mutations identified, one was identical to a previously reported mutation (C-- > T transition at codon 240), and three were novel  two in the glycine-rich region and one in the proline/serine/threonine-rich (PST) region. One PAX6 mutation found in the PST region was associated with cataracts in an aniridia family. Another splice mutation in the PST domain occurred in an aniridia patient with anosmia (inability to smell). The six new aniridia cases reported here have mutations predicted to generate incomplete PAX6 proteins. These results support the theory that human aniridia is caused by haploinsufficiency of PAX6.. 
7550230	12	20	aniridia	Modifier	D015783
7550230	55	63	Aniridia	SpecificDisease	D015783
7550230	65	80	iris hypoplasia	SpecificDisease	D007499
7550230	88	137	autosomal dominant congenital disorder of the eye	DiseaseClass	D005124
7550230	162	170	aniridia	Modifier	D015783
7550230	352	360	aniridia	SpecificDisease	D015783
7550230	667	676	cataracts	SpecificDisease	D002386
7550230	683	691	aniridia	Modifier	D015783
7550230	757	765	aniridia	Modifier	D015783
7550230	779	786	anosmia	SpecificDisease	D000857
7550230	821	829	aniridia	Modifier	D015783
7550230	957	965	aniridia	SpecificDisease	D015783
7550230	979	1005	haploinsufficiency of PAX6	SpecificDisease	OMIM:106210 

3354603|t|Hepatoblastoma, pigmented ocular fundus lesions and jaw lesions in Gardner syndrome.
3354603|a|Hepatoblastoma is a rare neoplasm of infants and children only recently documented in association with hereditary adenomatous polyposis of the colon [Kingston et al., 1983]. We report four children with hepatoblastoma from four unrelated families with Gardner syndrome (GS). One child, now 19 years old, survived after a resection of a hepatoblastoma in infancy and recently was found to have GS. He has an associated odontoma and pigmented ocular fundus lesions, both of which have been shown to be clinical markers of GS. Many individuals in these four GS families, both affected and at risk, have osteomatous jaw lesions and pigmented ocular fundus lesions. A search for colonic polyps should be made in families of infants and children with hepatoblastoma. If the child survives, he or she should be monitored for the later appearance of colonic polyps. The finding of jaw lesions and/or pigmented ocular fundus lesions in relatives at risk are indications of the possible presence of the GS gene. 
3354603	0	14	Hepatoblastoma	SpecificDisease	D018197
3354603	16	47	pigmented ocular fundus lesions	DiseaseClass	D015821
3354603	52	63	jaw lesions	DiseaseClass	D007571
3354603	67	83	Gardner syndrome	SpecificDisease	D005736
3354603	85	99	Hepatoblastoma	SpecificDisease	D018197
3354603	110	118	neoplasm	DiseaseClass	D009369
3354603	188	233	hereditary adenomatous polyposis of the colon	SpecificDisease	D011125
3354603	288	302	hepatoblastoma	SpecificDisease	D018197
3354603	337	353	Gardner syndrome	SpecificDisease	D005736
3354603	355	357	GS	SpecificDisease	D005736
3354603	421	435	hepatoblastoma	SpecificDisease	D018197
3354603	478	480	GS	SpecificDisease	D005736
3354603	503	511	odontoma	SpecificDisease	D009810
3354603	516	547	pigmented ocular fundus lesions	DiseaseClass	D015821
3354603	605	607	GS	SpecificDisease	D005736
3354603	640	642	GS	Modifier	D005736
3354603	685	708	osteomatous jaw lesions	DiseaseClass	D007571
3354603	713	744	pigmented ocular fundus lesions	DiseaseClass	D015821
3354603	759	773	colonic polyps	DiseaseClass	D003111
3354603	830	844	hepatoblastoma	SpecificDisease	D018197
3354603	927	941	colonic polyps	DiseaseClass	D003111
3354603	958	969	jaw lesions	DiseaseClass	D007571
3354603	977	1008	pigmented ocular fundus lesions	DiseaseClass	D015821
3354603	1078	1080	GS	Modifier	D005736

7981671|t|Mutation spectrum in the CHM gene of Danish and Swedish choroideremia patients.
7981671|a|The recent isolation of the complete open reading frame of the choroideremia (CHM) gene and the characterization of the exon-intron boundaries has paved the way to mutation detection in patients with classical choroideremia. We have performed mutation screening in patients from 15 Danish and Swedish families by using Southern blot hybridization and the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) technique. Causative mutations in the CHM gene were detected in at least 12 families, indicating that a substantial part of the mutations can be identified by this approach. In four of these families deletions of different sizes were found. Thus, in one patient, the deletion resulted in the absence of only one exon, while in another the deletion comprised the entire CHM gene. Mapping of the deletion endpoints in these four patients and in another 11 male patients with sizeable deletions enabled us to construct a very detailed map of intervals 2 and 3 of Xq21. In the remaining 11 Danish and Swedish families at least 8 causative mutations were found by PCR-SSCP analysis and direct sequencing. Interestingly, all CHM gene mutations detected thus far in choroideremia patients give rise to the introduction of a premature stop codon.. 
7981671	25	28	CHM	Modifier	D015794
7981671	56	69	choroideremia	Modifier	D015794
7981671	143	156	choroideremia	Modifier	D015794
7981671	158	161	CHM	Modifier	D015794
7981671	290	303	choroideremia	SpecificDisease	D015794
7981671	550	553	CHM	Modifier	D015794
7981671	881	884	CHM	Modifier	D015794
7981671	1231	1234	CHM	Modifier	D015794
7981671	1271	1284	choroideremia	Modifier	D015794

1562739|t|Diverse point mutations result in glucose-6-phosphate dehydrogenase (G6PD) polymorphism in Taiwan.
1562739|a|Glucose-6-PHOSPHATE dehydrogenase (G6PD; EC 1.1. 1. 49) deficiency is the most common human enzymopathy, affecting more than 200 million people worldwide. Although greater than 400 variants have been described based on clinical and biochemical criteria, little is known about the molecular basis of these G6PD deficiencies. Recently, the gene that encodes human G6PD has been cloned and sequenced, which enables us to examine directly the heterogeneity of G6PD at the DNA level. During the past 10 years, we examined the G6PD activity in 21, 271 newborn Chinese infants (11, 400 males and 9, 871 females) and identified 314 (2. 8%) males and 246 (2. 5%) females having low G6PD activity. The G6PD gene from 10 randomly selected affected individuals and their relatives was polymerase chain reaction (PCR) amplified, subcloned, and sequenced. Our results indicate that at least four types of mutation are responsible for the G6PD polymorphism in Taiwan. The first type of mutation (487 G----A) was found in an affected Chinese with a G to A change at nucleotide 487, which results in a (163) Gly to Ser substitution. The second type of mutation (493 A----G) is a novel mutation that has not been reported in any other ethnic group and was identified in two affected Chinese. This mutation causes an A to G change at nucleotide position 493, producing an (165) Asn to Asp substitution. Interestingly, the 487 G----A and 493 A----G mutations create Alu I and Ava II recognition sites, respectively, which enabled us to rapidly detect these two mutations by PCR/restriction enzyme (RE) digestion method. The third mutation (1376 G----T) was found in four affected Chinese. This mutation causes a G to T change at nucleotide position 1376 that results in an (459) Arg to Leu substitution. The 1376 G----T mutation seems to be the dominant allele that causes G6PD deficiency in Taiwan. Finally, two affected Chinese were identified as having the fourth mutation (1388 G----A). This mutation causes a G to A change at nucleotide 1388 that produces an (463) Arg to His substitution. Our studies provide the direct proof of the genetic heterogeneity of G6PD deficiency in the Chinese populations of Taiwan and the PCR/RE digestion method is suitable for simultaneous detection of the 487 G----A and 493 A----G mutations.
1562739	99	165	Glucose-6-PHOSPHATE dehydrogenase (G6PD; EC 1.1. 1. 49) deficiency	SpecificDisease	D005955
1562739	191	202	enzymopathy	DiseaseClass	D008661
1562739	404	421	G6PD deficiencies	SpecificDisease	D005955
1562739	1952	1967	G6PD deficiency	SpecificDisease	D005955
1562739	2243	2258	G6PD deficiency	SpecificDisease	D005955

10875918|t|Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations.
10875918|a|Heterozygous mutations encoding abnormal forms of the death receptor Fas dominantly interfere with Fas-induced lymphocyte apoptosis in human autoimmune lymphoproliferative syndrome. This effect, rather than depending on ligand-induced receptor oligomerization, was found to stem from ligand- independent interaction of wild-type and mutant Fas receptors through a specific region in the extracellular domain. Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein. These results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.. 
10875918	242	281	autoimmune lymphoproliferative syndrome	SpecificDisease	D056735

8434621|t|Familial Mediterranean fever in the colchicine era: the fate of one family.
8434621|a|In order to demonstrate the effect of prophylactic colchicine treatment on the natural history of familial Mediterranean fever (FMF), a family is presented with 6 out of 9 siblings affected by FMF. Each patient represents a different stage of the amyloidotic kidney disease of FMF and the effect of continuous colchicine treatment on its course. Considered together, the members of this family present an almost complete clinical, genetic, and behavioral picture of the disease.. 
8434621	0	28	Familial Mediterranean fever	SpecificDisease	D010505
8434621	174	202	familial Mediterranean fever	SpecificDisease	D010505
8434621	204	207	FMF	SpecificDisease	D010505
8434621	269	272	FMF	SpecificDisease	D010505
8434621	323	349	amyloidotic kidney disease	SpecificDisease	D007674
8434621	353	356	FMF	SpecificDisease	D010505

1684088|t|Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient.
1684088|a|Fragments of the arylsulfatase A (ARSA) gene from a patient with juvenile-onset metachromatic leukodystrophy (MLD) were amplified by PCR and ligated into MP13 cloning vectors. Clones hybridizing with cDNA for human ARSA were selected, examined for appropriate size inserts, and used to prepare single-stranded phage DNA. Examination of the entire coding and most of the intronic sequence revealed two putative disease-related mutations. One, a point mutation in exon 3, resulted in the substitution of isoleucine by serine. Introduction of this alteration into the normal ARSA cDNA sequence resulted in a substantial decrease in ARSA activity on transient expression in cultured baby hamster kidney cells. About 5% of the control expression was observed, suggesting a small residual activity in the mutated ARSA. The second mutation, a G-to-A transition, occurred in the other allele and resulted in an altered splice-recognition sequence between exon 7 and the following intron. The mutation also resulted in the loss of a restriction site. Apparently normal levels of mRNA were generated from this allele, but no ARSA activity or immuno-cross-reactive material could be detected. A collection of DNA samples from known or suspected MLD patients, members of their families, and normal controls was screened for these mutations. Four additional individuals carrying each of the mutations were found among the nearly 100 MLD patients in the sample. Gene segregation in the original patients family was consistent with available clinical and biochemical data. No individuals homozygous for either of these two mutations were identified. However, combinations with other MLD mutations suggest that the point mutation in exon 3 does result in some residual enzyme activity and is associated with late-onset forms of the disease. The splice-site mutation following exon 7 produces late-infantile MLD when combined with other enzyme-null mutations, implying that it is completely silent enzymatically.. 
1684088	55	83	metachromatic leukodystrophy	Modifier	D007966
1684088	85	88	MLD	Modifier	D007966
1684088	179	207	metachromatic leukodystrophy	SpecificDisease	D007966
1684088	209	212	MLD	SpecificDisease	D007966
1684088	1333	1336	MLD	Modifier	D007966
1684088	1519	1522	MLD	Modifier	D007966
1684088	1767	1770	MLD	Modifier	D007966
1684088	1990	1993	MLD	SpecificDisease	D007966

10441329|t|Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation.
10441329|a|The Atp7b protein is a copper-transporting ATPase expressed predominantly in the liver and to a lesser extent in most other tissues. Mutations in the ATP7B gene lead to Wilson disease, a copper toxicity disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neuro-logical abnormalities. Using homologous recombination to disrupt the normal translation of ATP7B, we have generated a strain of mice that are homozygous mutants (null) for the Wilson disease gene. The ATP7B null mice display a gradual accumulation of hepatic copper that increases to a level 60-fold greater than normal by 5 months of age. An increase in copper concentration was also observed in the kidney, brain, placenta and lactating mammary glands of homo-zygous mutants, although milk from the mutant glands was copper deficient. Morphological abnormalities resembling cirrhosis developed in the majority of the livers from homozygous mutants older than 7 months of age. Progeny of the homozygous mutant females demonstrated neurological abnormalities and growth retardation characteristic of copper deficiency. Copper concentration in the livers of the newborn homozygous null mutants was decreased dramatically. In summary, inactivation of the murine ATP7B gene produces a form of cirrhotic liver disease that resembles Wilson disease in humans and the toxic milk phenotype in the mouse.. 
10441329	35	49	Wilson disease	SpecificDisease	D006527
10441329	67	100	intracellular copper accumulation	DiseaseClass	C535468
10441329	105	146	late-onset hepatic nodular transformation	DiseaseClass	D020518
10441329	317	331	Wilson disease	SpecificDisease	D006527
10441329	335	359	copper toxicity disorder	DiseaseClass	C535468
10441329	443	482	hepatic and neuro-logical abnormalities	CompositeMention	D008107|D009422
10441329	637	651	Wilson disease	Modifier	D006527
10441329	980	996	copper deficient	DiseaseClass	C535468
10441329	998	1025	Morphological abnormalities	DiseaseClass	D000013
10441329	1037	1046	cirrhosis	SpecificDisease	D008103
10441329	1193	1219	neurological abnormalities	DiseaseClass	D009461
10441329	1224	1242	growth retardation	DiseaseClass	D006130
10441329	1261	1278	copper deficiency	SpecificDisease	C535468
10441329	1451	1474	cirrhotic liver disease	DiseaseClass	D008103
10441329	1490	1504	Wilson disease	SpecificDisease	D006527

218453|t|Adrenoleukodystrophy and adrenomyeloneuropathy associated with partial adrenal insufficiency in three generations of a kindred.
218453|a|Four cases of adrenoleukodystrophy (ALD) and one case of adrenomyeloneuropathy (AMN) have developed in a kindred over three generations demonstrating that AMN is a clinical variant of ALD. Pituitary-adrenal function studies were performed in 10 family members, including two affected males and four females identified as carriers of ALD/AMN. No pituitary-adrenal abnormality was found in the carriers. However, basal morning plasma adrenocorticotropic hormone (ACTH) levels were markedly elevated in the two males with ALD and AMN, despite the fact that they had no clinical signs of adrenal insufficiency and that morning plasma cortisol levels and their response to maximal exogenous ACTH stimulation appeared to be normal. In addition, the integrated 24-hour response to the administration were also subnormal in these two cases. Thus, people with ALD and AMN may have subclinical partial adrenocrotical insufficiency. No other endocrinologic dysfunction was identified.. 
218453	0	20	Adrenoleukodystrophy	SpecificDisease	D000326
218453	25	46	adrenomyeloneuropathy	SpecificDisease	D000326
218453	71	92	adrenal insufficiency	DiseaseClass	D000309
218453	142	162	adrenoleukodystrophy	SpecificDisease	D000326
218453	164	167	ALD	SpecificDisease	D000326
218453	185	206	adrenomyeloneuropathy	SpecificDisease	D000326
218453	208	211	AMN	SpecificDisease	D000326
218453	283	286	AMN	SpecificDisease	D000326
218453	312	315	ALD	SpecificDisease	D000326
218453	461	464	ALD	SpecificDisease	D000326
218453	465	468	AMN	SpecificDisease	D000326
218453	473	502	pituitary-adrenal abnormality	DiseaseClass	D010900+D000307
218453	647	650	ALD	SpecificDisease	D000326
218453	655	658	AMN	SpecificDisease	D000326
218453	712	733	adrenal insufficiency	DiseaseClass	D000309
218453	979	982	ALD	SpecificDisease	D000326
218453	987	990	AMN	SpecificDisease	D000326
218453	1020	1048	adrenocrotical insufficiency	DiseaseClass	D000224
218453	1059	1085	endocrinologic dysfunction	DiseaseClass	D004700

8566952|t|Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy.
8566952|a|Adrenoleukodystrophy (ALD), an X-linked inherited metabolic disorder, is the most frequent inborn peroxisomal disease. It leads to demyelination in the central and peripheral nervous system. Defective beta-oxidation of saturated very long chain fatty acids (VLCFAs; C22  0-C26  0) in peroxisomes has been shown to lead to an accumulation of VLCFAs in leukoid areas of the central nervous system, peripheral nerves, adrenal gland, and blood. The ALD gene has been recently identified and encodes a 745-amino-acid protein. We screened patients with adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN) from 20 kindreds for mutations in the ALD gene. Eleven missense and two nonsense mutations, five deletions, and one insertion were detected by direct sequencing of eight reverse transcribed fragments of the ALD-gene mRNA. Four mutations could be shown to be de novo. All mutations could be confirmed in carriers by sequencing genomic DNA. No correlation between the type of mutation and the severity of the phenotype could be observed. The mutations were not detected in the ALD gene of 30 healthy persons.. 
8566952	64	84	adrenoleukodystrophy	SpecificDisease	D000326
8566952	85	106	adrenomyeloneuropathy	SpecificDisease	D000326
8566952	108	128	Adrenoleukodystrophy	SpecificDisease	D000326
8566952	130	133	ALD	SpecificDisease	D000326
8566952	139	176	X-linked inherited metabolic disorder	DiseaseClass	D008661
8566952	199	225	inborn peroxisomal disease	DiseaseClass	D018901
8566952	239	297	demyelination in the central and peripheral nervous system	DiseaseClass	D003711
8566952	553	556	ALD	Modifier	D000326
8566952	655	675	adrenoleukodystrophy	SpecificDisease	D000326
8566952	676	697	adrenomyeloneuropathy	SpecificDisease	D000326
8566952	699	702	ALD	SpecificDisease	D000326
8566952	703	706	AMN	SpecificDisease	D000326
8566952	746	749	ALD	Modifier	D000326
8566952	915	918	ALD	Modifier	D000326
8566952	1183	1186	ALD	Modifier	D000326

8128954|t|Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG)n repeat variation and selection against extreme expansion in sperm.
8128954|a|Myotonic dystrophy (DM) is caused by abnormal expansion of a polymorphic (CTG) n repeat, located in the DM protein kinase gene. We determined the (CTG) n repeat lengths in a broad range of tissue DNAs from patients with mild, classical, or congenital manifestation of DM. Differences in the repeat length were seen in somatic tissues from single DM individuals and twins. Repeats appeared to expand to a similar extent in tissues originating from the same embryonal origin. In most male patients carrying intermediate- or small-sized expansions in blood, the repeat lengths covered a markedly wider range in sperm. In contrast, male patients with large allele expansions in blood (> 700 CTGs) had similar or smaller repeats in sperm, when detectable. Sperm alleles with > 1, 000 CTGs were not seen. We conclude that DM patients can be considered gonosomal mosaics, i. e e., combined somatic and germ-line tissue mosaics. Most remarkably, we observed multiple cases where the length distributions of intermediate- or small-sized alleles in fathers sperm were significantly different from that in their offsprings blood. Our combined findings indicate that intergenerational length changes in the unstable CTG repeat are most likely to occur during early embryonic mitotic divisions in both somatic and germ-line tissue formation. Both the initial CTG length, the overall number of cell divisions involved in tissue formation, and perhaps a specific selection process in spermatogenesis may influence the dynamics of this process. A model explaining mitotic instability and sex-dependent segregation phenomena in DM manifestation is discussed 
8128954	23	41	myotonic dystrophy	Modifier	D009223
8128954	159	177	Myotonic dystrophy	SpecificDisease	D009223
8128954	179	181	DM	SpecificDisease	D009223
8128954	263	265	DM	Modifier	D009223
8128954	427	429	DM	Modifier	D009223
8128954	505	507	DM	Modifier	D009223
8128954	975	977	DM	Modifier	D009223
8128954	1770	1772	DM	Modifier	D009223

10712209|t|Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics.
10712209|a|A previous linkage study provided evidence for a prostate cancer-susceptibility locus at 1q24-25. Subsequent reports in additional collections of families have yielded conflicting results. In addition, evidence for locus heterogeneity has been provided by the identification of other putative hereditary prostate cancer loci on Xq27-28, 1q42-43, and 1p36. The present study describes a combined analysis for six markers in the 1q24-25 region in 772 families affected by hereditary prostate cancer and ascertained by the members of the International Consortium for Prostate Cancer Genetics (ICPCG) from North America, Australia, Finland, Norway, Sweden, and the United Kingdom. Overall, there was some evidence for linkage, with a peak parametric multipoint LOD score assuming heterogeneity (HLOD) of 1. 40 (P =. 01) at D1S212. The estimated proportion of families (alpha) linked to the locus was. 06 (1-LOD support interval. 01-. 12). This evidence was not observed by a nonparametric approach, presumably because of the extensive heterogeneity. Further parametric analysis revealed a significant effect of the presence of male-to-male disease transmission within the families. In the subset of 491 such families, the peak HLOD was 2. In the subset of 491 such families, the peak HLOD was 2. 56 (P =. 0006) and alpha =. 11 (1-LOD support interval. 04-. 19), compared with HLODs of 0 in the remaining 281 families. Within the families with male-to-male disease transmission, alpha increased with the early mean age at diagnosis (< 65 years, alpha =. 19, with 1-LOD support interval. 06-. 34) and the number of affected family members (five or more family members, alpha =. 15, with 1-LOD support interval. 04-. 28). The highest value of alpha was observed for the 48 families that met all three criteria (peak HLOD = 2. 25, P =. 001, alpha =. 29, with 1-LOD support interval. 08-. 53). These results support the finding of a prostate cancer-susceptibility gene linked to 1q24-25, albeit in a defined subset of prostate cancer families. Although HPC1 accounts for only a small proportion of all families affected by hereditary prostate cancer, it appears to play a more prominent role in the subset of families with several members affected at an early age and with male-to-male disease transmission.
10712209	21	47	hereditary prostate cancer	Modifier	C537243
10712209	85	111	hereditary prostate cancer	Modifier	C537243
10712209	159	174	Prostate Cancer	Modifier	D011471
10712209	234	249	prostate cancer	Modifier	D011471
10712209	478	504	hereditary prostate cancer	Modifier	C537243
10712209	655	681	hereditary prostate cancer	SpecificDisease	C537243
10712209	749	764	Prostate Cancer	Modifier	D011471
10712209	2109	2124	prostate cancer	Modifier	D011471
10712209	2194	2209	prostate cancer	Modifier	D011471
10712209	2299	2325	hereditary prostate cancer	SpecificDisease	C537243

8466512|t|A novel disease with deficiency of mitochondrial very-long-chain acyl-CoA dehydrogenase.
8466512|a|Palmitoyl-CoA dehydrogenase activity in skin fibroblasts from seven patients with unidentified defects of fatty acid oxidation was measured in the presence and absence of antibodies against medium-chain, long-chain, and very-long-chain acyl-CoA dehydrogenases (VLCAD). Two of the patients, 4-5 month old boys, were found to have a novel disease, VLCAD deficiency, as judged from the results of very low palmitoyl-CoA dehydrogenase activity and the lack of immunoreactivity toward antibody raised to purified VLCAD.. 
8466512	21	87	deficiency of mitochondrial very-long-chain acyl-CoA dehydrogenase	SpecificDisease	C536353
8466512	435	451	VLCAD deficiency	SpecificDisease	C536353

1327525|t|Inherited WT1 mutation in Denys-Drash syndrome.
1327525|a|Patients with the Denys-Drash syndrome (Wilms tumor, genital anomalies, and nephropathy) have been demonstrated to carry de novo constitutional mutations in WT1, the Wilms tumor gene at chromosome 11p13. We report three new cases, two carrying a previously described WT1 exon 9 mutation and one with a novel WT1 exon 8 mutation. However, unlike patients in previous reports, one of our three patients inherited the affected allele from his phenotypically unaffected father. This observation indicates that the WT1 exon 9 mutation affecting 394Arg demonstrated in over one-half of the patients with the Denys-Drash syndrome may exhibit incomplete penetrance. Consequently, familial studies in patients affected by this syndrome are recommended.. 
1327525	26	46	Denys-Drash syndrome	SpecificDisease	D030321
1327525	66	86	Denys-Drash syndrome	SpecificDisease	D030321
1327525	88	99	Wilms tumor	SpecificDisease	D009396
1327525	101	118	genital anomalies	DiseaseClass	D014564
1327525	124	135	nephropathy	SpecificDisease	D007674
1327525	214	225	Wilms tumor	Modifier	D009396
1327525	650	670	Denys-Drash syndrome	SpecificDisease	D030321

2008213|t|Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter.
2008213|a|Glucose/galactose malabsorption (GGM) is an autosomal recessive disease manifesting within the first weeks of life and characterized by a selective failure to absorb dietary glucose and galactose from the intestine. The consequent severe diarrhoea and dehydration are usually fatal unless these sugars are eliminated from the diet. Intestinal biopsies of GGM patients have revealed a specific defect in Na (+) -dependent absorption of glucose in the brush border. Normal glucose absorption is mediated by the Na +/glucose cotransporter in the brush border membrane of the intestinal epithelium. Cellular influx is driven by the transmembrane Na + electrochemical potential gradient; thereafter the sugar moves to the blood across the basolateral membrane via the facilitated glucose carrier. We have previously cloned and sequenced a Na +/glucose cotransporter from normal human ileum and shown that this gene, SGLT1, resides on the distal q arm of chromosome 22. We have now amplified SGLT1 complementary DNA and genomic DNA from members of a family affected with GGM by the polymerase chain reaction. Sequence analysis of the amplified products has revealed a single missense mutation in SGLT1 which cosegregates with the GGM phenotype and results in a complete loss of Na (+) -dependent glucose transport in Xenopus oocytes injected with this complementary RNA.. 
2008213	0	31	Glucose/galactose malabsorption	SpecificDisease	OMIM:606824
2008213	85	116	Glucose/galactose malabsorption	SpecificDisease	OMIM:606824
2008213	118	121	GGM	SpecificDisease	OMIM:606824
2008213	129	156	autosomal recessive disease	DiseaseClass	D030342
2008213	323	332	diarrhoea	SpecificDisease	D003967
2008213	337	348	dehydration	SpecificDisease	D003681
2008213	440	443	GGM	Modifier	OMIM:606824
2008213	1150	1153	GGM	SpecificDisease	OMIM:606824
2008213	1309	1312	GGM	Modifier	OMIM:606824

10639175|t|Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system.
10639175|a|Ataxia-telangiectasia is a hereditary multisystemic disease resulting from mutations of ataxia telangiectasia, mutated (ATM) and is characterized by neurodegeneration, cancer, immune defects, and hypersensitivity to ionizing radiation. The molecular details of ATM function in the nervous system are unclear, although the neurological lesion in ataxia-telangiectasia becomes apparent early in life, suggesting a developmental origin. The central nervous system (CNS) of Atm-null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting ATM functions to eliminate neurons with excessive genomic damage. Here, we report that the death effector Bax is required for a large proportion of Atm-dependent apoptosis in the developing CNS after ionizing radiation (IR). Although many of the same regions of the CNS in both Bax-/- and Atm-/- mice were radioresistant, mice nullizygous for both Bax and Atm showed additional reduction in IR-induced apoptosis in the CNS. Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm- and Bax-independent branches. Further, Atm- and Bax-dependent apoptosis in the CNS also required caspase-3 activation. These data implicate Bax and caspase-3 as death effectors in neurodegenerative pathways.. 
10639175	93	114	Ataxia-telangiectasia	SpecificDisease	D001260
10639175	120	152	hereditary multisystemic disease	DiseaseClass	D030342
10639175	181	202	ataxia telangiectasia	SpecificDisease	D001260
10639175	242	259	neurodegeneration	DiseaseClass	D019636
10639175	261	267	cancer	DiseaseClass	D009369
10639175	269	283	immune defects	DiseaseClass	D007154
10639175	289	327	hypersensitivity to ionizing radiation	DiseaseClass	D004194
10639175	415	434	neurological lesion	DiseaseClass	D019636
10639175	438	459	ataxia-telangiectasia	SpecificDisease	D001260

1301190|t|Novel Tay-Sachs disease mutations from China.
1301190|a|We describe three HEXA mutations associated with infantile Tay-Sachs disease (TSD) in three unrelated nonconsanguineous Chinese families. Novel mutations were found in two of these families. The third is a previously reported mutation (G-- > A transition at nt 1444) (Nakano et al., 1988). Direct sequencing of PCR products identified a novel insertion of an A after nt 547 in family 1. This change generates an early termination codon 6 bp downstream from the insertion site. Allele-specific oligonucleotide hybridization confirmed homozygosity in the proband. Single strand conformational polymorphism analysis and direct sequencing of amplified exon 13 revealed a T-- > C transition at nt 1453 with the corresponding amino acid substitution W485R in the second family. This mutation creates an Fnu4HI restriction site. The proband is homozygous for this allele. When the site-specific mutagenized alpha cDNA carrying the T-- > C transition at nt 1453 was expressed in COS 1 cells hexosaminidase S activity was not detectable above background. A G-- > A transition at nt 1444 (exon 13) corresponding to the E482K substitution was found in the third family. This mutation occurs at a CpG dinucleotide. It has been reported in an Italian TSD proband and causes defective intracellular transport of the alpha-subunit from the rough endoplasmic reticulum to the Golgi apparatus. 
1301190	6	23	Tay-Sachs disease	Modifier	D013661
1301190	105	122	Tay-Sachs disease	SpecificDisease	D013661
1301190	124	127	TSD	SpecificDisease	D013661
1301190	1284	1287	TSD	Modifier	D013661

3348216|t|Glucose 6-phosphate dehydrogenase deficiency and incidence of hematologic malignancy.
3348216|a|We have evaluated the hypothesis of a negative association between glucose 6-phosphate dehydrogenase (G6PD) deficiency and cancer in a cohort of 481 Sardinian males with hematological malignancies. The frequency of G6PD deficiency in the patients was not different from the incidence in a group of 16, 219 controls. The same conclusion resulted from the comparison of the frequency of expression of the GdB gene in 23 heterozygous women having a clonal hematologic disease and a control group of 37 healthy heterozygotes. Therefore at present there is no evidence that G6PD deficiency has a protective effect against development of hematologic neoplasms.. 
3348216	0	44	Glucose 6-phosphate dehydrogenase deficiency	SpecificDisease	D005955
3348216	62	84	hematologic malignancy	DiseaseClass	D019337
3348216	153	204	glucose 6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
3348216	209	215	cancer	DiseaseClass	D009369
3348216	256	282	hematological malignancies	DiseaseClass	D019337
3348216	301	316	G6PD deficiency	SpecificDisease	D005955
3348216	539	558	hematologic disease	DiseaseClass	D006402
3348216	655	670	G6PD deficiency	SpecificDisease	D005955
3348216	718	739	hematologic neoplasms	DiseaseClass	D019337

7951316|t|A physical map and candidate genes in the BRCA1 region on chromosome 17q12-21.
7951316|a|We have constructed a physical map of a 4 cM region on chromosome 17q12-21 that contains the hereditary breast and ovarian cancer gene BRCA1. The map comprises a contig of 137 overlapping yeast artificial chromosomes and P1 clones, onto which we have placed 112 PCR markers. We have localized more than 20 genes on this map, ten of which had not been mapped to the region previously, and have isolated 30 cDNA clones representing partial sequences of as yet unidentified genes. Two genes that lie within a narrow region defined by meiotic breakpoints in BRCA1 patients have been sequenced in breast cancer patients without revealing any deleterious mutations. These new reagents should facilitate the identification of BRCA1.. 
7951316	172	208	hereditary breast and ovarian cancer	Modifier	D061325
7951316	671	684	breast cancer	Modifier	D001943

10404839|t|Sulfate transport is not impaired in pendred syndrome thyrocytes.
10404839|a|Pendred syndrome is the most common form of syndromic deafness, characterized by dyshormonogenic goiter associated with sensory-neural deafness. The gene responsible for the disease (PDS) has been cloned, but its function is as yet unknown and the connection between thyroid goiter and sensory-neural deafness remains an enigma. PDS codes for a novel protein, pendrin, which is closely related to a number of sufate transporters. Mechanisms by which abnormal sulfate transport could deleteriously affect iodide organification have been proposed. We tested sulfate transport in thyrocytes obtained from Pendred syndrome patients and found that it was not defective. This suggests that pendrin in fact may not be a sulfate transporter, and emphasizes the importance of functional studies on this novel protein.. 
10404839	37	53	pendred syndrome	Modifier	C536648
10404839	66	82	Pendred syndrome	SpecificDisease	C536648
10404839	110	128	syndromic deafness	DiseaseClass	D003638
10404839	147	169	dyshormonogenic goiter	SpecificDisease	D006042
10404839	186	209	sensory-neural deafness	DiseaseClass	D006319
10404839	249	252	PDS	SpecificDisease	C536648
10404839	333	347	thyroid goiter	DiseaseClass	D006042
10404839	352	375	sensory-neural deafness	DiseaseClass	D006319
10404839	668	684	Pendred syndrome	Modifier	C536648

10430841|t|Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis.
10430841|a|We describe seven Dutch patients from six families with a slowly progressive, mainly spinal cord syndrome that remained for many years the sole expression of cerebrotendinous xanthomatosis (CTX). MRI demonstrated white matter abnormalities in the lateral and dorsal columns of the spinal cord. Post-mortem examination of one of the patients showed extensive myelin loss in these columns. An array of genotypes was found in these patients. We conclude that spinal xanthomatosis is a clinical and radiological separate entity of CTX that should be included in the differential diagnosis of chronic myelopathy.. 
10430841	0	20	Spinal xanthomatosis	SpecificDisease	D014973
10430841	35	65	cerebrotendinous xanthomatosis	DiseaseClass	D019294
10430841	152	172	spinal cord syndrome	SpecificDisease	D013118
10430841	225	255	cerebrotendinous xanthomatosis	SpecificDisease	D019294
10430841	257	260	CTX	SpecificDisease	D019294
10430841	280	306	white matter abnormalities	DiseaseClass	D002493
10430841	523	543	spinal xanthomatosis	SpecificDisease	D014973
10430841	594	597	CTX	SpecificDisease	D019294
10430841	655	673	chronic myelopathy	DiseaseClass	D002908+D013118

10827109|t|The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. The BRCA1 Exon 13 Duplication Screening Group.
10827109|a|Recently, a 6-kb duplication of exon 13, which creates a frameshift in the coding sequence of the BRCA1 gene, has been described in three unrelated U. S S. families of European ancestry and in one Portuguese family. Here, our goal was to estimate the frequency and geographic diversity of carriers of this duplication. To do this, a collaborative screening study was set up that involved 39 institutions from 19 countries and included 3, 580 unrelated individuals with a family history of the disease and 934 early-onset breast and/or ovarian cancer cases. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they are likely to derive from a common ancestor, possibly of northern British origin. Our results demonstrate that it is strongly advisable, for laboratories carrying out screening either in English-speaking countries or in countries with historical links with Britain, to include within their BRCA1 screening protocols the polymerase chain reaction-based assay described in this report. 
10827109	679	707	breast and/or ovarian cancer	Modifier	D061325

7493024|t|Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.
7493024|a|Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3 third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.. 
7493024	40	65	breast and ovarian cancer	Modifier	D061325
7493024	226	239	breast cancer	SpecificDisease	D001943
7493024	288	316	breast and/or ovarian cancer	CompositeMention	D061325
7493024	560	584	breast to ovarian cancer	Modifier	D001943|D010051
7493024	742	756	ovarian cancer	SpecificDisease	D010051

10767347|t|Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation.
10767347|a|Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused in almost all cases by homozygous intronic expansions resulting in the loss of frataxin, a mitochondrial protein conserved through evolution, and involved in mitochondrial iron homeostasis. Yeast knockout models, and histological and biochemical data from patient heart biopsies or autopsies indicate that the frataxin defect causes a specific iron-sulfur protein deficiency and mitochondrial iron accumulation leading to the pathological changes. Affected human tissues are rarely available to further examine this hypothesis. To study the mechanism of the disease, we generated a mouse model by deletion of exon 4 leading to inactivation of the Frda gene product. We show that homozygous deletions cause embryonic lethality a few days after implantation, demonstrating an important role for frataxin during early development. These results suggest that the milder phenotype in humans is due to residual frataxin expression associated with the expansion mutations. Surprisingly, in the frataxin knockout mouse, no iron accumulation was observed during embryonic resorption, suggesting that cell death could be due to a mechanism independent of iron accumulation.. 
10767347	20	37	Friedreich ataxia	Modifier	D005621
10767347	64	83	embryonic lethality	SpecificDisease	D020964
10767347	111	128	Friedreich ataxia	SpecificDisease	D005621
10767347	130	134	FRDA	SpecificDisease	D005621
10767347	153	179	autosomal recessive ataxia	DiseaseClass	D013132
10767347	535	565	iron-sulfur protein deficiency	SpecificDisease	OMIM:255125
10767347	838	842	Frda	Modifier	D005621
10767347	897	916	embryonic lethality	SpecificDisease	D020964

1301189|t|A glycine250--> aspartate substitution in the alpha-subunit of hexosaminidase A causes juvenile-onset Tay-Sachs disease in a Lebanese-Canadian family.
1301189|a|The mutation causing juvenile Tay-Sachs disease (TSD) in two sibs of Lebanese-Maronite origin is described. An mRNA-containing extract of cultured fibroblasts obtained from one of the probands was used as a template to amplify the coding sequence of the hexosaminidase A (Hex A) alpha-subunit. Sequencing of amplified cDNA fragments revealed a single alteration, guanine to adenine at nt 749 creating a G250D mutation. The mutation introduces a new recognition site for the restriction enzyme Eco RV, permitting identification of heterozygotes for this allele following PCR amplification and Eco RV digestion of exon 7 sequences from genomic DNA templates. In order to test the effect of this substitution, an in vitro mutagenized cDNA construct was introduced into a mammalian expression vector and transfected into monkey Cos-1 cells separately or along with a beta-cDNA expression vector. When the mutant alpha-cDNA was the only gene introduced into COS cells no enzymatic activity above endogenous COS cell activity was detected. Cotransfection of normal alpha-cDNA and beta-cDNA followed by immunoprecipitation of human Hex A resulted in 20-fold increase in the ratio between positive and negative (mock transfection) control values. This allowed the detection of some residual activity (12% of the positive control) when the mutant alpha-cDNA replaced its wild-type counterpart. The predicted protein environment in which the mutation occurs is compared to that of the adult-onset Tay-Sachs disease mutation caused by a Gly269-- > Ser substitution in exon 7. (ABSTRACT TRUNCATED AT 250 WORDS). 
1301189	102	119	Tay-Sachs disease	SpecificDisease	D013661
1301189	181	198	Tay-Sachs disease	SpecificDisease	D013661
1301189	200	203	TSD	SpecificDisease	D013661
1301189	1638	1655	Tay-Sachs disease	Modifier	D013661

8252631|t|Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients.
8252631|a|In humans, alteration of the tumor suppressor gene, APC, causes adenomatous polyposis coli, a condition causing predisposition to colorectal cancer. The syndrome inconsistently associates characteristic patches of congenital hypertrophy of the retinal pigment epithelium (CHRPE). Ocular examination revealed that patients expressing CHRPE tend to cluster within specific families. The exact APC mutation was identified in 42 unrelated patients. In all cases these mutations were predicted to lead to the synthesis of a truncated protein. The extent of CHRPE was found to be dependent on the position of the mutation along the coding sequence. CHRPE lesions are almost always absent if the mutation occurs before exon 9, but are systematically present if it occurs after this exon. Thus, the range of phenotypic expression observed among affected patients may result in part from different allelic manifestations of APC mutations.. 
8252631	63	66	APC	Modifier	D011125
8252631	80	106	adenomatous polyposis coli	Modifier	D011125
8252631	146	151	tumor	Modifier	D009369
8252631	169	172	APC	Modifier	D011125
8252631	181	207	adenomatous polyposis coli	SpecificDisease	D011125
8252631	247	264	colorectal cancer	SpecificDisease	D015179
8252631	331	387	congenital hypertrophy of the retinal pigment epithelium	SpecificDisease	D012164
8252631	389	394	CHRPE	SpecificDisease	D012164
8252631	450	455	CHRPE	SpecificDisease	D012164
8252631	508	511	APC	Modifier	D011125
8252631	669	674	CHRPE	SpecificDisease	D012164
8252631	760	765	CHRPE	Modifier	D012164
8252631	1032	1035	APC	Modifier	D011125

7759076|t|Linkage analysis of 26 Canadian breast and breast-ovarian cancer families.
7759076|a|We have examined 26 Canadian families with hereditary breast or ovarian cancer for linkage to markers flanking the BRCA1 gene on chromosome 17q12-q21. Of the 15 families that contain cases of ovarian cancer, 94% were estimated to be linked to BRCA1. In contrast, there was no overall evidence of linkage in the group of 10 families with breast cancer without ovarian cancer. A genetic recombinant in a breast-ovarian cancer family indicates a placement of BRCA1 telomeric to D17S776, and helps to define the region of assignment of the cancer susceptibility gene. Other cancers of interest that appeared in the BRCA1-linked families included primary peritoneal cancer, cancer of the fallopian tube, and malignant melanoma.. 
7759076	32	64	breast and breast-ovarian cancer	Modifier	D001943|D061325
7759076	118	153	hereditary breast or ovarian cancer	CompositeMention	D061325
7759076	267	281	ovarian cancer	SpecificDisease	D010051
7759076	412	425	breast cancer	SpecificDisease	D001943
7759076	434	448	ovarian cancer	SpecificDisease	D010051
7759076	477	498	breast-ovarian cancer	Modifier	D061325
7759076	611	617	cancer	Modifier	D009369
7759076	645	652	cancers	DiseaseClass	D009369
7759076	717	742	primary peritoneal cancer	SpecificDisease	D010534
7759076	744	772	cancer of the fallopian tube	SpecificDisease	D005185
7759076	778	796	malignant melanoma	SpecificDisease	D008545

1248000|t|Malignant neoplasms in the families of patients with ataxia-telangiectasia.
1248000|a|Ataxia-telangiectasia (A-T) is an autosomal recessive syndrome associated with a greatly increased incidence of malignant neoplasms in homozygous affected individuals. Heterozygotes for the gene for A-T are thought to comprise about 1% of the general population and, therefore, it is important to know whether this gene also predisposes the heterozygous carrier to cancers. Heterozygous carriers of this gene are common among the close relatives of patients with A-T, although individual carriers cannot be identified by any clinical criterion or laboratory test. For this reason, we compared the incidence of death from malignant neoplasms in 2 families of patients with A-T to that expected in a random sample of the general population. There were 59 deaths from malignant neoplasms in relatives dying before age 75, compared to 42. 6 expected (p less than 0. 02). For A-T heterozygotes younger than age 45, the risk of dying from a malignant neoplasm was estimated to be greater than 5 times the risk for the general population. A-T heterozygotes may comprise more than 5% of all persons dying from a cancer before age 45. The incidence of ovarian, gastric, and biliary system carcinomas and of leukemia and lymphoma was increased in these A-T families. Other neoplasms that may be associated with this gene in heterozygotes include pancreatic, basal cell, colonic, breast, and cervical carcinomas.
1248000	0	19	Malignant neoplasms	DiseaseClass	D009369
1248000	53	74	ataxia-telangiectasia	SpecificDisease	D001260
1248000	76	97	Ataxia-telangiectasia	SpecificDisease	D001260
1248000	99	102	A-T	SpecificDisease	D001260
1248000	110	138	autosomal recessive syndrome	DiseaseClass	D030342
1248000	188	207	malignant neoplasms	DiseaseClass	D009369
1248000	275	278	A-T	SpecificDisease	D001260
1248000	441	448	cancers	DiseaseClass	D009369
1248000	539	542	A-T	SpecificDisease	D001260
1248000	697	716	malignant neoplasms	DiseaseClass	D009369
1248000	748	751	A-T	SpecificDisease	D001260
1248000	841	860	malignant neoplasms	DiseaseClass	D009369
1248000	947	950	A-T	Modifier	D001260
1248000	1011	1029	malignant neoplasm	DiseaseClass	D009369
1248000	1108	1111	A-T	Modifier	D001260
1248000	1180	1186	cancer	DiseaseClass	D009369
1248000	1219	1266	ovarian, gastric, and biliary system carcinomas	CompositeMention	D010051|D013274|D001661
1248000	1274	1282	leukemia	DiseaseClass	D007938
1248000	1287	1295	lymphoma	DiseaseClass	D008223
1248000	1319	1322	A-T	Modifier	D001260
1248000	1339	1348	neoplasms	DiseaseClass	D009369
1248000	1412	1476	pancreatic, basal cell, colonic, breast, and cervical carcinomas	CompositeMention	D010190|D002280|D015179|D001943|D002583

2309142|t|Molecular genetics of PKU in eastern Europe: a nonsense mutation associated with haplotype 4 of the phenylalanine hydroxylase gene.
2309142|a|Phenylketonuria (PKU) is a genetic disorder secondary to a deficiency of hepatic phenylalanine hydroxylase (PAH). Several mutations in the PAH gene have recently been reported, and linkage disequilibrium was observed between RFLP haplotypes and specific mutations. A new molecular lesion has been identified in exon 7 of the PAH gene in a Hungarian PKU patient by direct sequencing of PCR-amplified DNA. The C-to-T transition causes the substitution of Arg243 to a termination codon, and the mutant allele is associated with haplotype 4 of the PAH gene. The mutation is present in two of nine mutant haplotype 4 alleles among Eastern Europeans and is not present among Western Europeans and Asians. The rarity of this mutant allele and its restricted geographic distribution suggest that the mutational event occurred recently on a normal haplotype 4 background in Eastern Europe.. 
2309142	22	25	PKU	SpecificDisease	D010661
2309142	132	147	Phenylketonuria	SpecificDisease	D010661
2309142	149	152	PKU	SpecificDisease	D010661
2309142	159	175	genetic disorder	DiseaseClass	D030342
2309142	191	238	deficiency of hepatic phenylalanine hydroxylase	SpecificDisease	OMIM:261600
2309142	403	419	molecular lesion	DiseaseClass	D030342
2309142	481	484	PKU	Modifier	D010661

8575748|t|Isolation of the mouse homologue of BRCA1 and genetic mapping to mouse chromosome 11.
8575748|a|The BRCA1 gene is in large part responsible for hereditary human breast and ovarian cancer. Here we report the isolation of the murine Brca1 homologue cDNA clones. In addition, we identified genomic P1 clones that contain most, if not all, of the mouse Brca1 locus. DNA sequence analysis revealed that the mouse and human coding regions are 75% identical at the nucleotide level while the predicted amino acid identity is only 58%. A DNA sequence variant in the Brca1 locus was identified and used to map this gene on a (Mus m. musculus Czech II x C57BL/KsJ) F1 x C57BL/KsJ intersubspecific backcross to distal mouse chromosome 11. The mapping of this gene to a region highly syntenic with human chromosome 17, coupled with Southern and Northern analyses, confirms that we isolated the murine Brca1 homologue rather than a related RING finger gene. The isolation of the mouse Brca1 homologue will facilitate the creation of mouse models for germline BRCA1 defects.. 
8575748	134	176	hereditary human breast and ovarian cancer	CompositeMention	D061325
8575748	1036	1049	BRCA1 defects	SpecificDisease	OMIM:604370

6783144|t|Human deficiency of the sixth component of complement in a patient with meningococcal meningitis and no haemostasis abnormality.
6783144|a|A case of human complete C6 deficiency is reported. The patient, a 31 year old white male, was seen on the occasion of an isolated episode of meningococcal meningitis. Serum complement hemolytic and bactericidal activities were lacking and could be restored to normal by addition of appropriate amounts of purified C6. No hemostatic abnormalities were observed.. 
6783144	6	53	deficiency of the sixth component of complement	SpecificDisease	OMIM:612446
6783144	72	96	meningococcal meningitis	SpecificDisease	D008585
6783144	104	127	haemostasis abnormality	DiseaseClass	D020141
6783144	154	167	C6 deficiency	SpecificDisease	OMIM:612446
6783144	271	295	meningococcal meningitis	SpecificDisease	D008585
6783144	451	475	hemostatic abnormalities	DiseaseClass	D020141

1346773|t|The Wiskott-Aldrich syndrome: refinement of the localization on Xp and identification of another closely linked marker locus, OATL1.
1346773|a|The Wiskott-Aldrich syndrome (WAS) has previously been mapped to the proximal short arm of the X chromosome between the DXS14 and DXS7 loci. In this study, further segregation analysis has been performed using a newly identified WAS family as well as an additional marker probe, HOATL1. The results indicate close linkage between the WAS and OATL1 loci (Z = 6. 08 at theta = 0. 00) and localize the TIMP, OATL1, DXS255, and WAS loci distal to DXS146 and the OATL1 and WAS loci proximal to TIMP. These linkage data narrow the boundaries within which the WAS locus maps to the chromosomal region bracketed by TIMP and DXS146 and support the loci order Xpter-DXS7-TIMP- (OATL1, WAS, DXS255) -DXS146.
1346773	4	28	Wiskott-Aldrich syndrome	SpecificDisease	D014923
1346773	137	161	Wiskott-Aldrich syndrome	SpecificDisease	D014923
1346773	163	166	WAS	SpecificDisease	D014923
1346773	362	365	WAS	Modifier	D014923
1346773	467	470	WAS	SpecificDisease	D014923
1346773	557	560	WAS	Modifier	D014923
1346773	601	604	WAS	Modifier	D014923
1346773	686	689	WAS	Modifier	D014923

318684|t|Hereditary deficiency of the third component of complement in a child with fever, skin rash, and arthralgias: response to transfusion of whole blood.
318684|a|A previously well 34-month-old male presenting with fever, skin rash, and arthralgias was found to lack C3 by immunochemical (undetectable) and hemolytic (1% normal) assays. No infectious agent could be demonstrated. Protein levels of Clq. C4, C5, properdin, and C3b-INA and hemolytic activities of complement components C1 to C9 except C3 were normal or elevated; total hemolytic complement activity was 13% of normal and was reconstituted by purified C3. Properdin factor B was 702 (normal 175 to 275) mug/ml, and was not cleaver upon addition of zymosan or cobra venom factor. The serum had normal immune adherence activity, but was deficient in ability to opsonize Candida albicans for uptake and Escherichia coli for killing by neurophils, generate neutrophil chemotactic factors and inhibit the growth of E. coli; these activities were restored by purified C3. A transfusion of 320 ml 1-hour-old normal whole blood on the fifty-second day resulted in transitory elevation of the C3 level to 25 mg/dl with a fall-off (approximately 2 1/2% per hour) to undetectable levels by 69 hours; it was followed by disappearance of the skin rash and arthralgias and return to normal of the previously elevated temperature and CRP levels. C3 levels in family members (seven of 24 half-normal), lack of anti-C3 activity, normal C3b-INA levels and a normal rate of catabolism of transfused C3 indicated that the deficiency was inherited with autosomal codominance and involved decreased synthesis of C3. Thus, this child is a unique individual with inherited C3 deficiency presenting with absence of repeated infections, whose symptoms of fever, skin rash, and arthralgia were abated by whole blood transfusion.. 
318684	0	58	Hereditary deficiency of the third component of complement	SpecificDisease	OMIM:613779
318684	75	80	fever	DiseaseClass	D005334
318684	82	91	skin rash	DiseaseClass	D005076
318684	97	108	arthralgias	DiseaseClass	D018771
318684	202	207	fever	DiseaseClass	D005334
318684	209	218	skin rash	DiseaseClass	D005076
318684	224	235	arthralgias	DiseaseClass	D018771
318684	1280	1289	skin rash	DiseaseClass	D005076
318684	1294	1305	arthralgias	DiseaseClass	D018771
318684	1618	1643	decreased synthesis of C3	DiseaseClass	OMIM:613779
318684	1690	1713	inherited C3 deficiency	SpecificDisease	OMIM:613779
318684	1780	1785	fever	DiseaseClass	D005334
318684	1787	1796	skin rash	DiseaseClass	D005076
318684	1802	1812	arthralgia	DiseaseClass	D018771

2544995|t|Cloning of breakpoints of a chromosome translocation identifies the AN2 locus.
2544995|a|Chromosome translocations involving 11p13 have been associated with familial aniridia in two kindreds highlighting the chromosomal localization of the AN2 locus. This locus is also part of the WAGR complex (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation). In one kindred, the translocation is associated with a deletion, and probes for this region were used to identify and clone the breakpoints of the translocation in the second kindred. Comparison of phage restriction maps exclude the presence of any sizable deletion in this case. Sequences at the chromosome 11 breakpoint are conserved in multiple species, suggesting that the translocation falls within the AN2 gene.. 
2544995	147	164	familial aniridia	SpecificDisease	D015783
2544995	272	276	WAGR	Modifier	D017624
2544995	286	297	Wilms tumor	SpecificDisease	D009396
2544995	299	307	aniridia	SpecificDisease	D015783
2544995	309	336	genitourinary abnormalities	DiseaseClass	D014564
2544995	342	360	mental retardation	DiseaseClass	D008607

10923035|t|Study of the voltage-gated sodium channel beta 1 subunit gene (SCN1B) in the benign familial infantile convulsions syndrome (BFIC).
10923035|a|Benign familial infantile convulsions (BFIC) is a rare autosomal dominant epilepsy syndrome. This syndrome has been recently described in Italian and French pedigrees. Patients present with partial, then generalized seizures, with onset at age three months. The seizures usually spontaneously cease after one year without treatment, leaving no neurological abnormalities. We have mapped BFIC to chromosome 19q in five Italian pedigrees. The sodium channel beta1 subunit gene (SCN1B) maps to this candidate region and has been shown to be involved in one Australian pedigree with generalized epilepsy and febrile seizures " plus " (GEFS +). In this family, a missense mutation in SCN1B cosegregates with the GEFS + phenotype. BFIC and GEFS + have clinical features in common, therefore SCN1B is a candidate gene for BFIC. We studied SCN1B exons 1, 2, 3, 4, and 5, using four SSCP methods in 10 Caucasian BFIC probands of Western Europe. We found no exon variants. One variant was identified in intron 5 (IVS5-10C > G), which did not segregate with BFIC and was observed in 9. 2% controls. A second variant in intron 5 was identified (IVS5 + 30G > A). It was rare, as not observed in controls, but not segregating with the BFIC phenotype. 
10923035	77	123	benign familial infantile convulsions syndrome	SpecificDisease	D020936
10923035	125	129	BFIC	SpecificDisease	D020936
10923035	132	169	Benign familial infantile convulsions	SpecificDisease	D020936
10923035	171	175	BFIC	SpecificDisease	D020936
10923035	187	223	autosomal dominant epilepsy syndrome	DiseaseClass	D030342+D004827
10923035	476	502	neurological abnormalities	DiseaseClass	D009461
10923035	519	523	BFIC	SpecificDisease	D020936
10923035	711	761	generalized epilepsy and febrile seizures   plus  	SpecificDisease	D004829+D003294
10923035	857	861	BFIC	SpecificDisease	D020936
10923035	947	951	BFIC	SpecificDisease	D020936
10923035	1035	1039	BFIC	Modifier	D020936
10923035	1179	1183	BFIC	SpecificDisease	D020936
10923035	1353	1357	BFIC	Modifier	D020936

7696601|t|Brain disease and molecular analysis in myotonic dystrophy.
7696601|a|Abnormal amplification of a CTG repeat on chromosome 19 is the molecular basis of myotonic dystrophy (DM). Expansion of the repeat has been correlated with severity of several clinical features of the disease. We performed extensive cognitive testing, cerebral magnetic resonance imaging (MRI) and a molecular analysis in 28 cases of DM to determine the relationship between the molecular defect and brain disease. Performance in two or more cognitive tests was pathological in 10 cases. Fourteen patients had subcortical white matter lesions on MRI, 14 had cerebral atrophy. Amplification of the CTG repeat showed a strong correlation with cognitive test deficits when exceeding a length of over 1000 trinucleotides. MRI lesions were associated with impaired psychometric performance, but MRI and molecular findings were only weakly related. Disease duration influenced the appearance and amount of white matter lesions on MRI. Quantification of CTG repeat size may allow an early estimate on the probability of brain involvement in DM; cognitive dysfunction is associated with white matter lesions and cerebral atrophy later on in the course.. 
7696601	0	13	Brain disease	DiseaseClass	D001927
7696601	40	58	myotonic dystrophy	SpecificDisease	D009223
7696601	142	160	myotonic dystrophy	SpecificDisease	D009223
7696601	162	164	DM	SpecificDisease	D009223
7696601	394	396	DM	SpecificDisease	D009223
7696601	460	473	brain disease	DiseaseClass	D001927
7696601	582	602	white matter lesions	DiseaseClass	D056784
7696601	618	634	cerebral atrophy	SpecificDisease	D001284
7696601	960	980	white matter lesions	DiseaseClass	D056784
7696601	1094	1096	DM	SpecificDisease	D009223
7696601	1098	1119	cognitive dysfunction	DiseaseClass	D003072
7696601	1139	1159	white matter lesions	DiseaseClass	D056784
7696601	1164	1180	cerebral atrophy	SpecificDisease	D001284

10528853|t|A highly accurate, low cost test for BRCA1 mutations.
10528853|a|The hereditary breast and ovarian cancer syndrome is associated with a high frequency of BRCA1 mutations. However, the widespread use of BRCA1 testing has been limited to date by three principal concerns  the fear of loss of health and life insurance, the uncertain clinical value of a positive test result, and the current lack of an inexpensive and sensitive screening test for BRCA1 mutations. We have developed an inexpensive system for gene mutational scanning, based on a combination of extensive multiplex PCR amplification and two dimensional electrophoresis. The efficiency of this system, as a screening test for BRCA1 mutations, was evaluated in a panel of 60 samples from high risk women, 14 of which contained a previously identified mutation in BRCA1. All 14 mutations were identified, as well as an additional five that had previously escaped detection. In addition to the 19 mutations, a total of 15 different polymorphic variants were scored, most of which were recurring. All were confirmed by nucleotide sequencing. The cost of screening per sample was calculated to be approximately US $ 70 for the manual technique used in this study, and may be reduced to approximately US $ 10 with the introduction of commercially available PCR robotics and fluorescent imaging. Implementation of this method of mutation screening in the research and clinical setting should permit rapid accrual of quantitative data on genotype-phenotype associations for the evaluation of diagnostic testing.. 
10528853	58	103	hereditary breast and ovarian cancer syndrome	CompositeMention	D061325

10083733|t|Germline mutations of the APC gene in Korean familial adenomatous polyposis patients.
10083733|a|We extensively analyzed genomic DNA and messenger RNA (mRNA) from 62 unrelated Korean patients with familial adenomatous polyposis (FAP) for identification of germline adenomatous polyposis coli (APC) gene mutations. We adopted both single-strand conformation polymorphism (SSCP) analysis and a method of analysis involving the reverse transcription-polymerase chain reaction (RT-PCR) followed by a protein truncation test (PTT). DNA sequencing confirmed all alterations represented by aberrant bands. Germline mutations were identified in 38 patients (61%). Nineteen of the detected mutations were presumed to be novel, thus emphasizing the heterogeneity of the mutational spectrum in Korean FAP patients. In the initial 48 patients, SSCP analysis was followed by PTT for those patients for whom no detectable mutations were found by SSCP. Using this combined approach, we identified germline APC gene mutations in 29 of the 48 FAP patients (60%), including 6 patients in whom SSCP analysis failed to distinguish the mutant allele. In the 14 later patients, we identified truncating mutations in 9 patients (64%) using PTT only. Our results confirm that the mutation detection rate with PTT was superior to that with SSCP, and suggest that PTT would be a more practical screening method to detect germline mutations of the APC gene in FAP patients.
10083733	26	29	APC	Modifier	D011125
10083733	45	75	familial adenomatous polyposis	Modifier	D011125
10083733	186	216	familial adenomatous polyposis	SpecificDisease	D011125
10083733	218	221	FAP	SpecificDisease	D011125
10083733	254	280	adenomatous polyposis coli	Modifier	D011125
10083733	282	285	APC	Modifier	D011125
10083733	779	782	FAP	Modifier	D011125
10083733	980	983	APC	Modifier	D011125
10083733	1015	1018	FAP	Modifier	D011125
10083733	1410	1413	APC	Modifier	D011125
10083733	1422	1425	FAP	Modifier	D011125

10842298|t|Homozygosity mapping in a family with microcephaly, mental retardation, and short stature to a Cohen syndrome region on 8q21.3-8q22.1: redefining a clinical entity.
10842298|a|A syndrome of microcephaly, progressive postnatal growth deficiency, and mental retardation was observed in two brothers and their cousin from a multiply consanguineous kindred of Lebanese descent. Hypotonia, chorioretinal dystrophy, and myopia were also identified. The severity of the condition varied among the closely related patients. Because of absence of a distinctive facial appearance, the degree of mental retardation, and short stature, the initially considered clinical diagnosis of Cohen syndrome was withdrawn and a novel genetic entity was assumed. Homozygosity mapping in this family assigned the gene to a 26. 8-cM region on the chromosome band 8q21. 3 -22. 1, between the microsatellites at D8S270 and D8S514. The maximum two-point LOD score was found for marker at D8S267 (Zmax = 3.. 237 at Omax = 0. 00). Intriguingly enough, the identified gene region overlaps the refined gene region for Cohen syndrome (COH1) [Kolehmainen et al., 1997  Euro J Hum Genet 5  206-213]. This fact encourages the hypothesis that the described kindred segregates for a variant of Cohen syndrome and suggests a redefinition of its phenotype 
10842298	38	50	microcephaly	DiseaseClass	D008831
10842298	52	70	mental retardation	DiseaseClass	D008607
10842298	76	89	short stature	DiseaseClass	D006130
10842298	95	109	Cohen syndrome	Modifier	C536438
10842298	179	191	microcephaly	DiseaseClass	D008831
10842298	205	232	postnatal growth deficiency	DiseaseClass	D006130
10842298	238	256	mental retardation	DiseaseClass	D008607
10842298	363	372	Hypotonia	DiseaseClass	D009123
10842298	374	397	chorioretinal dystrophy	DiseaseClass	 D015862+D058499
10842298	403	409	myopia	DiseaseClass	D009216
10842298	574	592	mental retardation	DiseaseClass	D008607
10842298	598	611	short stature	DiseaseClass	D006130
10842298	660	674	Cohen syndrome	SpecificDisease	C536438
10842298	1075	1089	Cohen syndrome	SpecificDisease	C536438
10842298	1245	1259	Cohen syndrome	SpecificDisease	C536438

2835825|t|Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement.
2835825|a|Molecular analysis of an unusual patient with the Lesch-Nyhan syndrome has suggested that the mutation is due to a partial HPRT gene duplication. We now report the cloning and sequencing of the mutant HPRT cDNA which shows the precise duplication of exons 2 and 3. This mutation is the result of an internal duplication of 16-20 kilobases of the gene. The structure of the mutant gene suggests that the duplication was not generated by a single unequal crossing-over event between two normal HPRT alleles. Growth of Epstein-Barr virus-transformed lymphoblasts from this patient in selective medium has permitted isolation of spontaneous HPRT + revertants of this mutation. The reversion event involves a second major HPRT gene rearrangement where most or all of the duplicated portion of the mutant gene is deleted. The original mutation therefore has the potential for spontaneous somatic reversion. This may explain the relatively mild symptoms of the Lesch-Nyhan syndrome exhibited by this patient.. 
2835825	31	42	Lesch-Nyhan	Modifier	D007926
2835825	130	150	Lesch-Nyhan syndrome	SpecificDisease	D007926
2835825	596	608	Epstein-Barr	Modifier	D020031
2835825	1034	1054	Lesch-Nyhan syndrome	SpecificDisease	D007926

7422429|t|Nephropathy in the Wiskott-Aldrich syndrome.
7422429|a|Nephropathy was detected in five of 32 patients with the Wiskott-Aldrich syndrome who were participating in a study of transfer factor (TF) therapy. In two patients, nephropathy was present before TF and did not appear changed by TF therapy. One of these patients subsequently developed progressive renal failure requiring dialysis beginning 5 1/2 years after TF therapy. In two patients, decreased renal function appeared very soon after the administration of TF. One patient showed gradually decreasing renal function beginning after two years of TF therapy. An additional patient was identified who died with renal failure without having received TF. The results suggest that renal failure occurs in the Wiskott-Aldrich syndrome more frequently than generally recognized and that administration of TF may precipitate or accelerate the renal disease in patients with this syndrome.. 
7422429	0	11	Nephropathy	SpecificDisease	D007674
7422429	19	43	Wiskott-Aldrich syndrome	SpecificDisease	D014923
7422429	45	56	Nephropathy	SpecificDisease	D007674
7422429	102	126	Wiskott-Aldrich syndrome	SpecificDisease	D014923
7422429	211	222	nephropathy	SpecificDisease	D007674
7422429	344	357	renal failure	SpecificDisease	D051437
7422429	657	670	renal failure	SpecificDisease	D051437
7422429	724	737	renal failure	SpecificDisease	D051437
7422429	752	776	Wiskott-Aldrich syndrome	SpecificDisease	D014923
7422429	883	896	renal disease	SpecificDisease	D007674

7795596|t|Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype.
7795596|a|Current evidence suggests that aniridia (absence of iris) is caused by loss of function of one copy of the PAX6 gene, which maps to 11p13. We present the further characterisation of two aniridia pedigrees in which the disease segregates with chromosomal rearrangements which involve 11p13 but do not disrupt the PAX6 gene. We have isolated three human YAC clones which encompass the PAX6 locus and we have used these to show that in both cases the chromosomal breakpoint is at least 85 kb distal of the 3 end of PAX6. In addition, the open reading frame of PAX6 is apparently free of mutations. We propose that the PAX6 gene on the rearranged chromosome 11 is in an inappropriate chromatin environment for normal expression and therefore that a position effect is the underlying mechanism of disease in these families.. 
7795596	0	8	Aniridia	Modifier	D015783
7795596	141	149	aniridia	SpecificDisease	D015783
7795596	151	166	absence of iris	SpecificDisease	D015783
7795596	296	304	aniridia	Modifier	D015783

7962532|t|Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol.
7962532|a|Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G (+ 1) -to-A mutation (Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C > or = 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products  a novel intron 14 splice donor site mutation caused by a T insertion at position + 3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C > or = 60 mg/dl, with combined allele frequencies of 9%, 12%, 21% and 43% for HDL-C 60-79, 80-99, 100-119, and > or = 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86 +/- 26 mg/dl) were lower than in Int14 A homozygotes (158 +/- 35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91 +/- 23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69 +/- 15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population.. 
7962532	8	53	cholesteryl ester transfer protein deficiency	SpecificDisease	OMIM:143470
7962532	307	359	cholesteryl ester transfer protein (CETP) deficiency	SpecificDisease	OMIM:143470
7962532	2289	2304	CETP deficiency	SpecificDisease	OMIM:143470
7962532	2388	2406	genetic deficiency	Modifier	D030342

3377761|t|X-linked glucose-6-phosphate dehydrogenase deficiency in Mus musculus.
3377761|a|A mouse with X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency has been recovered in offspring of 1-ethyl-1-nitrosourea-treated male mice. The activity alteration was detected in blood but can also be observed in other tissue extracts. Hemizygous, heterozygous, and homozygous mutants have, respectively, about 15, 60, and 15% G6PD remaining activity in the blood as compared to the wild type. Erythrocyte indices did not show differences between mutants and wild types. The mutation does not affect the electrophoretic migration, the isoelectric point, or the thermal stability. Kinetic properties, such as the Km for glucose-6-phosphate or for NADP and the relative utilization of substrate analogues, showed no differences between wild types and mutants with the exception of the relative utilization of deamino-NADP which was significantly lower in mutants. This is presently the only animal model for X-linked G6PD deficiency in humans.. 
3377761	0	53	X-linked glucose-6-phosphate dehydrogenase deficiency	SpecificDisease	D005955
3377761	84	144	X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
3377761	988	1012	X-linked G6PD deficiency	SpecificDisease	D005955

10798358|t|Human glycine decarboxylase gene (GLDC) and its highly conserved processed pseudogene (psiGLDC): their structure and expression, and the identification of a large deletion in a family with nonketotic hyperglycinemia.
10798358|a|Mutations in the glycine decarboxylase gene (GLDC) cause nonketotic hyperglycinemia (NKH), an in-born error of metabolism characterized by severe neurological disturbance. We have determined the structure of GLDC and of its pseudogene (psiGLDC) and studied their expression for a molecular analysis of NKH. The GLDC gene spans at least 135 kb and consists of 25 exons. All donor and acceptor sites adhere to the canonical GT-AG rule, except for the donor site of intron 21, where a variant form GC is used instead of GT. The transcription initiation site has been assigned to a residue 163 bp upstream from the translation initiation triplet by primer extension analysis. The psiGLDC gene has no intron and shares 97. 5% homology with the coding region of functional GLDC, suggesting that psiGLDC is a processed pseudogene that arose from the GLDC transcript about 4-8 million years ago. RNA blotting analysis has revealed that GLDC is expressed in human liver, kidney, brain, and placenta. We have also examined a patient with NKH with no detectable GLDC mRNA in his lymphoblasts. Exons 1-3 of the functional GLDC gene from this patient are not amplified by polymerase chain reaction (PCR), whereas those from control subjects are. These results suggest a large homozygous deletion (at least 30 kb) in the patient. Furthermore, we have devised a semi-quantitative PCR to estimate the number of GLDC alleles by using psiGLDC as an internal control and have confirmed the homozygosity and heterozygosity of the deletion in the patient and his parents, respectively. Structural information of GLDC and psiGLDC should facilitate the molecular analysis of NKH. 
10798358	189	215	nonketotic hyperglycinemia	SpecificDisease	D020158
10798358	274	300	nonketotic hyperglycinemia	SpecificDisease	D020158
10798358	302	305	NKH	SpecificDisease	D020158
10798358	311	338	in-born error of metabolism	DiseaseClass	D008661
10798358	363	387	neurological disturbance	DiseaseClass	D009461
10798358	519	522	NKH	SpecificDisease	D020158
10798358	1245	1248	NKH	SpecificDisease	D020158
10798358	1869	1872	NKH	SpecificDisease	D020158

8589721|t|Growth retardation and tumour inhibition by BRCA1.
8589721|a|Inherited mutations in BRCA1 predispose to breast and ovarian cancer, but the role of BRCA1 in sporadic breast and ovarian cancer has previously been elusive. Here, we show that retroviral transfer of the wild-type BRCA1 gene inhibits growth in vitro of all breast and ovarian cancer cell lines tested, but not colon or lung cancer cells or fibroblasts. Mutant BRCA1 has no effect on growth of breast cancer cells; ovarian cancer cell growth is not affected by BRCA1 mutations in the 5 portion of the gene, but is inhibited by 3 BRCA1 mutations. Development of MCF-7 tumours in nude mice is inhibited when MCF-7 cells are transfected with wild-type, but not mutant, BRCA1. Most importantly, among mice with established MCF-7 tumours, peritoneal treatment with a retroviral vector expressing wild-type BRCA1 significantly inhibits tumour growth and increased survival.. 
8589721	0	18	Growth retardation	DiseaseClass	D006130
8589721	23	29	tumour	Modifier	D009369
8589721	94	119	breast and ovarian cancer	CompositeMention	D061325
8589721	155	180	breast and ovarian cancer	CompositeMention	D001943|D010051
8589721	309	334	breast and ovarian cancer	Modifier	D001943|D010051
8589721	362	382	colon or lung cancer	Modifier	D003110|D008175
8589721	445	458	breast cancer	Modifier	D001943
8589721	466	480	ovarian cancer	Modifier	D010051
8589721	612	625	MCF-7 tumours	DiseaseClass	D009369
8589721	770	783	MCF-7 tumours	DiseaseClass	D009369
8589721	881	887	tumour	Modifier	D009369

126380|t|Striking prevalence of ankylosing spondylitis in "healthy" w27 positive males and females.
126380|a|Ankylosing spondylitis is diagnosed once or twice in each 1000 males and one tenth as frequently in females, but the true prevalence is unknown. Indentification of genetic marker, HL-A W27, for susceptible persons has provided a tool facilitating epidemiologic studies and allowing identification of " control " populations without the marker. Evaluation by postal questionnaires, and pelvic radiography of 78 HL-A 27W-positive blood donors selected from a group of apparently healthy subjects revealed 14 who satisfied the criteria for definite ankylosing spondylitis. The prevalence was similar in both sexes. One hundred and twenty-six W27-negative controls matched for race, sex, and age failed to yield a single case. For a person of either sex with HL-A W27, there appears to be about a 20 per cent chance that ankylosing spondylitis will develop, suggesting a prevalence of 10 to 15 per thousand. Hitherto accepted figures may underestimate the frequency by a factor of 10 to 20.. 
126380	23	45	ankylosing spondylitis	SpecificDisease	D013167
126380	91	113	Ankylosing spondylitis	SpecificDisease	D013167
126380	637	659	ankylosing spondylitis	SpecificDisease	D013167
126380	908	930	ankylosing spondylitis	SpecificDisease	D013167

7663517|t|Rapid detection of BRCA1 mutations by the protein truncation test.
7663517|a|More than 75% of the reported mutations in the hereditary breast and ovarian cancer gene, BRCA1, result in truncated proteins. We have used the protein truncation test (PTT) to screen for mutations in exon 11, which encodes 61% of BRCA1. In 45 patients from breast and/or ovarian cancer families we found six novel mutations  two single nucleotide insertions, three small deletions (1-5 bp) and a nonsense mutation identified two unrelated families. Furthermore, we were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA. Combined with PTT, we detected aberrantly spliced products affecting exons 5 and 6 in one of two BRCA1-linked families examined. The protein truncation test promises to become a valuable technique in detecting BRCA1 mutations.. 
7663517	114	150	hereditary breast and ovarian cancer	Modifier	D061325
7663517	325	353	breast and/or ovarian cancer	Modifier	D001943|D010051

1376553|t|New variant in exon 3 of the proteolipid protein (PLP) gene in a family with Pelizaeus-Merzbacher disease.
1376553|a|A C--greater than G transversion has been found in exon 3 of the PLP gene of affected males and their mother in a single sibship with Pelizaeus-merzbacher disease (PMD). The transversion should not result in an amino acid change in the protein but it does result in the loss of a HaeIII restriction endonuclease cleavage site. It is concordant with the disease in this family. One-hundred-ten unrelated X chromosomes are negative for this mutation. No other sequence defect was found in the PLP exons of the affected males. The cause of disease in this family remains unknown, but the association between this rare mutation and PMD is intriguing. The mutation can serve as a marker for following segregation of the PLP gene.. 
1376553	77	105	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
1376553	241	269	Pelizaeus-merzbacher disease	SpecificDisease	OMIM:312080
1376553	271	274	PMD	SpecificDisease	OMIM:312080
1376553	735	738	PMD	SpecificDisease	OMIM:312080

7390473|t|Variants of erythrocyte glucose-6-phosphate dehydrogenase (G6PD) in Bulgarian populations.
7390473|a|Ten variants of erythrocyte glucose-6-phosphate dehydrogenase were identified in 22 patients with G6PD deficiency from three districts of Bulgaria. Corinth-like and Fayoum-like variants were the most frequent; Mediterranean, Ohut II, Kilgore, Boston, Poznan, and Panay variants and two new variants, Petrich and Gotze Delchev, were each found in one or two carriers. No correlation was revealed between clinical and biochemical polymorphism.. 
7390473	189	204	G6PD deficiency	SpecificDisease	D005955

10381492|t|The C282Y mutation causing hereditary hemochromatosis does not produce a null allele.
10381492|a|Targeted mutagenesis was used to produce two mutations in the murine hemochromatosis gene (Hfe) locus. The first mutation deletes a large portion of the coding sequence, generating a null allele. The second mutation introduces a missense mutation (C282Y) into the Hfe locus, but otherwise leaves the gene intact. This mutation is identical to the disease-causing mutation in patients with hereditary hemochromatosis. Mice carrying each of the two mutations were bred and analyzed. Homozygosity for either mutation results in postnatal iron loading. The effects of the null mutation are more severe than the effects of the C282Y mutation. Mice heterozygous for either mutation accumulate more iron than normal controls. Interestingly, although liver iron stores are greatly increased, splenic iron is decreased. We conclude that the C282Y mutation does not result in a null allele.. 
10381492	27	53	hereditary hemochromatosis	SpecificDisease	D006432
10381492	155	170	hemochromatosis	Modifier	D006432
10381492	475	501	hereditary hemochromatosis	SpecificDisease	D006432

2209091|t|Regional localisation of the Friedreich ataxia locus to human chromosome 9q13----q21.1.
2209091|a|We have previously assigned the Friedreich ataxia locus (FRDA) to chromosome 9; the current maximal lod score between FRDA and MCT112 (D9S15) is greater than 50 at a recombination fraction of theta = 0. The physical assignment of the locus defined by MCT112, and hence FRDA, has not been determined, although linkage analysis of MCT112 with other chromosome 9 markers inferred a location close to the centromere. We have used in situ hybridisation with MCT112, a corresponding cosmid MJ1, and DR47 (D9S5), coupled with mapping studies on hybrid cell panels, to define more precisely the location of the disease locus. The in situ location of all three probes is 9q13----q21. 1, distal to the variable heterochromatin region. Physical assignment of FRDA will allow us to identify hybrid cell lines containing the mutated gene. 
2209091	29	46	Friedreich ataxia	Modifier	D005621
2209091	120	137	Friedreich ataxia	Modifier	D005621

10470286|t|Mxi1 mutations in human neurofibrosarcomas.
10470286|a|Mxi1 is thought to negatively regulate Myc function and may therefore be a potential tumor suppressor gene. Little effort has yet been made to find alterations involving this gene in human solid tumors. We screened 31 human gastric cancers, 7 esophageal cancers, 85 bone and soft tissue tumors of various types, including 4 neurofibrosarcomas. We also examined 29 human tumor cell lines consisting of 12 esophageal cancers, 7 glioma/glioblastomas and 10 others for Mxi1 mutations in exons 1, 2, 4 (HLH domain), 5 and 6. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and subsequent sequencing revealed three distinct polymorphisms in the intron-exon boundary upstream from exon 6. We discovered a missense mutation, GCA to GTA (Ala 54 Val), in exon 2 in a neurofibrosarcoma patient (case 1), two missense mutations, AAA to CAA (Lys 118 Gln) and GAA to GGA (Glu 154 Gly) in exon 5 of another neurofibrosarcoma patient (case 2), and 3 amino acid substitutions, GTG to GCG (Val 179 Ala), GTT to GCT (Val 181 Ala) and TTC to CTC (Phe 186 Leu), in a third neurofibrosarcoma patient (case 3). In case 3, loss of heterozygosity was also demonstrated by informative (TTC) 3/(TTC) 2 polymorphism. Our data demonstrate that mutations occur in the Mxi1 gene in neurofibrosarcoma. Missense mutations in the functional domain of Mxi1 in these cases may be involved in the pathogenesis of neurofibrosarcoma.. 
10470286	24	42	neurofibrosarcomas	SpecificDisease	D018319
10470286	129	134	tumor	Modifier	D009369
10470286	233	245	solid tumors	DiseaseClass	D009369
10470286	268	283	gastric cancers	SpecificDisease	D013274
10470286	287	305	esophageal cancers	SpecificDisease	D004938
10470286	310	337	bone and soft tissue tumors	CompositeMention	D001859|D012983
10470286	368	386	neurofibrosarcomas	SpecificDisease	D018319
10470286	414	419	tumor	Modifier	D009369
10470286	448	466	esophageal cancers	SpecificDisease	D004938
10470286	470	476	glioma	SpecificDisease	D005910
10470286	477	490	glioblastomas	SpecificDisease	D005909
10470286	830	847	neurofibrosarcoma	Modifier	D018319
10470286	965	982	neurofibrosarcoma	Modifier	D018319
10470286	1125	1142	neurofibrosarcoma	Modifier	D018319
10470286	1324	1341	neurofibrosarcoma	SpecificDisease	D018319
10470286	1449	1466	neurofibrosarcoma	SpecificDisease	D018319

7833921|t|Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase).
7833921|a|Essential fructosuria is one of the oldest known inborn errors of metabolism. It is a benign condition which is believed to result from deficiency of hepatic fructokinase (ketohexokinase, KHK, E. C. 2. 7. 1. 3). This enzyme catalyses the first step of metabolism of dietary fructose, conversion of fructose to fructose-1-phosphate. Despite the early recognition of this disorder, the primary structure of human KHK and the molecular basis of essential fructosuria have not been previously defined. In this report, the isolation and sequencing of full-length cDNA clones encoding human ketohexokinase are described. Alternative mRNA species and alternative KHK isozymes are produced by alternative polyadenylation and splicing of the KHK gene. The KHK proteins show a high level of sequence conservation relative to rat KHK. Direct evidence that mutation of the KHK structural gene is the cause of essential fructosuria was also obtained. In a well-characterized family, in which three of eight siblings have fructosuria, all affected individuals are compound heterozygotes for two mutations Gly40Arg and Ala43Thr. Both mutations result from G-- > A transitions, and each alters the same conserved region of the KHK protein. Neither mutation was seen in a sample of 52 unrelated control individuals. An additional conservative amino acid change (Val49IIe) was present on the KHK allele bearing Ala43Thr 
7833921	19	40	essential fructosuria	SpecificDisease	C538068
7833921	124	145	Essential fructosuria	SpecificDisease	C538068
7833921	173	200	inborn errors of metabolism	DiseaseClass	D008661
7833921	260	294	deficiency of hepatic fructokinase	SpecificDisease	C538068
7833921	566	587	essential fructosuria	SpecificDisease	C538068
7833921	1021	1042	essential fructosuria	SpecificDisease	C538068
7833921	1132	1143	fructosuria	DiseaseClass	C538068

10449794|t|Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs.
10449794|a|Ataxia-telangiectasia (A-T) is characterized by a markedly increased sensitivity to ionizing radiation, increased incidence of cancer, and neurodegeneration, especially of the cerebellar Purkinje cells. Ionizing radiation oxidizes macromolecules and causes tissue damage through the generation of reactive oxygen species (ROS). We therefore hypothesized that A-T is due to oxidative damage resulting from loss of function of the A-T gene product. To assess this hypothesis, we employed an animal model of A-T, the mouse with a disrupted Atm gene. We show that organs which develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebellar Purkinje cells are particularly affected. These observations provide a mechanistic basis for the A-T phenotype and lay a rational foundation for therapeutic intervention.. 
10449794	12	33	ataxia-telangiectasia	Modifier	D001260
10449794	89	110	Ataxia-telangiectasia	SpecificDisease	D001260
10449794	112	115	A-T	SpecificDisease	D001260
10449794	216	222	cancer	DiseaseClass	D009369
10449794	228	245	neurodegeneration	DiseaseClass	D019636
10449794	448	451	A-T	SpecificDisease	D001260
10449794	518	521	A-T	Modifier	D001260
10449794	594	597	A-T	SpecificDisease	D001260
10449794	865	868	A-T	Modifier	D001260

6604602|t|Family studies in Bechterew's syndrome (ankylosing spondylitis) III. Genetics.
6604602|a|The results of segregation analyses in 75 families where the proband had ankylosing spondylitis, are presented. Of the 278 adult, living first degree relatives, approximately 85% cooperated in the study. Clinical and radiographical examinations were performed and HLA typing was conducted. The results were in agreement with our hypothesis that ankylosing spondylitis is part of a syndrome where different genetic factors interact. Such known factors are HLA B27 associated disease susceptibility, susceptibility to psoriatic arthropathy and susceptibility to entero-arthropathy. Radiographical sacro-iliitis was restricted to HLA B27 positive relatives, and was more frequently found in relatives to probands with psoriasis than in relatives to probands without psoriasis. Environmental factors (intestinal bacteria) are known to trigger the disease at least in some persons, and we have postulated that all or most of them have the predisposition to develop disease. Thus, the syndrome has a multifactorial etiology. The phenotypic expressions of the different genetic predispositions involved, include sacro-iliitis, psoriasis, acute anterior uveitis, peripheral arthropathy and inflammatory bowel disease. We suggest the descriptive name HEREDITARY MULTIFOCAL RELAPSING INFLAMMATION (HEMRI) for this syndrome. Ankylosing spondylitis, psoriatic arthropathy and entero-arthropathy may be regarded as clinical sub-types of the syndrome.. 
6604602	18	38	Bechterew's syndrome	SpecificDisease	D013167
6604602	40	62	ankylosing spondylitis	SpecificDisease	D013167
6604602	152	174	ankylosing spondylitis	SpecificDisease	D013167
6604602	424	446	ankylosing spondylitis	SpecificDisease	D013167
6604602	595	616	psoriatic arthropathy	SpecificDisease	D015535
6604602	639	657	entero-arthropathy	SpecificDisease	C538273+D001168
6604602	674	687	sacro-iliitis	SpecificDisease	D058566
6604602	794	803	psoriasis	SpecificDisease	D011565
6604602	842	851	psoriasis	SpecificDisease	D011565
6604602	1184	1197	sacro-iliitis	SpecificDisease	D058566
6604602	1199	1208	psoriasis	SpecificDisease	D011565
6604602	1210	1232	acute anterior uveitis	SpecificDisease	D014606
6604602	1245	1256	arthropathy	SpecificDisease	D007592
6604602	1261	1287	inflammatory bowel disease	SpecificDisease	D015212
6604602	1321	1365	HEREDITARY MULTIFOCAL RELAPSING INFLAMMATION	SpecificDisease	D007249+D030342
6604602	1367	1372	HEMRI	SpecificDisease	D007249+D030342
6604602	1393	1415	Ankylosing spondylitis	SpecificDisease	D013167
6604602	1417	1438	psoriatic arthropathy	SpecificDisease	D015535
6604602	1443	1461	entero-arthropathy	SpecificDisease	C538273+D007592

1315306|t|Chromosome mapping of the rod photoreceptor cGMP phosphodiesterase beta-subunit gene in mouse and human: tight linkage to the Huntington disease region (4p16.3).
1315306|a|The retinal degeneration mouse (gene symbol, rd) is an animal model for certain forms of human hereditary retinopathies. Recent findings of a nonsense mutation in the rd mouse PDE beta-subunit gene (Pdeb) prompted us to investigate the chromosome locations of the mouse and human genes. We have utilized backcross analysis in mice to verify and define more precisely the location of the Pdeb locus 6. 1 +/- 2. 3 cM distal of Mgsa on mouse chromosome 5. We have determined that the human gene (PDEB) maps to 4p16. 3, very close to the Huntington disease (HD) region. Analysis of the comparative map for mice and humans shows that the mouse homologue of the HD gene will reside on chromosome 5. Linkage of the mouse Pdeb locus with other homologues in the human 4p16. 3 region is maintained but gene order is not, suggesting at least three possible sites for the corresponding mouse HD gene.
1315306	126	144	Huntington disease	Modifier	D006816
1315306	166	186	retinal degeneration	Modifier	D012162
1315306	257	281	hereditary retinopathies	DiseaseClass	D015785
1315306	696	714	Huntington disease	Modifier	D006816
1315306	716	718	HD	Modifier	D006816
1315306	818	820	HD	Modifier	D006816
1315306	1043	1045	HD	Modifier	D006816

777027|t|Hereditary deficiency of the fifth component of complement in man. II. Biological properties of C5-deficient human serum.
777027|a|The first known human kindred with hereditary deficiency of the fifth component of complement (C5) was documented in the accompanying report. This study examines several biological properties of C5-deficient (C5D) human serum, particularly sera obtained from two C5D homozygotes. The proband, who has inactive systemic lupus erythematosus is completely lacking C5, while her healthy half-sister has 1-2% of normal levels. Both sera were severely impaired in their ability to generate chemotactic activity for normal human neutrophils upon incubation with aggregated human gamma-globulin or Escherichia coli endotoxin. This function was fully restored in the siblings serum, and substantially improved in the probands serum, by addition of highly purified human C5 to normal serum concentrations. Sera from eight family members who were apparently heterozygous for C5 deficiency gave normal chemotactic scores. The ability of C5D serum to opsonize Saccharomyces cerevisiae (bakers yeast) or Candida albicans for ingestion by normal neutrophils was completely normal. In addition, C5D serum was capable of promoting normal phagocytosis and intracellular killing of Staphylococcus aureus. The probands serum was incapable of mediating lysis of erythrocytes from a patient with paroxysmal nocturnal hemoglobinuria in both the sucrose hemolysia and acid hemolysis tests, and also lacked bactericidal activity against sensitized or unsensitized Salmonella typhi. The siblings serum, containing only 1-2% of normal C5, effectively lysed S. typhi, but only at eightfold lower serum dilutions as compared to normals. These findings underscore the critical role of C5 in the generation of chemotactic activity and in cytolytic reactions, as opposed to a nonobligatory or minimal role in opsonization, at least for the organisms under study.. 
777027	0	58	Hereditary deficiency of the fifth component of complement	SpecificDisease	OMIM:609536
777027	96	108	C5-deficient	Modifier	OMIM:609536
777027	157	215	hereditary deficiency of the fifth component of complement	SpecificDisease	OMIM:609536
777027	317	329	C5-deficient	Modifier	OMIM:609536
777027	331	334	C5D	Modifier	OMIM:609536
777027	385	388	C5D	Modifier	OMIM:609536
777027	432	460	systemic lupus erythematosus	SpecificDisease	D008180
777027	986	999	C5 deficiency	SpecificDisease	OMIM:609536
777027	1047	1050	C5D	Modifier	OMIM:609536
777027	1201	1204	C5D	Modifier	OMIM:609536
777027	1396	1431	paroxysmal nocturnal hemoglobinuria	SpecificDisease	D006457

10807793|t|The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators.
10807793|a|Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and neutrophil-mediated serosal inflammation. We recently identified the gene causing FMF, designated MEFV, and found it to be expressed in mature neutrophils, suggesting that it functions as an inflammatory regulator. To facilitate our understanding of the normal function of MEFV, we extended our previous studies. MEFV messenger RNA was detected by reverse transcriptase-polymerase chain reaction in bone marrow leukocytes, with differential expression observed among cells by in situ hybridization. CD34 hematopoietic stem-cell cultures induced toward the granulocytic lineage expressed MEFV at the myelocyte stage, concurrently with lineage commitment. The prepromyelocytic cell line HL60 expressed MEFV only at granulocytic and monocytic differentiation. MEFV was also expressed in the monocytic cell lines U937 and THP-1. Among peripheral blood leukocytes, MEFV expression was detected in neutrophils, eosinophils, and to varying degrees, monocytes. Consistent with the tissue specificity of expression, complete sequencing and analysis of upstream regulatory regions of MEFV revealed homology to myeloid-specific promoters and to more broadly expressed inflammatory promoter elements. In vitro stimulation of monocytes with the proinflammatory agents interferon (IFN) gamma, tumor necrosis factor, and lipopolysaccharide induced MEFV expression, whereas the antiinflammatory cytokines interleukin (IL) 4, IL-10, and transforming growth factor beta inhibited such expression. Induction by IFN-gamma occurred rapidly and was resistant to cycloheximide. IFN-alpha also induced MEFV expression. In granulocytes, MEFV was up-regulated by IFN-gamma and the combination of IFN-alpha and colchicine. These results refine understanding of MEFV by placing the gene in the myelomonocytic-specific proinflammatory pathway and identifying it as an IFN-gamma immediate early gene.. 
10807793	13	41	familial Mediterranean fever	SpecificDisease	D010505
10807793	149	177	Familial Mediterranean fever	SpecificDisease	D010505
10807793	179	182	FMF	SpecificDisease	D010505
10807793	189	207	recessive disorder	DiseaseClass	D030342
10807793	237	242	fever	DiseaseClass	D005334
10807793	247	287	neutrophil-mediated serosal inflammation	SpecificDisease	D007249
10807793	329	332	FMF	SpecificDisease	D010505
10807793	1526	1531	tumor	Modifier	D009369

10556283|t|Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations.
10556283|a|The hSNF5/INI1 gene which encodes a member of the SWI/SNF chromatin ATP-dependent remodeling complex, is a new tumor suppressor gene localized on chromosome 22q11. 2 and recently shown to be mutated in malignant rhabdoid tumors. We have searched for hSNF5/INI1 mutations in 229 tumors of various origins using a screening method based on denaturing high-performance liquid chromatography. A total of 31 homozygous deletions and 36 point alterations were identified. Point mutations were scattered along the coding sequence and included 15 nonsense, 15 frameshift, three splice site, two missense and one editing mutations. Mutations were retrieved in most rhabdoid tumors, whatever their sites of occurrence, indicating the common pathogenetic origin of these tumors. Recurrent hSNF5/INI1 alterations were also observed in choroid plexus carcinomas and in a subset of central primitive neuroectodermal tumors (cPNETs) and medulloblastomas. In contrast, hSNF5/INI1 point mutations were not detected in breast cancers, Wilms tumors, gliomas, ependymomas, sarcomas and other tumor types, even though most analyzed cases harbored loss of heterozygosity at 22q11. 2 loci. These results suggest that rhabdoid tumors, choroid plexus carcinomas and a subset of medulloblastomas and cPNETs share common pathways of oncogenesis related to hSNF5/INI1 alteration and that hSNF5/INI1 mutations define a genetically homogeneous family of highly aggressive cancers mainly occurring in young children and frequently, but not always, exhibiting a rhabdoid phenotype 
10556283	50	56	cancer	DiseaseClass	D009369
10556283	205	210	tumor	Modifier	D009369
10556283	296	321	malignant rhabdoid tumors	DiseaseClass	D018335
10556283	372	378	tumors	DiseaseClass	D009369
10556283	750	765	rhabdoid tumors	DiseaseClass	D018335
10556283	854	860	tumors	DiseaseClass	D009369
10556283	917	942	choroid plexus carcinomas	SpecificDisease	D020288
10556283	980	1002	neuroectodermal tumors	DiseaseClass	D017599
10556283	1016	1032	medulloblastomas	SpecificDisease	D008527
10556283	1095	1109	breast cancers	SpecificDisease	D001943
10556283	1111	1123	Wilms tumors	SpecificDisease	D009396
10556283	1125	1132	gliomas	SpecificDisease	D005910
10556283	1134	1145	ependymomas	SpecificDisease	D004806
10556283	1147	1155	sarcomas	DiseaseClass	D012509
10556283	1166	1171	tumor	Modifier	D009369
10556283	1288	1303	rhabdoid tumors	DiseaseClass	D018335
10556283	1305	1330	choroid plexus carcinomas	SpecificDisease	D020288
10556283	1347	1363	medulloblastomas	SpecificDisease	D008527
10556283	1536	1543	cancers	DiseaseClass	D009369
10556283	1624	1632	rhabdoid	Modifier	D018335

624546|t|Heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Algeria. Study in Northern Algeria with description of five new variants.
624546|a|Glucose-6-phosphate dehydrogenase (G6PD) deficiency was found in 3. 2% of the male population living in the urban area of Algiers. The deficient subjects originated from multiple geographic regions of Northern Algeria, with prevalence of individuals of Berber-Kabyle origin. Red blood cell G6PD was partially purified and characterized in deficient males from 17 families, and six different variants were found. Among them, only one, the Gd (-) Kabyle variant, had been previously described. It was detected in nine families. The other five variants were new  Gd (-) Laghouat (four cases), Gd (-) Blida (one case), Gd (-) Thenia (one case), Gd (-) Titteri (one case), and Gd (-) Alger (two brothers). Strikingly, the common Mediterranean variant was not found. G6PD deficiency is heterogeneous in northern Algeria where autochtonous variants seem to prevail. The Kabyle variant may be common in this country. 
624546	17	61	glucose-6-phosphate dehydrogenase deficiency	SpecificDisease	D005955
624546	139	190	Glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
624546	900	915	G6PD deficiency	SpecificDisease	D005955

1302032|t|Fragile X syndrome without CCG amplification has an FMR1 deletion.
1302032|a|We describe a patient with typical clinical features of the fragile X syndrome, but without cytogenetic expression of the fragile X or an amplified CCG trinucleotide repeat fragment. The patient has a previously uncharacterized submicroscopic deletion encompassing the CCG repeat, the entire FMR1 gene and about 2. 5 megabases of flanking sequences. This finding confirms that the fragile X phenotype can exist, without amplification of the CCG repeat or cytogenetic expression of the fragile X, and that fragile X syndrome is a genetically homogeneous disorder involving FMR1. We also found random X-inactivation in the mother of the patient who was shown to be a carrier of this deletion. 
1302032	0	18	Fragile X syndrome	SpecificDisease	D005600
1302032	127	145	fragile X syndrome	SpecificDisease	D005600
1302032	189	198	fragile X	SpecificDisease	D005600
1302032	448	457	fragile X	Modifier	D005600
1302032	552	561	fragile X	SpecificDisease	D005600
1302032	572	590	fragile X syndrome	SpecificDisease	D005600

10589394|t|Confirmation of linkage of Van der Woude syndrome to chromosome 1q32: evidence of association with STR alleles suggests possible unique origin of the disease mutation.
10589394|a|Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with high penetrance and variable expression. Its clinical features are variably expressed, but include cleft lip and/or cleft palate, lip pits and hypodontia. All VWS families studied to date map the disease gene to a < 2 cM region of chromosome 1q32, with no evidence of locus heterogeneity. The aim of this study is to refine the localization of the VWS gene and to further assess possible heterogeneity. We analyzed four multiplex VWS families. All available members were clinically assessed and genotyped for 19 short tandem repeat markers on chromosome 1 in the VWS candidate gene region. We performed two-point and multipoint limit of detection (LOD) score analyses using a high penetrance autosomal dominant model. All families showed positive LOD scores without any recombination in the candidate region. The largest two-point LOD score was 5. 87 87. Our assay method for short tandem repeat (STR) markers provided highly accurate size estimation of marker allele fragment sizes, and therefore enabled us to determine the specific alleles segregating with the VWS gene in each of our four families. We observed a striking pattern of STR allele sharing at several closely linked loci among our four Caucasian VWS families recruited at three different locations in the US. These results suggest the possibility of a unique origin for a mutation responsible for many or most cases of VWS. 
10589394	27	49	Van der Woude syndrome	SpecificDisease	C536528
10589394	168	190	Van der Woude syndrome	SpecificDisease	C536528
10589394	192	195	VWS	SpecificDisease	C536528
10589394	203	243	autosomal dominant craniofacial disorder	DiseaseClass	D019465
10589394	348	357	cleft lip	SpecificDisease	D002971
10589394	365	377	cleft palate	SpecificDisease	D002972
10589394	379	387	lip pits	SpecificDisease	C536528
10589394	392	402	hypodontia	SpecificDisease	D000848
10589394	408	411	VWS	Modifier	C536528
10589394	597	600	VWS	Modifier	C536528
10589394	679	682	VWS	Modifier	C536528
10589394	812	815	VWS	Modifier	C536528
10589394	1313	1316	VWS	Modifier	C536528
10589394	1461	1464	VWS	Modifier	C536528
10589394	1634	1637	VWS	SpecificDisease	C536528

7550349|t|The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.
7550349|a|Since BRCA1, the first major gene responsible for inherited breast cancer, was cloned, more than 50 unique mutations have been detected in the germline of individuals with breast and ovarian cancer. In high-risk pedigrees, female carriers of BRCA1 mutations have an 80-90% lifetime risk of breast cancer, and a 40-50% risk of ovarian cancer. However, the mutation stats of individuals unselected for breast or ovarian cancer has not been determined, and it is not known whether mutations in such individuals confer the same risk of cancer as in individuals from the high-risk families studied so far. Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families, we have determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference individuals not selected for ethnic origin. We observed the 185delAG mutation in 0. 9% of Ashkenazim (95% confidence limit, 0. 4-1. 8%) and in none of the reference samples. Our results suggest that one in a hundred women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer.
7550349	163	186	inherited breast cancer	SpecificDisease	D061325
7550349	285	310	breast and ovarian cancer	CompositeMention	D061325
7550349	403	416	breast cancer	SpecificDisease	D001943
7550349	439	453	ovarian cancer	SpecificDisease	D010051
7550349	513	537	breast or ovarian cancer	CompositeMention	D010051|D001943
7550349	645	651	cancer	DiseaseClass	D009369
7550349	943	949	cancer	DiseaseClass	D009369
7550349	1260	1288	breast and/or ovarian cancer	CompositeMention	D010051|D001943

8460149|t|Targeted modification of the apolipoprotein B gene results in hypobetalipoproteinemia and developmental abnormalities in mice.
8460149|a|Familial hypobetalipoproteinemia is an autosomal codominant disorder resulting in a dramatic reduction in plasma concentrations of apolipoprotein (apo) B, cholesterol, and beta-migrating lipoproteins. A benefit of hypobetalipoproteinemia is that mildly affected individuals may be protected from coronary vascular disease. We have used gene targeting to generate mice with a modified Apob allele. Mice containing this allele display all of the hallmarks of human hypobetalipoproteinemia  they produce a truncated apoB protein, apoB70, and have markedly decreased plasma concentrations of apoB, beta-lipoproteins, and total cholesterol. In addition, the mice manifest several characteristics that are occasionally observed in human hypobetalipoproteinemia, including reduced plasma triglyceride concentrations, fasting chylomicronemia, and reduced high density lipoprotein cholesterol. An unexpected finding is that the modified Apob allele is strongly associated with exencephalus and hydrocephalus. These mice should help increase our understanding of hypobetalipoproteinemia, atherogenesis, and the etiology of exencephalus and hydrocephalus.. 
8460149	62	85	hypobetalipoproteinemia	SpecificDisease	D006995
8460149	90	117	developmental abnormalities	DiseaseClass	D006130
8460149	127	159	Familial hypobetalipoproteinemia	SpecificDisease	D052476
8460149	166	195	autosomal codominant disorder	DiseaseClass	D030342
8460149	341	364	hypobetalipoproteinemia	SpecificDisease	D006995
8460149	423	448	coronary vascular disease	DiseaseClass	D003323
8460149	590	613	hypobetalipoproteinemia	SpecificDisease	D006995
8460149	858	881	hypobetalipoproteinemia	SpecificDisease	D006995
8460149	945	960	chylomicronemia	SpecificDisease	OMIM:238600
8460149	1095	1107	exencephalus	SpecificDisease	D009436
8460149	1112	1125	hydrocephalus	SpecificDisease	D006849
8460149	1180	1203	hypobetalipoproteinemia	SpecificDisease	D006995
8460149	1205	1218	atherogenesis	DiseaseClass	D050197
8460149	1240	1252	exencephalus	SpecificDisease	D009436
8460149	1257	1270	hydrocephalus	SpecificDisease	D006849

10398279|t|Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men.
10398279|a|BACKGROUND  Families with a high incidence of hereditary breast cancer, and subsequently shown to have terminating mutations in BRCA1 or BRCA2, appear to have a higher incidence of prostate cancer among male relatives. We aimed to determine whether the common germline mutations of BRCA1 or BRCA2 in Ashkenazi Jewish men predisposed them to prostate cancer. METHODS  We examined genomic DNA from 83 (for BRCA1 185delAG) or 82 (for BRCA2 6174delT) Ashkenazi Jewish prostate cancer patients, most of whom were treated at a relatively young age, for the most common germline mutation in each gene seen in the Ashkenazi population. RESULTS  Our study should have been able to detect a 4-5-fold increase in the risk of prostate cancer due to mutation of BRCA1 or BRCA2. However, only one (1. 15%; 95% confidence interval, 0-3. 6%) of the patients was heterozygous for the BRCA1 mutant allele, and only two were heterozygous for the BRCA2 mutation (2. 4%; 95% confidence interval, 0-6. 2%). CONCLUSIONS  The incidence of each of the germline mutations in these prostate cancer patients closely matched their incidence (about 1%) in the general Ashkenazi Jewish population. This suggests that unlike cases of breast and ovarian cancers, mutations in BRCA1 or BRCA2 do not significantly predispose men to prostate cancer 
10398279	63	78	prostate cancer	SpecificDisease	D011471
10398279	140	164	hereditary breast cancer	SpecificDisease	D001943
10398279	275	290	prostate cancer	SpecificDisease	D011471
10398279	435	450	prostate cancer	SpecificDisease	D011471
10398279	558	573	prostate cancer	Modifier	D011471
10398279	808	823	prostate cancer	SpecificDisease	D011471
10398279	1149	1164	prostate cancer	Modifier	D011471
10398279	1296	1322	breast and ovarian cancers	CompositeMention	D001943|D010051
10398279	1391	1406	prostate cancer	SpecificDisease	D011471

3565372|t|Two new variants of glucose-6-phosphate dehydrogenase associated with hereditary non-spherocytic hemolytic anemia: G6PD Wayne and G6PD Huron.
3565372|a|Two new deficient variants of glucose-6-phosphate dehydrogenase (G6PD) causing hereditary nonspherocytic hemolytic anemia (HNSHA) are described. Both of these are unique and they have been named G6PD Wayne and G6PD Huron. Patients with G6PD Wayne underwent splenectomy and no objective improvement was noted. The patients with G6PD Huron were under medical observation for a considerable period of time without the diagnosis of G6PD deficiency being entertained because the family was of Northern European origin. Since sporadic variants of G6PD causing HNSHA show no special racial predilection, the diagnosis of G6PD deficiency should always be considered in patients with this syndrome.. 
3565372	70	113	hereditary non-spherocytic hemolytic anemia	SpecificDisease	D000746
3565372	221	263	hereditary nonspherocytic hemolytic anemia	SpecificDisease	D000746
3565372	265	270	HNSHA	SpecificDisease	D000746
3565372	570	585	G6PD deficiency	SpecificDisease	D005955
3565372	696	701	HNSHA	SpecificDisease	D000746
3565372	756	771	G6PD deficiency	SpecificDisease	D005955

6650504|t|The Tay-Sachs disease gene in North American Jewish populations: geographic variations and origin.
6650504|a|From data collected in a North American Tay-Sachs disease (TSD) heterozygote screening program, the TSD carrier frequency among 46, 304 Jewish individuals was found to be. 0324 (1 in 31 individuals). This frequency is consistent with earlier estimates based on TSD incidence data. TSD carrier frequencies were then examined by single country and single region of origin in 28, 029 Jews within this sample for whom such data were available for analysis. Jews with Polish and/or Russian ancestry constituted 88% of this sample and had a TSD carrier frequency of. 0327. No TSD carriers were observed among the 166 Jews of Near Eastern origins. Relative to Jews of Polish and Russian origins, there was at least a twofold increase in the TSD carrier frequency in Jews of Austrian, Hungarian, and Czechoslovakian origins (P less than. 005). These findings suggest that the TSD gene proliferated among the antecedents of modern Ashkenazi Jewry after the Second Diaspora (70 A. D.) and before their major migrations to regions of Poland and Russia (before 1100 A. D.).  
6650504	4	21	Tay-Sachs disease	Modifier	D013661
6650504	139	156	Tay-Sachs disease	Modifier	D013661
6650504	158	161	TSD	Modifier	D013661
6650504	199	202	TSD	Modifier	D013661
6650504	360	363	TSD	Modifier	D013661
6650504	380	383	TSD	Modifier	D013661
6650504	634	637	TSD	Modifier	D013661
6650504	669	672	TSD	Modifier	D013661
6650504	833	836	TSD	Modifier	D013661
6650504	967	970	TSD	Modifier	D013661

8533757|t|Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.
8533757|a|Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3-UTR and 1. 3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families  16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2. 
8533757	189	202	breast cancer	SpecificDisease	D001943
8533757	206	231	breast and ovarian cancer	CompositeMention	D001943+D010051
8533757	619	632	breast cancer	SpecificDisease	D001943
8533757	641	655	ovarian cancer	SpecificDisease	D010051
8533757	794	807	breast cancer	SpecificDisease	D001943
8533757	811	825	ovarian cancer	SpecificDisease	D010051
8533757	858	874	prostatic cancer	SpecificDisease	D011471
8533757	941	954	breast cancer	SpecificDisease	D001943
8533757	1115	1128	breast cancer	SpecificDisease	D001943
8533757	1133	1147	ovarian cancer	SpecificDisease	D010051
8533757	1526	1540	breast cancers	SpecificDisease	D001943

10767343|t|Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability.
10767343|a|Myotonic dystrophy (DM) is caused by a CTG repeat expansion in the 3UTR of the DM protein kinase (DMPK) gene. A very high level of instability is observed through successive generations and the size of the repeat is generally correlated with the severity of the disease and with age at onset. Furthermore, tissues from DM patients exhibit somatic mosaicism that increases with age. We generated transgenic mice carrying large human genomic sequences with 20, 55 or > 300 CTG, cloned from patients from the same affected DM family. Using large human flanking sequences and a large amplification, we demonstrate that the intergenerational CTG repeat instability is reproduced in mice, with a strong bias towards expansions and with the same sex- and size-dependent characteristics as in humans. Moreover, a high level of instability, increasing with age, can be observed in tissues and in sperm. Although we did not observe dramatic expansions (or big jumps over several hundred CTG repeats) as in congenital forms of DM, our model carrying > 300 CTG is the first to show instability so close to the human DM situation. Our three models carrying different sizes of CTG repeat provide insight on the different factors modulating the CTG repeat instability.. 
10767343	98	100	DM	Modifier	D009223
10767343	155	173	Myotonic dystrophy	SpecificDisease	D009223
10767343	175	177	DM	SpecificDisease	D009223
10767343	234	236	DM	Modifier	D009223
10767343	474	476	DM	Modifier	D009223
10767343	675	677	DM	Modifier	D009223
10767343	1171	1173	DM	SpecificDisease	D009223
10767343	1259	1261	DM	Modifier	D009223

133535|t|Linkage of gene for C2 deficiency and the major histocompatibility complex MHC in man. Family study of a further case.
133535|a|Close linkage between HL-A and C2 deficiency was first reported by FU and co-workers in 1974. We present here a pedigree of a 31-year-old C2-deficient individual with clinical manifestations of Hodgkins disease. The following markers were tested  C2 levels, factor B polymorphism, blood groups, and enzyme typing. In addition to close linkage between HL-A and C2 deficiency, both parents were heterozygous for Bf (HL-A linked, electrophoretic variation of B). The two HL-A haplotypes closely linked to C2 deficiency are different  2, W18 and W24, W18. They share, however, the SD2 antigen W18 and the LD type 7a.. 
133535	20	33	C2 deficiency	SpecificDisease	OMIM:217000
133535	150	163	C2 deficiency	SpecificDisease	OMIM:217000
133535	257	269	C2-deficient	Modifier	OMIM:217000
133535	313	329	Hodgkins disease	SpecificDisease	D006689
133535	479	492	C2 deficiency	SpecificDisease	OMIM:217000
133535	621	634	C2 deficiency	SpecificDisease	OMIM:217000

10051007|t|Age of onset in Huntington disease : sex specific influence of apolipoprotein E genotype and normal CAG repeat length.
10051007|a|Age of onset (AO) of Huntington disease (HD) is known to be correlated with the length of an expanded CAG repeat in the HD gene. Apolipoprotein E (APOE) genotype, in turn, is known to influence AO in Alzheimer disease, rendering the APOE gene a likely candidate to affect AO in other neurological diseases too. We therefore determined APOE genotype and normal CAG repeat length in the HD gene for 138 HD patients who were previously analysed with respect to CAG repeat length. Genotyping for APOE was performed blind to clinical information. In addition to highlighting the effect of the normal repeat length upon AO in maternally inherited HD and in male patients, we show that the APOE epsilon2epsilon3 genotype is associated with significantly earlier AO in males than in females. Such a sex difference in AO was not apparent for any of the other APOE genotypes. Our findings suggest that subtle differences in the course of the neurodegeneration  in HD  may allow interacting genes to exert gender specific effects upon AO.
10051007	16	34	Huntington disease	SpecificDisease	D006816
10051007	140	158	Huntington disease	SpecificDisease	D006816
10051007	160	162	HD	SpecificDisease	D006816
10051007	239	241	HD	Modifier	D006816
10051007	319	336	Alzheimer disease	SpecificDisease	D000544
10051007	403	424	neurological diseases	DiseaseClass	D020271
10051007	504	506	HD	Modifier	D006816
10051007	520	522	HD	Modifier	D006816
10051007	760	762	HD	SpecificDisease	D006816
10051007	1051	1068	neurodegeneration	DiseaseClass	D019636
10051007	1073	1075	HD	SpecificDisease	D006816

1978564|t|Genetic linkage map of six polymorphic DNA markers around the gene for familial adenomatous polyposis on chromosome 5.
1978564|a|A genetic linkage map of six polymorphic DNA markers close to the gene (APC) for familial adenomatous polyposis (FAP) on chromosome 5q is reported. One hundred fifty-five typed members of nine FAP kindred provided more than 90 meioses for linkage analysis. A number of crucial recombination events have been identified which are informative at three or more loci, allowing confident ordering of parts of the map. There was no evidence of genetic heterogeneity, with all families showing linkage of at least one chromosome 5 marker to the gene. Recombination data and two-point linkage analysis support a locus order of centromere-pi 227-C11P11-ECB27-L5. 62-APC-EF5 62-APC-EF5. 44-YN5 44-YN5. 48-telomer e, although EF5. 44 could lie in the interval L5. 62-APC or ECB27-L5. 62. No recombinants were identified between APC and either EF5. 44 or YN5. 48, but published deletion mapping in colorectal carcinomas and linkage analysis in FAP suggest that YN5. 48 is 1-3 cM from APC. The present study suggests that YN5. 48 and L5. 62 delineate a small region of chromosome 5 within which the EF5. 44 locus lies very close to the APC gene. These data not only allow use of flanking markers for presymptomatic diagnosis of FAP but also provide a high-density map of the region for isolation of the APC gene itself and for further assessment of the role of chromosome 5 deletions in the biology of sporadic colorectal cancer.
1978564	71	101	familial adenomatous polyposis	SpecificDisease	D011125
1978564	200	230	familial adenomatous polyposis	SpecificDisease	D011125
1978564	232	235	FAP	SpecificDisease	D011125
1978564	312	315	FAP	Modifier	D011125
1978564	1005	1026	colorectal carcinomas	SpecificDisease	D015179
1978564	1051	1054	FAP	SpecificDisease	D011125
1978564	1242	1245	APC	Modifier	D011125
1978564	1334	1337	FAP	SpecificDisease	D011125
1978564	1409	1412	APC	Modifier	D011125
1978564	1517	1534	colorectal cancer	SpecificDisease	D015179

8370681|t|Detection of a novel arginine vasopressin defect by dideoxy fingerprinting.
8370681|a|Autosomal dominant neurohypophyseal diabetes insipidus is a familial form of diabetes insipidus. This disorder is associated with variable levels of arginine vasopressin (AVP) and diabetes insipidus of varying severity, which responds to exogenous AVP. To determine the molecular basis of autosomal dominant neurohypophyseal diabetes insipidus, the AVP genes of members of a large kindred were analyzed. A new method, called dideoxy fingerprinting, was used to detect an AVP mutation that was characterized by DNA sequencing. The novel defect found changes the last codon of the AVP signal peptide from alanine to threonine, which should perturb cleavage of mature AVP from its precursor protein and inhibit its secretion or action.. 
8370681	76	130	Autosomal dominant neurohypophyseal diabetes insipidus	SpecificDisease	OMIM:125700
8370681	153	171	diabetes insipidus	DiseaseClass	D003919
8370681	256	274	diabetes insipidus	DiseaseClass	D003919
8370681	365	419	autosomal dominant neurohypophyseal diabetes insipidus	SpecificDisease	OMIM:125700

8259519|t|Association of the APC tumor suppressor protein with catenins.
8259519|a|Mutations of APC appear to initiate sporadic and inherited forms of human colorectal cancer. Although these mutations have been well characterized, little is known about the function of the APC gene product. Two cellular proteins that associate with APC were identified by nucleotide sequence analysis and peptide mapping as the E-cadherin-associated proteins alpha- and beta-catenin. A 27-residue fragment of APC containing a 15-amino acid repeat was sufficient for the interaction with the catenins. These results suggest an important link between tumor initiation and cell adhesion.. 
8259519	19	28	APC tumor	Modifier	D011125
8259519	137	154	colorectal cancer	SpecificDisease	D015179
8259519	253	256	APC	Modifier	D011125
8259519	313	316	APC	SpecificDisease	D011125
8259519	613	618	tumor	Modifier	D009369

2703233|t|Myotonic dystrophy is closely linked to the gene for muscle-type creatine kinase (CKMM).
2703233|a|We have studied genetic linkage between the gene for creatine kinase muscle type (CKMM) and the gene for myotonic dystrophy (DM). In a panel of 65 myotonic dystrophy families from Canada and the Netherlands, a maximum lod score (Zmax) of 22. 8 at a recombination frequency (theta) of 0. 03 was obtained. Tight linkage was also demonstrated for CKMM and the gene for apolipoprotein C2 (ApoC2). This establishes CKMM as a useful marker for myotonic dystrophy 
2703233	0	18	Myotonic dystrophy	SpecificDisease	D009223
2703233	194	212	myotonic dystrophy	SpecificDisease	D009223
2703233	214	216	DM	SpecificDisease	D009223
2703233	236	254	myotonic dystrophy	Modifier	D009223
2703233	527	545	myotonic dystrophy	SpecificDisease	D009223

7767095|t|Discordant clinical outcome in myotonic dystrophy relatives showing (CTG)n > 700 repeats.
7767095|a|A myotonic dystrophy (DM) family is described in which discordant DM phenotypes were found in the children of two affected sisters with similar CTG expansion and clinical manifestations. In this family, congenital as well as early severe childhood and later childhood onset DM coexist. This observation strengthens the limited ability of lymphocytes CTG repeat number analysis in predicting genotype-phenotype correlations in DM patients.. 
7767095	31	49	myotonic dystrophy	Modifier	D009223
7767095	92	110	myotonic dystrophy	Modifier	D009223
7767095	112	114	DM	Modifier	D009223
7767095	156	158	DM	Modifier	D009223
7767095	364	366	DM	SpecificDisease	D009223
7767095	516	518	DM	Modifier	D009223

10554035|t|Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.
10554035|a|von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer syndrome predisposing to a variety of tumor types that include retinal hemangioblastomas, hemangioblastomas of the central nervous system, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, endolymphatic sac tumors, and epididymal cystadenomas [W. M. Linehan et al., J. Am. Med. Assoc., 273  564-570, 1995; E. A. Maher and W. G. Kaelin, Jr., Medicine (Baltimore), 76  381-391, 1997; W. M. Linehan and R. D. Klausner, In  B. Vogelstein and K. Kinzler (eds.), The Genetic Basis of Human Cancer, pp. 455-473, McGraw-Hill, 1998]. The VHL gene was localized to chromosome 3p25-26 and cloned [F. Latif et al., Science (Washington DC), 260  1317-1320, 1993]. Germline mutations in the VHL gene have been detected in the majority of VHL kindreds. The reported frequency of detection of VHL germline mutations has varied from 39 to 80% (J. M. Whaley et al., Am. J. Hum. Genet., 55  1092-1102, 1994; Clinical Research Group for Japan, Hum. Mol. Genet., 4  2233-2237, 1995; F. Chen et al., Hum. Mutat., 5  66-75, 1995; E. R. Maher et al., J. Med. Genet., 33  328-332, 1996; B. Zbar, Cancer Surv., 25  219-232, 1995). Recently a quantitative Southern blotting procedure was found to improve this frequency (C. Stolle et al., Hum. Mutat., 12  417-423, 1998). In the present study, we report the use of fluorescence in situ hybridization (FISH) as a method to detect and characterize VHL germline deletions. We reexamined a group of VHL patients shown previously by single-strand conformation and sequencing analysis not to harbor point mutations in the VHL locus. We found constitutional deletions in 29 of 30 VHL patients in this group using cosmid and P1 probes that cover the VHL locus. We then tested six phenotypically normal offspring from four of these VHL families  two were found to carry the deletion and the other four were deletion-free. In addition, germline mosaicism of the VHL gene was identified in one family. In sum, FISH was found to be a simple and reliable method to detect VHL germline deletions and practically useful in cases where other methods of screening have failed to detect a VHL gene abnormality 
10554035	15	32	von Hippel-Lindau	Modifier	D006623
10554035	34	37	VHL	Modifier	D006623
10554035	66	69	VHL	Modifier	D006623
10554035	118	149	von Hippel-Lindau (VHL) disease	SpecificDisease	D006623
10554035	156	202	autosomal dominantly inherited cancer syndrome	DiseaseClass	D009386
10554035	232	237	tumor	Modifier	D009369
10554035	265	282	hemangioblastomas	DiseaseClass	D018325
10554035	284	301	hemangioblastomas	DiseaseClass	D018325
10554035	333	354	renal cell carcinomas	SpecificDisease	D002292
10554035	356	383	pancreatic cysts and tumors	CompositeMention	D010181|D010190
10554035	385	402	pheochromocytomas	DiseaseClass	D010673
10554035	404	428	endolymphatic sac tumors	DiseaseClass	D036821
10554035	434	457	epididymal cystadenomas	DiseaseClass	D003537
10554035	744	747	VHL	Modifier	D006623
10554035	892	895	VHL	Modifier	D006623
10554035	939	942	VHL	Modifier	D006623
10554035	992	995	VHL	Modifier	D006623
10554035	1584	1587	VHL	Modifier	D006623
10554035	1633	1636	VHL	Modifier	D006623
10554035	1754	1757	VHL	Modifier	D006623
10554035	1811	1814	VHL	Modifier	D006623
10554035	1880	1883	VHL	Modifier	D006623
10554035	1961	1964	VHL	Modifier	D006623
10554035	2090	2093	VHL	Modifier	D006623
10554035	2197	2200	VHL	Modifier	D006623
10554035	2309	2329	VHL gene abnormality	SpecificDisease	D006623

7481765|t|Aberrant subcellular localization of BRCA1 in breast cancer.
7481765|a|The BRCA1 gene product was identified as a 220-kilodalton nuclear phosphoprotein in normal cells, including breast ductal epithelial cells, and in 18 of 20 tumor cell lines derived from tissues other than breast and ovary. In 16 of 17 breast and ovarian cancer lines and 17 of 17 samples of cells obtained from malignant effusions, however, BRCA1 localized mainly in cytoplasm. Absence of BRCA1 or aberrant subcellular location was also observed to a variable extent in histological sections of many breast cancer biopsies. These findings suggest that BRCA1 abnormalities may be involved in the pathogenesis of many breast cancers, sporadic as well as familial.. 
7481765	46	59	breast cancer	SpecificDisease	D001943
7481765	217	222	tumor	Modifier	D009369
7481765	296	321	breast and ovarian cancer	Modifier	D001943|D010051
7481765	561	574	breast cancer	Modifier	D001943
7481765	613	632	BRCA1 abnormalities	DiseaseClass	OMIM:604370
7481765	677	691	breast cancers	SpecificDisease	D001943

107868|t|HLA B27 and the genetics of ankylosing spondylitis.
107868|a|One hundred and twenty-eight of 145 patients with ankylosing spondylitis (AS) were found to be HLA B27 positive. Five patients had evidence of a sero-negative peripheral arthritis resembling peripheral psoriatic arthritis and 3 of these were B27 negative. One further B27 negative patients had a sister with ankylosing spondylitis and ulcerative colitis and a mother with ulcerative colitis. There was evidence of a somewhat later age of onset of symptoms in B27 negative patients. These findings are interpreted as suggesting some degree of clinical and genetic heterogeneity in ankylosing spondylitis with genes for psoriasis and inflammatory bowel disease being important in some individuals, particularly those who are B27 negative. Twenty-five first-degree relatives with ankylosing spondylitis were all B27 positive. The only instance of disassociation of B27 and spondylitis in a family was where the proband had ulcerative colitis as well as spondylitis. Of 13 B27 positive fathers 3 could be diagnosed as having definite ankylosing spondylitis (23%). These findings are thought to provide evidence against the concept that the gene for ankylosing spondylitis is not B27 but a closely linked gene and favour the occurrence of an environmental event affecting approximately one-fifth of B27 positive males to result in disease.. 
107868	28	50	ankylosing spondylitis	SpecificDisease	D013167
107868	102	124	ankylosing spondylitis	SpecificDisease	D013167
107868	126	128	AS	SpecificDisease	D013167
107868	211	231	peripheral arthritis	SpecificDisease	D001168
107868	243	273	peripheral psoriatic arthritis	SpecificDisease	D015535
107868	360	382	ankylosing spondylitis	SpecificDisease	D013167
107868	387	405	ulcerative colitis	SpecificDisease	D003093
107868	424	442	ulcerative colitis	SpecificDisease	D003093
107868	632	654	ankylosing spondylitis	SpecificDisease	D013167
107868	670	679	psoriasis	SpecificDisease	D011565
107868	684	710	inflammatory bowel disease	SpecificDisease	D015212
107868	829	851	ankylosing spondylitis	SpecificDisease	D013167
107868	922	933	spondylitis	SpecificDisease	D013166
107868	972	990	ulcerative colitis	SpecificDisease	D003093
107868	1002	1013	spondylitis	SpecificDisease	D013166
107868	1082	1104	ankylosing spondylitis	SpecificDisease	D013167
107868	1197	1219	ankylosing spondylitis	SpecificDisease	D013167

7858169|t|Late infantile metachromatic leukodystrophy in Israel.
7858169|a|Metachromatic Leukodystrophy (MLD) is a neurodegenerative disease in which the lysosomal enzyme, Aryl sulfatase A (ARSA) is deficient. The disease is inherited as an autosomal recessive trait and its frequency is estimated to be 1/40, 000 live births. The gene of ARSA has been cloned and up to now eight mutations causing MLD have been reported. Another mutation, PD, leads to the deficiency of the enzyme in vitro (pseudodeficiency) without any known clinical effect. The PD mutation is frequent in all populations. In Israel, late infantile MLD was found to be very frequent in a small Jewish isolate, the Habbanite Jews (1/75 live births). The molecular analysis demonstrated that in the Habbanite population, the mutation occurred on an allele with the PD mutation. The loss of ARSA activity is due to a point mutation C > T leading to a change of proline to leucine. MLD is also frequent among Moslem Arabs in Jerusalem. The mutation is a transition G > A destroying the splice donor site of exon 2. This mutation has been reported in patients with the late infantile MLD from different ethnic groups. The Christian Arabs in Israel also have a high incidence of the disease (1/10, 000 live births); the mutation in this population is still unknown. Knowledge of the different mutations causing MLD in these defined populations will allow a carrier screening program to be carried out and prevent the birth of additional affected children.. 
7858169	15	43	metachromatic leukodystrophy	SpecificDisease	D007966
7858169	55	83	Metachromatic Leukodystrophy	SpecificDisease	D007966
7858169	85	88	MLD	SpecificDisease	D007966
7858169	95	120	neurodegenerative disease	DiseaseClass	D019636
7858169	378	381	MLD	SpecificDisease	D007966
7858169	599	602	MLD	SpecificDisease	D007966
7858169	928	931	MLD	SpecificDisease	D007966
7858169	1129	1132	MLD	SpecificDisease	D007966
7858169	1355	1358	MLD	SpecificDisease	D007966

10982189|t|Genomic rearrangements of the APC tumor-suppressor gene in familial adenomatous polyposis.
10982189|a|Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in the hereditary colorectal cancer syndrome familial adenomatous polyposis (FAP). Almost all APC mutations that have been identified are single-nucleotide alterations, small insertions, or small deletions that would truncate the protein product of the gene. No well-characterized intragenic rearrangement of APC has been described, and the prevalence of this type of mutation in FAP patients is not clear. We screened 49 potential FAP families and identified 26 different germline APC mutations in 30 families. Four of these mutations were genomic rearrangements resulting from homologous and nonhomologous recombinations mediated by Alu elements. Two of these four rearrangements were complex, involving deletion and insertion of nucleotides. Of these four rearrangements, one resulted in the deletion of exons 11 and 12 and two others resulted in either complete or partial deletion of exon 14. The fourth rearrangement grossly altered the sequence within intron 14. Although this rearrangement did not affect any coding sequence of APC at the genomic DNA level, it caused inappropriate splicing of exon 14. These rearrangements were initially revealed by analyzing cDNAs and could not have been identified by using mutation detection methods that screened each exon individually. The identification of a rearrangement that did not alter any coding exons yet affected the splicing further underscores the importance of using cDNA for mutation analysis. The identification of four genomic rearrangements among 30 mutations suggests that genomic rearrangements are frequent germline APC mutations.. 
10982189	30	39	APC tumor	Modifier	D011125
10982189	59	89	familial adenomatous polyposis	SpecificDisease	D011125
10982189	117	155	adenomatous polyposis coli (APC) tumor	Modifier	D011125
10982189	186	223	hereditary colorectal cancer syndrome	SpecificDisease	D015179
10982189	224	254	familial adenomatous polyposis	SpecificDisease	D011125
10982189	256	259	FAP	SpecificDisease	D011125
10982189	273	276	APC	Modifier	D011125
10982189	559	562	FAP	Modifier	D011125
10982189	611	614	FAP	Modifier	D011125
10982189	661	664	APC	Modifier	D011125
10982189	1763	1766	APC	Modifier	D011125

8075631|t|Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q.
8075631|a|Breast cancer in men is about a hundredfold less common than in women and this has hindered research into its genetic basis. We have examined 22 families with at least one case of male breast cancer for linkage to the hereditary breast and ovarian cancer locus, BRCA1, on chromosome 17q. We found strong evidence against linkage to BRCA1 (lod score-16. 63) and the best estimate of the proportion of linked families was 0% (95% CI 0-18%). Our results indicate that there is a gene (s) other than BRCA1 which predisposes to early-onset breast cancer in women and which confers a higher risk of male breast cancer. Identification of additional pedigrees that include cases of male breast cancer may therefore facilitate the mapping and isolation of this gene. 
8075631	0	27	Familial male breast cancer	SpecificDisease	D018567
8075631	80	93	Breast cancer	SpecificDisease	D001943
8075631	260	278	male breast cancer	SpecificDisease	D018567
8075631	298	334	hereditary breast and ovarian cancer	Modifier	D061325
8075631	615	628	breast cancer	SpecificDisease	D001943
8075631	673	691	male breast cancer	SpecificDisease	D018567
8075631	754	772	male breast cancer	SpecificDisease	D018567

8528200|t|Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease.
8528200|a|The size of the (CAG)n repeat array in the 3' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD). Our data provide five novel observations. First, MJD is associated with expansion fo the array from the normal range of 14-37 repeats to 68-84 repeats in most Japanese and Caucasian subjects, but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups. Second, the expanded allele associated with MJD displays inter-generational instability, particularly in male meioses, and this instability was associated with the clinical phenomenon of anticipation. Third, the size of the expanded allele is not only inversely correlated with the age-of-onset of MJD (r = -0.738, p < 0.001), but is also correlated with the frequency of other clinical features [e.g. pseudoexophthalmos and pyramidal signs were more frequent in subjects with large repeats (p < 0.001 and p < 0.05 respectively)]. Fourth, the disease phenotype is significantly more severe and had an early age of onset (16 years) in a subject homozygous for the expanded allele, which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect (putatively excluded in HD) or by a gain of function effect as proposed for HD. Finally, Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene, which are uncommon in the normal Japanese and Caucasian population, and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene.
8528200	173	195	Machado-Joseph disease	SpecificDisease	D017827
8528200	427	449	Machado-Joseph disease	SpecificDisease	D017827
8528200	451	454	MJD	SpecificDisease	D017827
8528200	506	509	MJD	SpecificDisease	D017827
8528200	748	751	MJD	Modifier	D017827
8528200	813	816	MJD	SpecificDisease	D017827
8528200	1067	1070	MJD	SpecificDisease	D017827
8528200	1470	1488	Huntington disease	SpecificDisease	D006816
8528200	1628	1630	HD	SpecificDisease	D006816
8528200	1680	1682	HD	SpecificDisease	D006816
8528200	1739	1742	MJD	SpecificDisease	D017827

3674116|t|Familial Prader-Willi syndrome with apparently normal chromosomes.
3674116|a|We report on 4 sibs (2F, 2M) with Prader-Willi syndrome (PWS). Diagnosis was made clinically on the basis of history, behavior, and physical findings in 3 of the sibs. The other child had died at age 10 months with a history and clinical findings typical of first phase of PWS. Results of chromosome studies on the parents and surviving sibs were normal. The implications of this unusual familial occurrence for our understanding of PWS are discussed.. 
3674116	9	30	Prader-Willi syndrome	SpecificDisease	D011218
3674116	101	122	Prader-Willi syndrome	SpecificDisease	D011218
3674116	124	127	PWS	SpecificDisease	D011218
3674116	340	343	PWS	SpecificDisease	D011218
3674116	500	503	PWS	SpecificDisease	D011218

7759075|t|Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer.
7759075|a|We searched for criteria that could indicate breast cancer families with a high prior probability of being caused by the breast/ovarian cancer susceptibility locus BRCA1 on chromosome 17. To this end, we performed a linkage study with 59 consecutively collected Dutch breast cancer families, including 16 with at least one case of ovarian cancer. We used an intake cut-off of at least three first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of the breast-ovarian cancer families were estimated to be linked to BRCA1, which could be due to a founder effect in the Dutch population. Given the expected logistical problems in clinical management now that BRCA1 has been identified, we propose an interim period in which only families with a strong positive family history for early onset breast and/or ovarian cancer will be offered BRCA1 mutation testing.. 
7759075	73	95	familial breast cancer	SpecificDisease	D001943
7759075	142	155	breast cancer	Modifier	D001943
7759075	218	239	breast/ovarian cancer	Modifier	D061325
7759075	365	378	breast cancer	Modifier	D001943
7759075	428	442	ovarian cancer	SpecificDisease	D010051
7759075	516	544	breast and/or ovarian cancer	CompositeMention	D001943|D010051
7759075	618	631	breast cancer	Modifier	D001943
7759075	731	752	breast-ovarian cancer	Modifier	D061325
7759075	1068	1096	breast and/or ovarian cancer	CompositeMention	D001943|D010051

1999339|t|Some Mexican glucose-6-phosphate dehydrogenase variants revisited.
1999339|a|Glucose-6-phosphate dehydrogenase (G6PD) deficiency appears to be fairly common in Mexico. We have now examined the DNA of three previously reported electrophoretically fast Mexican G6PD variants, -G6PD Distrito Federal, G6PD Tepic, and G6PD Castilla. All three of these variants, believed on the basis of biochemical characterization and population origin to be unique, have the G----A transition at nucleotide 202 and the A----G transition at nucleotide 376, mutations that we now recognize to be characteristic of G6PD A-. Two other Mexican males with G6PD deficiency were found to have the same mutation. All five have the (NlaIII/FokI/PvuII/PstI) haplotype characteristic of G6PD A -in Africa. Since the PvuII + genotype seems to be rare in Europe, we conclude that all of these G6PD A - genes had their ancient origin in Africa, although in many of the Mexican patients with G6PD A -202A/376G the gene may have been imported more recently from Spain, where this variant, formerly known as G6PD Betica, is also prevalent.. 
1999339	67	118	Glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
1999339	622	637	G6PD deficiency	SpecificDisease	D005955

10924409|t|Inactivation of germline mutant APC alleles by attenuated somatic mutations: a molecular genetic mechanism for attenuated familial adenomatous polyposis.
10924409|a|Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in familial adenomatous polyposis (FAP). Patients with FAP typically develop hundreds to thousands of benign colorectal tumors and early-onset colorectal cancer. A subset of germline APC mutations results in an attenuated FAP (AFAP) phenotype, in which patients develop fewer tumors and develop them at an older age. Although a genotype-phenotype correlation between the locations of APC germline mutations and the development of AFAP has been well documented, the mechanism for AFAP has not been well defined. We investigated the mechanism for AFAP in patients carrying a mutant APC allele (APC (AS9)) that has a mutation in the alternatively spliced region of exon 9. APC (AS9) was found to down-regulate beta-catenin-regulated transcription, the major tumor-suppressor function of APC, as did the wild-type APC. Mutation analysis showed that both APC (AS9) and the wild-type APC alleles were somatically mutated in most colorectal tumors from these patients. Functional analysis showed that 4666insA, a common somatic mutation in APC (AS9) in these tumors, did not inactivate the wild-type APC. Our results indicate that carriers of APC (AS9) develop fewer colorectal tumors than do typical patients with FAP because somatic inactivation of both APC alleles is necessary for colorectal tumorigenesis. However, these patients develop colorectal tumors more frequently than does the general population because APC (AS9) is inactivated by mutations that do not inactivate the wild-type APC.. 
10924409	32	35	APC	Modifier	D011125
10924409	111	152	attenuated familial adenomatous polyposis	SpecificDisease	C538265
10924409	180	218	adenomatous polyposis coli (APC) tumor	Modifier	D011125
10924409	245	275	familial adenomatous polyposis	SpecificDisease	D011125
10924409	277	280	FAP	SpecificDisease	D011125
10924409	297	300	FAP	SpecificDisease	D011125
10924409	344	368	benign colorectal tumors	SpecificDisease	D015179
10924409	385	402	colorectal cancer	SpecificDisease	D015179
10924409	425	428	APC	Modifier	D011125
10924409	453	467	attenuated FAP	Modifier	C538265
10924409	469	473	AFAP	Modifier	C538265
10924409	518	524	tumors	DiseaseClass	D009369
10924409	626	629	APC	Modifier	D011125
10924409	672	676	AFAP	SpecificDisease	C538265
10924409	721	725	AFAP	SpecificDisease	C538265
10924409	787	791	AFAP	SpecificDisease	C538265
10924409	822	825	APC	Modifier	D011125
10924409	997	1002	tumor	Modifier	D009369
10924409	1120	1123	APC	Modifier	D011125
10924409	1165	1182	colorectal tumors	SpecificDisease	D015179
10924409	1294	1300	tumors	DiseaseClass	D009369
10924409	1402	1419	colorectal tumors	SpecificDisease	D015179
10924409	1450	1453	FAP	SpecificDisease	D011125
10924409	1491	1494	APC	Modifier	D011125
10924409	1578	1595	colorectal tumors	SpecificDisease	D015179

1334370|t|Submicroscopic deletions at the WAGR locus, revealed by nonradioactive in situ hybridization.
1334370|a|Fluorescence in situ hybridization (FISH) with biotin-labeled probes mapping to 11p13 has been used for the molecular analysis of deletions of the WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) locus. We have detected a submicroscopic 11p13 deletion in a child with inherited aniridia who subsequently presented with Wilms tumor in a horseshoe kidney, only revealed at surgery. The mother, who has aniridia, was also found to carry a deletion including both the aniridia candidate gene (AN2) and the Wilms tumor predisposition gene (WT1). This is therefore a rare case of an inherited WAGR deletion. Wilms tumor has so far only been associated with sporadic de novo aniridia cases. We have shown that a cosmid probe for a candidate aniridia gene, homologous to the mouse Pax-6 gene, is deleted in cell lines from aniridia patients with previously characterized deletions at 11p13, while another cosmid marker mapping between two aniridia-associated translocation breakpoints (and hence a second candidate marker) is present on both chromosomes. These results support the Pax-6 homologue as a strong candidate for the AN2 gene. FISH with cosmid probes has proved to be a fast and reliable technique for the molecular analysis of deletions. It can be used with limited amounts of material and has strong potential for clinical applications.. 
1334370	32	36	WAGR	Modifier	D017624
1334370	241	245	WAGR	Modifier	D017624
1334370	247	258	Wilms tumor	Modifier	D009396
1334370	260	268	aniridia	Modifier	D015783
1334370	270	297	genitourinary abnormalities	Modifier	D014564
1334370	303	321	mental retardation	Modifier	D008607
1334370	405	413	aniridia	SpecificDisease	D015783
1334370	446	457	Wilms tumor	SpecificDisease	D009396
1334370	527	535	aniridia	SpecificDisease	D015783
1334370	591	599	aniridia	Modifier	D015783
1334370	629	640	Wilms tumor	Modifier	D009396
1334370	714	718	WAGR	Modifier	D017624
1334370	729	740	Wilms tumor	SpecificDisease	D009396
1334370	795	803	aniridia	Modifier	D015783
1334370	861	869	aniridia	Modifier	D015783
1334370	942	950	aniridia	Modifier	D015783
1334370	1058	1066	aniridia	Modifier	D015783

8279472|t|Haplotype studies in Wilson disease.
8279472|a|In 51 families with Wilson disease, we have studied DNA haplotypes of dinucleotide repeat polymorphisms (CA repeats) in the 13q14. 3 region, to examine these markers for association with the Wilson disease gene (WND). In addition to a marker (D13S133) described elsewhere, we have developed three new highly polymorphic markers (D13S314, D13S315, and D13S316) close to the WND locus. We have examined the distribution of marker alleles at the loci studied and have found that D13S314, D13S133, and D13S316 each show nonrandom distribution on chromosomes carrying the WND mutation. We have studied haplotypes of these three markers and have found that there are highly significant differences between WND and normal haplotypes in northern European families. These findings have important implications for mutation detection and molecular diagnosis in families with Wilson disease. 
8279472	21	35	Wilson disease	SpecificDisease	D006527
8279472	57	71	Wilson disease	SpecificDisease	D006527
8279472	228	242	Wilson disease	Modifier	D006527
8279472	249	252	WND	SpecificDisease	D006527
8279472	410	413	WND	SpecificDisease	D006527
8279472	604	607	WND	SpecificDisease	D006527
8279472	737	740	WND	SpecificDisease	D006527
8279472	901	915	Wilson disease	SpecificDisease	D006527

10541953|t|Growth hormone treatment increases CO(2) response, ventilation and central inspiratory drive in children with Prader-Willi syndrome.
10541953|a|We studied whether the beneficial effects of growth hormone (GH) treatment on growth and body composition in PWS are accompanied by an improvement in respiratory function. We measured resting ventilation, airway occlusion pressure (P (0. 1)) and ventilatory response to CO (2) in nine children, aged 7-14 years, before and 6-9 months after the start of GH treatment. During GH treatment, resting ventilation increased by 26%, P (0. 1) by 72% and the response to CO (2) by 65% (P < 0. 002, < 0. 04 and < 0. 02, respectively). This observed increase in ventilatory output was not correlated to changes in body mass index. CONCLUSION  Treatment of children with Prader-Willi syndrome (PWS) seems to have a stimulatory effect on central respiratory structures. The observed increase in ventilation and inspiratory drive may contribute to the improved activity level reported by parents of PWS children during growth hormone therapy 
10541953	110	131	Prader-Willi syndrome	SpecificDisease	D011218
10541953	242	245	PWS	SpecificDisease	D011218
10541953	792	813	Prader-Willi syndrome	SpecificDisease	D011218
10541953	815	818	PWS	SpecificDisease	D011218
10541953	1018	1021	PWS	Modifier	D011218

8522307|t|Somatic von Hippel-Lindau mutation in clear cell papillary cystadenoma of the epididymis.
8522307|a|Papillary cystadenoma of the epididymis is an uncommon benign lesion that may occur sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Neither immunohistochemical studies nor molecular genetic analyses of the VHL gene have been reported previously for this lesion. The authors describe two cases of clear cell papillary cystadenoma of the epididymis, both of which were initially confused with metastatic renal cell carcinoma. Both lesions showed positive immunohistochemical staining for low and intermediate molecular weight keratins (Cam 5. 2 and AE1/AE3), EMA, vimentin, alpha 1-antitrypsin, and alpha 1-antichymotrypsin. Each was negative for CEA. Because clear cell papillary cystadenoma is similar to renal cell carcinoma histologically, and because both occur as components of the von Hippel-Lindau disease complex, the authors analyzed both cases for the presence of mutations in the VHL gene. A somatic VHL gene mutation was detected in one of the two tumors by polymerase chain reaction followed by single-strand conformation polymorphism analysis. Direct sequencing revealed a cytosine to thymine transition at nucleotide 694, resulting in the replacement of an arginine with a stop codon after the sixth amino acid of exon 3. As the VHL gene is believed to function as a tumor suppressor gene, VHL gene mutations may play a role in the initiation of tumorigenesis in sporadic cystadenomas of the epididymis. 
8522307	8	25	von Hippel-Lindau	Modifier	D006623
8522307	49	88	papillary cystadenoma of the epididymis	SpecificDisease	D018292
8522307	90	129	Papillary cystadenoma of the epididymis	SpecificDisease	D018292
8522307	212	243	von Hippel-Lindau (VHL) disease	SpecificDisease	D006623
8522307	319	322	VHL	Modifier	D006623
8522307	420	459	papillary cystadenoma of the epididymis	SpecificDisease	D018292
8522307	504	535	metastatic renal cell carcinoma	SpecificDisease	C538445
8522307	782	803	papillary cystadenoma	SpecificDisease	D018292
8522307	818	838	renal cell carcinoma	SpecificDisease	D002292
8522307	899	924	von Hippel-Lindau disease	Modifier	D006623
8522307	1003	1006	VHL	Modifier	D006623
8522307	1023	1026	VHL	Modifier	D006623
8522307	1072	1078	tumors	DiseaseClass	D009369
8522307	1356	1359	VHL	Modifier	D006623
8522307	1394	1399	tumor	Modifier	D009369
8522307	1417	1420	VHL	Modifier	D006623
8522307	1499	1529	cystadenomas of the epididymis	SpecificDisease	D003537

7825586|t|An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Breast Cancer Linkage Consortium.
7825586|a|The breast-ovary cancer-family syndrome is a dominant predisposition to cancer of the breast and ovaries which has been mapped to chromosome region 17q12-q21. The majority, but not all, of breast-ovary cancer families show linkage to this susceptibility locus, designated BRCA1. We report here the results of a linkage analysis of 145 families with both breast and ovarian cancer. These families contain either a total of three or more cases of early-onset (before age 60 years) breast cancer or ovarian cancer. All families contained at least one case of ovarian cancer. Overall, an estimated 76% of the 145 families are linked to the BRCA1 locus. None of the 13 families with cases of male breast cancer appear to be linked, but it is estimated that 92% (95% confidence interval 76% -100%) of families with no male breast cancer and with two or more ovarian cancers are linked to BRCA1. These data suggest that the breast-ovarian cancer-family syndrome is genetically heterogeneous. However, the large majority of families with early-onset breast cancer and with two or more cases of ovarian cancer are likely to be due to BRCA1 mutations.. 
7825586	46	67	breast-ovarian cancer	Modifier	D061325
7825586	78	91	Breast Cancer	Modifier	D001943
7825586	116	151	breast-ovary cancer-family syndrome	SpecificDisease	D061325
7825586	184	216	cancer of the breast and ovaries	CompositeMention	D001943|D010051
7825586	301	320	breast-ovary cancer	Modifier	D061325
7825586	466	491	breast and ovarian cancer	CompositeMention	D001943|D010051
7825586	591	604	breast cancer	SpecificDisease	D001943
7825586	608	622	ovarian cancer	SpecificDisease	D010051
7825586	668	682	ovarian cancer	SpecificDisease	D010051
7825586	799	817	male breast cancer	SpecificDisease	D018567
7825586	924	942	male breast cancer	SpecificDisease	D018567
7825586	964	979	ovarian cancers	SpecificDisease	D010051
7825586	1029	1066	breast-ovarian cancer-family syndrome	SpecificDisease	D061325
7825586	1154	1167	breast cancer	SpecificDisease	D001943
7825586	1198	1212	ovarian cancer	SpecificDisease	D010051

4019732|t|Genetic analysis in families with van der Woude syndrome.
4019732|a|We have brought together information on 864 affected individuals in 164 families (including three new pedigrees) reported in the 137 year period since 1845 when Demarquay first described a family with what was later called van der Woude syndrome (VWS). Both types of oral cleft, cleft palate (CP) and cleft lip with or without CP (CLP), segregate in these families together with lower lip pits or fistulae in an autosomal dominant mode with high penetrance estimated to be K =. 89 and. 99 by different methods. Cleft types (CLP and CP) occur in VWS in the same proportions as in the general non-VWS population, ie, about twice as many cleft-bearing individuals have CLP as have CP. On the other hand, we do not find the usually observed excess of females with CP and excess of males with CLP; in VWS the sex ratios are more nearly equal. Lip pits also are equally distributed between the sexes. Affected males and females are equally likely to transmit VWS. However, there is an excess of less severely affected individuals among transmitters and a deficiency of more severely affected, brought about by a proband bias and differential fecundity. The expression of VWS is significantly modified by the genetic background  More extreme phenotypes in parents tend to produce more extreme expression in their children. For a VWS gene carrier the relative risk of transmitting a cleft is 26. 45%; that of transmitting lower lip pits is 23. 55%. Three pedigrees of lip pits in the literature show no clefts among a significant number of affected individuals. Control of gene expression in VWS in the three target tissues appears to be independent and separately designated. Mutation rate of the VWS gene is calculated to be 1. 8 X 10 (-5) 
4019732	34	56	van der Woude syndrome	SpecificDisease	C536528
4019732	281	303	van der Woude syndrome	SpecificDisease	C536528
4019732	305	308	VWS	SpecificDisease	C536528
4019732	325	335	oral cleft	SpecificDisease	D002971|D002972
4019732	337	349	cleft palate	SpecificDisease	D002972
4019732	351	353	CP	SpecificDisease	D002972
4019732	359	368	cleft lip	SpecificDisease	D002971
4019732	385	387	CP	SpecificDisease	D002972
4019732	389	392	CLP	SpecificDisease	D002971
4019732	443	451	lip pits	SpecificDisease	C536528
4019732	455	463	fistulae	SpecificDisease	D005402
4019732	582	585	CLP	SpecificDisease	D002971
4019732	590	592	CP	SpecificDisease	D002972
4019732	603	606	VWS	SpecificDisease	C536528
4019732	724	727	CLP	SpecificDisease	D002971
4019732	736	738	CP	SpecificDisease	D002972
4019732	818	820	CP	SpecificDisease	D002972
4019732	846	849	CLP	SpecificDisease	D002971
4019732	854	857	VWS	SpecificDisease	C536528
4019732	896	904	Lip pits	SpecificDisease	C536528
4019732	1011	1014	VWS	SpecificDisease	C536528
4019732	1223	1226	VWS	SpecificDisease	C536528
4019732	1380	1383	VWS	Modifier	C536528
4019732	1478	1486	lip pits	SpecificDisease	C536528
4019732	1518	1526	lip pits	SpecificDisease	C536528
4019732	1642	1645	VWS	SpecificDisease	C536528
4019732	1748	1751	VWS	Modifier	C536528

2491010|t|Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene.
2491010|a|Eighty unrelated individuals with Duchenne muscular dystrophy (DMD)or Becker muscular dystrophy (BMD) were found to have deletions in the major deletion-rich region of the DMD locus. This region includes the last five exons detected by cDNA5b-7, all exons detected by cDNA8, and the first two exons detected by cDNA9. These 80 individuals account for approximately 75% of 109 deletions of the gene, detected among 181 patients analyzed with the entire dystrophin cDNA. Endpoints for many of these deletions were further characterized using two genomic probes, p20 (DXS269; Wapenaar et al.) and GMGX11 (DXS239; present paper). Clinical findings are presented for all 80 patients allowing a correlation of phenotypic severity with the genotype. Thirty-eight independent patients were old enough to be classified as DMD, BMD, or intermediate phenotype and had deletions of exons with sequenced intron/exon boundaries. Of these, eight BMD patients and one intermediate patient had gene deletions predicted to leave the reading frame intact, while 21 DMD patients, 7 intermediate patients, and 1 BMD patient had gene deletions predicted to disrupt the reading frame. Thus, with two exceptions, frameshift deletions of the gene resulted in more severe phenotype than did in-frame deletions. This is in agreement with recent findings by Baumbach et al. and Koenig et al. but is in contrast to findings, by Malhotra et al. at the 5 ' end of the gene.
2491010	100	127	Duchenne muscular dystrophy	Modifier	D020388
2491010	129	132	DMD	Modifier	D020388
2491010	174	201	Duchenne muscular dystrophy	SpecificDisease	D020388
2491010	203	206	DMD	SpecificDisease	D020388
2491010	210	235	Becker muscular dystrophy	SpecificDisease	C537666
2491010	237	240	BMD	SpecificDisease	C537666
2491010	312	315	DMD	Modifier	D020388
2491010	953	956	DMD	SpecificDisease	D020388
2491010	958	961	BMD	SpecificDisease	C537666
2491010	1071	1074	BMD	Modifier	C537666
2491010	1186	1189	DMD	Modifier	D020388
2491010	1231	1234	BMD	Modifier	C537666

10417279|t|Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher Disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. The Clinical European Network on Brain Dysmyelinating Disease.
10417279|a|Pelizaeus-Merzbacher Disease (PMD) is an X-linked developmental defect of myelination affecting the central nervous system and segregating with the proteolipoprotein (PLP) locus. Investigating 82 strictly selected sporadic cases of PMD, we found PLP mutations in 77%; complete PLP-gene duplications were the most frequent abnormality (62%), whereas point mutations in coding or splice-site regions of the gene were involved less frequently (38%). We analyzed the maternal status of 56 cases to determine the origin of both types of PLP mutation, since this is relevant to genetic counseling. In the 22 point mutations, 68% of mothers were heterozygous for the mutation, a value identical to the two-thirds of carrier mothers that would be expected if there were an equal mutation rate in male and female germ cells. In sharp contrast, among the 34 duplicated cases, 91% of mothers were carriers, a value significantly (chi2 = 9. 20, P <. 01) in favor of a male bias, with an estimation of the male/female mutation frequency (k) of 9. 3 3. Moreover, we observed the occurrence of de novo mutations between parental and grandparental generations in 17 three-generation families, which allowed a direct estimation of the k value (k = 11). Again, a significant male mutation imbalance was observed only for the duplications. 
10417279	61	89	Pelizaeus-Merzbacher Disease	SpecificDisease	OMIM:312080
10417279	244	272	Brain Dysmyelinating Disease	DiseaseClass	D020279
10417279	274	302	Pelizaeus-Merzbacher Disease	SpecificDisease	OMIM:312080
10417279	304	307	PMD	SpecificDisease	D020371
10417279	315	359	X-linked developmental defect of myelination	DiseaseClass	D020279
10417279	506	509	PMD	SpecificDisease	D020371

2569949|t|Haplotype analysis of the phenylalanine hydroxylase gene in Turkish phenylketonuria families.
2569949|a|We have estimated the haplotype distribution of mutant and normal phenylalanine hydroxylase (PAH) alleles for 17 Turkish phenylketonuria (PKU) families  20 normal and 27 mutated PAH alleles could be identified. Of the latter, the most prevalent were associated with haplotype 6 (29. 6%), 1 (18. 5%) and 36 (11. 1%), while the normal alleles were preferentially associated with haplotype 1 (20%). Of the 19 different haplotypes observed, 5 have not been described previously. The haplotype distribution differed significantly from that of the Northern European population. Two of the eight polymorphic sites were in association with PKU. No deletions of exon sequences were found in the families analysed.
2569949	68	83	phenylketonuria	Modifier	D010661
2569949	215	230	phenylketonuria	Modifier	D010661
2569949	232	235	PKU	Modifier	D010661
2569949	726	729	PKU	SpecificDisease	D010661

7668252|t|Cloning of human very-long-chain acyl-coenzyme A dehydrogenase and molecular characterization of its deficiency in two patients.
7668252|a|Two overlapping cDNA clones (1, 991 bp and 736 bp, respectively) encoding the precursor of human mitochondrial very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) were cloned and sequenced. The cDNA inserts of these clones together encompass a region of 2, 177 bases, encoding the entire protein of 655 amino acids, including a 40-amino acid leader peptide and a 615-amino acid mature polypeptide. PCR-amplified VLCAD cDNAs were sequenced in cultured fibroblasts from two VLCAD-deficient patients. In both patients, a 105-bp deletion encompassing bases 1078-1182 in VLCAD cDNA was identified. The deletion seems to occur due to exon skipping during processing of VLCAD pre-mRNA. This is the first demonstration of a mutation causing VLCAD deficiency. Quantitative cDNA expression of normal human VLCAD was performed in the patients fibroblasts, using vaccinia viral system, which demonstrated that the deficiency of the normal VLCAD protein causes impaired long-chain fatty acid beta-oxidation activity in the patients fibroblasts. In patient fibroblasts, raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts, which may offer important information for the rational design of future somatic gene therapy for VLCAD deficiency.. 
7668252	603	618	VLCAD-deficient	Modifier	C536353
7668252	864	880	VLCAD deficiency	SpecificDisease	C536353
7668252	1033	1071	deficiency of the normal VLCAD protein	SpecificDisease	C536353
7668252	1450	1466	VLCAD deficiency	SpecificDisease	C536353

2601691|t|Mutations in the RB1 gene and their effects on transcription.
2601691|a|Inactivation of both alleles of the RB1 gene during normal retinal development initiates the formation of a retinoblastoma (RB) tumor. To identify the mutations which inactivate RB1, 21 RB tumors isolated from 19 patients were analyzed with the polymerase chain reaction or an RNase protection assay or both. Mutations were identified in 13 of 21 RB tumors; in 8 tumors, the precise errors in nucleotide sequence were characterized. Each of four germ line mutations involved a small deletion or duplication, while three somatic mutations were point mutations leading to splice alterations and loss of an exon from the mature RB1 mRNA. We were unable to detect expression of the mutant allele in lymphoblasts of three bilaterally affected patients, although the mutation was present in the genomic DNA and transcripts containing the mutations were obvious in the RB tumors in the absence of a normal RB1 allele. The variations in the level of expression of mutant transcripts suggest deregulation of RB1 transcription in the absence of a functional RB1 gene product.. 
2601691	170	195	retinoblastoma (RB) tumor	SpecificDisease	D012175
2601691	248	257	RB tumors	SpecificDisease	D012175
2601691	409	418	RB tumors	SpecificDisease	D012175
2601691	425	431	tumors	DiseaseClass	D009369
2601691	924	933	RB tumors	SpecificDisease	D012175

1505982|t|Resolution of the two loci for autosomal dominant aniridia, AN1 and AN2, to a single locus on chromosome 11p13.
1505982|a|Two distinct loci have been proposed for aniridia; AN1 for autosomal dominant aniridia on chromosome 2p and AN2 for the aniridia in the WAGR contiguous gene syndrome on chromosome 11p13. In this report, the kindred segregating for autosomal dominant aniridia, which suggested linkage to acid phosphatase-1 (ACP1) and led to the assignment of the AN1 locus on chromosome 2p, has been updated and expanded. Linkage analysis between the aniridia phenotype and ACP1 does not support the original linkage results, excluding linkage up to theta = 0. 17 with Z = -2. Tests for linkage to other chromosome 2p markers. APOB, D2S71, D2S5, and D2S1, also excluded linkage to aniridia. Markers that have been isolated from the chromosome 11p13 region were then analyzed in this aniridia family. Two RFLPs at the D11S323 locus give significant evidence for linkage. The PvuII polymorphism detected by probe p5S1. 6 detects no recombinants, with a maximum lod score of Z = 6. 97 at theta = 0. 00 00. The HaeIII polymorphism detected by the probe p5BE1. 2 gives a maximum lod score of Z = 2. 57 at theta = 0. 00 00. Locus D11S325 gives a lod score of Z = 1. 53 at theta = 0. 00 00. These data suggest that a locus for aniridia (AN1) on chromosome 2p has been misassigned and that this autosomal dominant aniridia family is segregating for an aniridia mutation linked to markers in the 11p13 region.
1505982	50	58	aniridia	SpecificDisease	D015783
1505982	153	161	aniridia	SpecificDisease	D015783
1505982	190	198	aniridia	SpecificDisease	D015783
1505982	232	240	aniridia	SpecificDisease	D015783
1505982	248	277	WAGR contiguous gene syndrome	SpecificDisease	D017624
1505982	362	370	aniridia	SpecificDisease	D015783
1505982	546	554	aniridia	SpecificDisease	D015783
1505982	776	784	aniridia	SpecificDisease	D015783
1505982	878	886	aniridia	Modifier	D015783
1505982	1315	1323	aniridia	SpecificDisease	D015783
1505982	1401	1409	aniridia	Modifier	D015783
1505982	1439	1447	aniridia	Modifier	D015783

3615198|t|GT to AT transition at a splice donor site causes skipping of the preceding exon in phenylketonuria.
3615198|a|Classical Phenylketonuria (PKU) is an autosomal recessive human genetic disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). We isolated several mutant PAH cDNA clones from a PKU carrier individual and showed that they contained an internal 116 base pair deletion, corresponding precisely to exon 12 of the human chromosomal PAH gene. The deletion causes the synthesis of a truncated protein lacking the C-terminal 52 amino acids. Gene transfer and expression studies using the mutant PAH cDNA indicated that the deletion abolishes PAH activity in the cell as a result of protein instability. To determine the molecular basis of the deletion, the mutant chromosomal PAH gene was isolated from this individual and shown to contain a GT-- greater than AT substitution at the 5 splice donor site of intron 12. Thus, the consequence of the splice donor site mutation in the human liver is the skipping of the preceding exon during RNA splicing.. 
3615198	84	99	phenylketonuria	SpecificDisease	D010661
3615198	101	126	Classical Phenylketonuria	SpecificDisease	D010661
3615198	128	131	PKU	SpecificDisease	D010661
3615198	139	181	autosomal recessive human genetic disorder	DiseaseClass	D030342
3615198	194	241	deficiency of hepatic phenylalanine hydroxylase	SpecificDisease	OMIM:261600
3615198	299	302	PKU	Modifier	D010661

10521293|t|Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1.
10521293|a|Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and progressive optic atrophy. mtDNA deletions have been described, and a gene (WFS1) recently has been identified, on chromosome 4p16, encoding a predicted 890 amino acid transmembrane protein. Direct DNA sequencing was done to screen the entire coding region of the WFS1 gene in 30 patients from 19 British kindreds with Wolfram syndrome. DNA was also screened for structural rearrangements (deletions and duplications) and point mutations in mtDNA. No pathogenic mtDNA mutations were found in our cohort. We identified 24 mutations in the WFS1 gene  8 nonsense mutations, 8 missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4 frameshift mutations. Of these, 23 were novel mutations, and most occurred in exon 8. The majority of patients were compound heterozygotes for two mutations, and there was no common founder mutation. The data were also analyzed for genotype-phenotype relationships. Although some interesting cases were noted, consideration of the small sample size and frequency of each mutation indicated no clear-cut correlations between any of the observed mutations and disease severity. There were no obvious mutation hot spots or clusters. Hence, molecular screening for Wolfram syndrome in affected families and for Wolfram syndrome-carrier status in subjects with psychiatric disorders or diabetes mellitus will require complete analysis of exon 8 and upstream exons.. 
10521293	46	62	Wolfram syndrome	Modifier	OMIM:222300
10521293	124	140	Wolfram syndrome	SpecificDisease	OMIM:222300
10521293	147	193	autosomal recessive neurodegenerative disorder	DiseaseClass	D020271
10521293	211	243	juvenile-onset diabetes mellitus	SpecificDisease	D003922
10521293	260	273	optic atrophy	SpecificDisease	D009896
10521293	567	583	Wolfram syndrome	SpecificDisease	OMIM:222300
10521293	1452	1468	Wolfram syndrome	SpecificDisease	OMIM:222300
10521293	1498	1514	Wolfram syndrome	Modifier	OMIM:222300
10521293	1547	1568	psychiatric disorders	DiseaseClass	D001523
10521293	1572	1589	diabetes mellitus	SpecificDisease	D003920

10528860|t|Maternal uniparental disomy for chromosome 14 in a boy with a normal karyotype.
10528860|a|We report on a boy with a maternal uniparental disomy for chromosome 14 (UPD (14)). At 7 years of age he was referred to us by the paediatrician because of symptoms of Prader-Willi syndrome (PWS). He showed short stature, obesity, mild developmental delay, cryptorchidism, and some mild dysmorphic features. The history further indicated intrauterine growth retardation at the end of the pregnancy. His mother was 44 years of age at the time of his birth. After birth he showed hypotonia with poor sucking, for which gavage feeding was needed. Motor development was delayed. After 1 year he became obese despite a normal appetite. Recurrent middle ear infections, a high pain threshold, and a great skill with jigsaw puzzles were reported. There were no behavioural problems or sleep disturbance. Chromosomal analysis was normal (46, XY). DNA analysis for Prader-Willi syndrome showed no abnormalities. Two years later he was re-examined because we thought his features fitted the PWS-like phenotype associated with maternal UPD (14). At that time precocious puberty was evident. DNA analysis showed maternal heterodisomy for chromosome 14. In all the previously described 11 cases with maternal UPD (14), a Robertsonian translocation involving chromosome 14 was detected cytogenetically before DNA analysis. This is the first report of diagnosis of maternal UPD (14) based on clinical features. This finding underlines the importance of DNA analysis for maternal UPD (14) in patients with a similar PWS-like phenotype even without previous identification of a Robertsonian translocation involving chromosome 14.. 
10528860	0	45	Maternal uniparental disomy for chromosome 14	SpecificDisease	D024182
10528860	106	151	maternal uniparental disomy for chromosome 14	SpecificDisease	D024182
10528860	153	156	UPD	SpecificDisease	D024182
10528860	248	269	Prader-Willi syndrome	SpecificDisease	D011218
10528860	271	274	PWS	SpecificDisease	D011218
10528860	287	300	short stature	DiseaseClass	D006130
10528860	302	309	obesity	SpecificDisease	D009765
10528860	316	335	developmental delay	DiseaseClass	D002658
10528860	337	351	cryptorchidism	SpecificDisease	D003456
10528860	367	386	dysmorphic features	DiseaseClass	D000013
10528860	418	449	intrauterine growth retardation	DiseaseClass	D005317
10528860	558	567	hypotonia	DiseaseClass	D009123
10528860	678	683	obese	Modifier	D009765
10528860	721	742	middle ear infections	SpecificDisease	D010033
10528860	936	957	Prader-Willi syndrome	SpecificDisease	D011218
10528860	1061	1064	PWS	Modifier	D011218
10528860	1105	1108	UPD	SpecificDisease	D024182
10528860	1180	1201	maternal heterodisomy	DiseaseClass	D024182
10528860	1276	1279	UPD	SpecificDisease	D024182
10528860	1439	1442	UPD	SpecificDisease	D024182
10528860	1580	1583	PWS	Modifier	D011218

7611277|t|Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer.
7611277|a|Genetic epidemiological evidence suggests that mutations in BRCA1 may be responsible for approximately one half of early onset familial breast cancer and the majority of familial breast/ovarian cancer. The recent cloning of BRCA1 allows for the direct detection of mutations, but the feasibility of presymptomatic screening for cancer susceptibility is unknown. We analyzed genomic DNA from one affected individual from each of 24 families with at least three cases of ovarian or breast cancer, using SSCP assays. Variant SSCP bands were subcloned and sequenced. Allele-specific oligonucleotide hybridization was used to verify sequence changes and to screen DNA from control individuals. Six frameshift and two missense mutations were detected in 10 different families. A frameshift mutation was detected in a male proband affected with both breast and prostate cancer. A 40-bp deletion was detected in a patient who developed intra-abdominal carcinomatosis 1 year after prophylactic oophorectomy. Mutations were detected throughout the gene, and only one was detected in more than a single family. These results provide further evidence that inherited breast and ovarian cancer can occur as a consequence of a wide array of BRCA1 mutations. These results suggests that development of a screening test for BRCA1 mutations will be technically challenging. The finding of a mutation in a family with male breast cancer, not previously thought to be related to BRCA1, also illustrates the potential difficulties of genetic counseling for individuals known to carry mutations.. 
7611277	41	62	breast/ovarian cancer	Modifier	D061325
7611277	97	115	male breast cancer	SpecificDisease	D018567
7611277	244	266	familial breast cancer	SpecificDisease	D001943
7611277	287	317	familial breast/ovarian cancer	CompositeMention	D061325
7611277	445	451	cancer	Modifier	D009369
7611277	586	610	ovarian or breast cancer	CompositeMention	D010051|D001943
7611277	960	986	breast and prostate cancer	CompositeMention	D001943|D011471
7611277	1045	1075	intra-abdominal carcinomatosis	DiseaseClass	D000008+D002277
7611277	1261	1296	inherited breast and ovarian cancer	CompositeMention	D061325
7611277	1516	1534	male breast cancer	SpecificDisease	D018567

2729274|t|Color vision defects in adrenomyeloneuropathy.
2729274|a|The relationship between abnormal color vision and adrenomyeloneuropathy (AMN) was investigated in 27 AMN patients and 31 age-matched controls by using the Farnsworth-Munsell 100 Hue test. Twelve (44%) of 27 patients showed test scores significantly above normal. The axes of bipolarity determined by the testing differed widely between the patients with abnormal scores, compatible with the notion that different alterations in visual pigment genes occur in different AMN kindreds. These observations confirm our earlier impression that the frequency of abnormal color vision is increased in these kindreds, and it supports our contentions that (1) AMN (and its companion, adrenoleukodystrophy) are very closely linked to the visual pigment loci at Xq28 and (2) this proximity might provide the opportunity to observe contiguous gene defects.. 
2729274	0	20	Color vision defects	DiseaseClass	D003117
2729274	24	45	adrenomyeloneuropathy	SpecificDisease	D000326
2729274	72	93	abnormal color vision	DiseaseClass	D003117
2729274	98	119	adrenomyeloneuropathy	SpecificDisease	D000326
2729274	121	124	AMN	SpecificDisease	D000326
2729274	149	152	AMN	Modifier	D000326
2729274	516	519	AMN	Modifier	D000326
2729274	602	623	abnormal color vision	DiseaseClass	D003117
2729274	697	700	AMN	SpecificDisease	D000326
2729274	721	741	adrenoleukodystrophy	DiseaseClass	D000326
2729274	866	889	contiguous gene defects	DiseaseClass	D025063

3169738|t|Patterns of exon deletions in Duchenne and Becker muscular dystrophy.
3169738|a|A panel of patients with Duchenne and Becker muscular dystrophy (DMD and BMD) has been screened with the cDNA probes Cf56a and Cf23a, which detect exons in the central part of the DMD gene. One or more exons were deleted in 60% of patients. The deletions were mapped and prove to be heterogeneous in size and extent, particularly in DMD. Deletions specific to DMD and to BMD are described. Half of all BMD patients have a deletion of one particular small group of exons; smaller deletions within this same group produce the more severe DMD.. 
3169738	30	68	Duchenne and Becker muscular dystrophy	CompositeMention	D020388|C537666
3169738	95	133	Duchenne and Becker muscular dystrophy	CompositeMention	D020388|C537666
3169738	135	138	DMD	SpecificDisease	D020388
3169738	143	146	BMD	SpecificDisease	C537666
3169738	250	253	DMD	Modifier	D020388
3169738	403	406	DMD	SpecificDisease	D020388
3169738	430	433	DMD	SpecificDisease	D020388
3169738	441	444	BMD	SpecificDisease	C537666
3169738	472	475	BMD	Modifier	C537666
3169738	606	609	DMD	SpecificDisease	D020388

7951327|t|The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene.
7951327|a|The Long-Evans Cinnamon (LEC) rat shows similarity to Wilson disease in many clinical and biochemical features. We have cloned cDNAs for the rat gene (Atp7b) homologous to the human Wilson disease gene (ATP7B) and have used them to identify a partial deletion in the Atp7b gene in the LEC rat. The deletion removes at least 900 bp of the coding region at the 3 end, includes the crucial ATP binding domain and extends downstream of the gene. Our results provide convincing evidence for defining the LEC rat as an animal model for Wilson disease. This model will be important for studying liver pathophysiology, for developing therapy for Wilson disease and for studying the pathway of copper transport and its possible interaction with other heavy metals.. 
7951327	84	98	Wilson disease	Modifier	D006527
7951327	159	173	Wilson disease	SpecificDisease	D006527
7951327	287	301	Wilson disease	Modifier	D006527
7951327	635	649	Wilson disease	SpecificDisease	D006527
7951327	743	757	Wilson disease	SpecificDisease	D006527

8440142|t|Detection of a new submicroscopic Norrie disease deletion interval with a novel DNA probe isolated by differential Alu PCR fingerprint cloning.
8440142|a|Differential Alu PCR fingerprint cloning was used to isolate a DNA probe from the Xp11. 4-- > p11. 21 region of the human X chromosome. This novel sequence, cpXr318 (DXS742), detects a new submicroscopic deletion interval at the Norrie disease locus (NDP). Combining our data with the consensus genetic map of the proximal short arm of the X chromosome, we propose the physical order Xcen-DXS14-DXS255- (DXS426, TIMP) - (DXS742- ([MAOB-MAOA-DXS7], NDP) -DXS77-DXS228) -DXS209-DXS148-DXS196- + + + Xpter. The cpXr318 probe and a subclone from a cosmid corresponding to the DXS7 locus were converted into sequence-tagged sites. Finally, DXS742, DSX7, DXS77, and MAOA were integrated into a physical map spanning the Norrie disease locus 
8440142	34	48	Norrie disease	Modifier	C537849
8440142	373	387	Norrie disease	Modifier	C537849
8440142	858	872	Norrie disease	Modifier	C537849

1731805|t|Genetic analysis of a Japanese family with normotriglyceridemic abetalipoproteinemia indicates a lack of linkage to the apolipoprotein B gene.
1731805|a|Normotriglyceridemic abetalipoproteinemia is a rare familial disorder characterized by an isolated deficiency of apoB-100. We have previously reported a patient with this disease, who had normal apoB-48 but no apoB-100. To elucidate the genetic abnormalities in this family, we studied the linkage of apoB gene using three genetic markers. The proband and her affected brother showed completely different apoB gene alleles, suggesting that the apoB gene itself is not related to this disorder in this family. By contrast, an American case had a point substitution in the apoB gene generating an in-frame stop codon. These results indicate that this disorder can be caused by defect (s) of either an apoB gene or other genes.. 
1731805	43	84	normotriglyceridemic abetalipoproteinemia	SpecificDisease	D000012
1731805	143	184	Normotriglyceridemic abetalipoproteinemia	SpecificDisease	D000012
1731805	195	212	familial disorder	DiseaseClass	D009358
1731805	242	264	deficiency of apoB-100	SpecificDisease	OMIM:200100
1731805	380	401	genetic abnormalities	DiseaseClass	D030342

10788334|t|Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.
10788334|a|We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age < 50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities - 5382insC, C61G, and 4153delA - accounted for 51%, 20%, and 11% of the identified mutations, respectively.. 
10788334	60	81	breast-ovarian cancer	CompositeMention	D061325
10788334	260	266	cancer	DiseaseClass	D009369
10788334	321	345	breast or ovarian cancer	CompositeMention	D001943|D010051
10788334	358	364	cancer	DiseaseClass	D009369
10788334	474	500	breast and ovarian cancers	CompositeMention	D001943|D010051
10788334	517	532	ovarian cancers	SpecificDisease	D010051
10788334	559	573	breast cancers	SpecificDisease	D001943
10788334	982	1001	BRCA1 abnormalities	DiseaseClass	OMIM:604370
10788334	1044	1058	ovarian cancer	SpecificDisease	D010051
10788334	1097	1122	breast and ovarian cancer	CompositeMention	D001943|D010051
10788334	1155	1168	breast cancer	SpecificDisease	D001943
10788334	1223	1253	breast-ovarian cancer syndrome	SpecificDisease	D061325
10788334	1448	1467	BRCA1 abnormalities	DiseaseClass	OMIM:604370

7762560|t|New founder haplotypes at the myotonic dystrophy locus in southern Africa.
7762560|a|The association between normal alleles at the CTG repeat and two nearby polymorphisms in the myotonin protein kinase gene, the Alu insertion/deletion polymorphism and the myotonic dystrophy kinase (DMK) (G/T) intron 9/HinfI polymorphism, has been analyzed in South African Negroids, a population in which myotonic dystrophy (DM) has not been described. South African Negroids have a CTG allelic distribution that is significantly different from that in Caucasoids and Japanese  the CTG repeat lengths of > or = 19 are very rare. The striking linkage disequilibrium between specific alleles at the Alu polymorphism (Alu (ins) and Alu (del)), the HinfI polymorphism (HinfI-1 and HinfI-2), and the CTG repeat polymorphism seen in Caucasoid (Europeans and Canadians) populations was also found in the South African Negroid population. Numerous haplotypes, not previously described in Europeans, were, however, found. It thus seems likely that only a small number of these " African " chromosomes were present in the progenitors of all non-African peoples. These data provide support for the " out of Africa " model for the origin of modern humans and suggest that the rare ancestral DM mutation event may have occurred after the migration from Africa, hence the absence of DM in sub-Saharan Negroid peoples.. 
7762560	30	48	myotonic dystrophy	Modifier	D009223
7762560	246	264	myotonic dystrophy	Modifier	D009223
7762560	380	398	myotonic dystrophy	SpecificDisease	D009223
7762560	400	402	DM	SpecificDisease	D009223
7762560	1254	1256	DM	Modifier	D009223
7762560	1344	1346	DM	SpecificDisease	D009223

7573040|t|Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus.
7573040|a|The spinocerebellar ataxia 3 locus (SCA3) for type I autosomal dominant cerebellar ataxia (ADCA type I), a clinically and genetically heterogeneous group of neurodegenerative disorders, has been mapped to chromosome 14q32. 1 1. ADCA type I patients from families segregating SCA3 share clinical features in common with those with Machado-Joseph disease (MJD), the gene of which maps to the same region. We show here that the disease gene segregating in each of three French ADCA type I kindreds and in a French family with neuropathological findings suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy carries an expanded CAG repeat sequence located at the same locus as that for MJD. Analysis of the mutation in these families shows a strong negative correlation between size of the expanded CAG repeat and age at onset of clinical disease. Instability of the expanded triplet repeat was not found to be affected by sex of the parent transmitting the mutation. Evidence was found for somatic and gonadal mosaicism for alleles carrying expanded trinucleotide repeats. 
7573040	90	137	spinocerebellar ataxia 3/Machado-Joseph disease	Modifier	D017827
7573040	149	173	spinocerebellar ataxia 3	Modifier	D017827
7573040	181	185	SCA3	SpecificDisease	D017827
7573040	191	234	type I autosomal dominant cerebellar ataxia	SpecificDisease	OMIM:109150
7573040	236	247	ADCA type I	SpecificDisease	OMIM:109150
7573040	302	329	neurodegenerative disorders	DiseaseClass	D019636
7573040	373	384	ADCA type I	Modifier	OMIM:109150
7573040	420	424	SCA3	SpecificDisease	D017827
7573040	475	497	Machado-Joseph disease	SpecificDisease	D017827
7573040	499	502	MJD	SpecificDisease	D017827
7573040	619	630	ADCA type I	Modifier	OMIM:109150
7573040	731	765	dentatorubropallidoluysian atrophy	SpecificDisease	OMIM:125370
7573040	844	847	MJD	SpecificDisease	D017827

2309698|t|The red-green visual pigment gene region in adrenoleukodystrophy.
2309698|a|Although recent data established that a specific very-long-chain fatty acyl-CoA synthetase is defective in X-linked adrenoleukodystrophy (ALD), the ALD gene is still unidentified. The ALD locus has been mapped to Xq28, like the red and green color pigment genes. Abnormal color vision has been observed in 12 of 27 patients with adrenomyeloneuropathy (AMN), a milder form of ALD. Furthermore, rearrangements of the color vision gene cluster were found in four of eight ALD kindreds. This led us to propose that a single DNA rearrangement could underlie both ALD and abnormal color vision in these patients. Study of 34 French ALD patients failed to reveal a higher than expected frequency of green/red visual pigment rearrangements 3 to the red/green color vision gene complex. The previous report of such rearrangements was based on small numbers and lack of knowledge that the frequency of " abnormal " color vision arrays on molecular analysis was twice as high as expected on the basis of the frequency of phenotypic color vision defects. The red/green color pigment (R/GCP) region was studied by pulsed-field gel electrophoresis in 14 of these patients, and we did not find any fragment size difference between the patients and normal individuals who have the same number of pigment genes. The R/GCP region was also analyzed in 29 French and seven North American ALD patients by using six genomic DNA probes, isolated from a cosmid walk, that flank the color vision genes. No deletions were found with probes that lie 3 of the green pigment genes. One of the eight previously reported ALD individuals has a long deletion 5 of the red pigment gene, a deletion causing blue cone monochromacy. This finding and the previous findings of a 45% frequency of phenotypic color vision defects in patients with AMN may suggest that the ALD/AMN gene lies 5 to the red pigment gene and that the frequent phenotypic color vision anomalies owe their origin to deleted DNA that includes regulatory genes for color vision. It is possible, however, that phenotypic color vision anomalies in AMN may be phenocopies secondary to retinal or neural involvement by the disease. The single case of blue cone monochromacy may therefore be a fortuitous coincidence of two diseases.. 
2309698	44	64	adrenoleukodystrophy	SpecificDisease	D000326
2309698	173	202	X-linked adrenoleukodystrophy	SpecificDisease	D000326
2309698	204	207	ALD	SpecificDisease	D000326
2309698	214	217	ALD	Modifier	D000326
2309698	250	253	ALD	Modifier	D000326
2309698	329	350	Abnormal color vision	DiseaseClass	D003117
2309698	395	416	adrenomyeloneuropathy	SpecificDisease	D000326
2309698	418	421	AMN	SpecificDisease	D000326
2309698	441	444	ALD	SpecificDisease	D000326
2309698	535	538	ALD	Modifier	D000326
2309698	624	627	ALD	SpecificDisease	D000326
2309698	632	653	abnormal color vision	SpecificDisease	D003117
2309698	692	695	ALD	Modifier	D000326
2309698	1076	1107	phenotypic color vision defects	SpecificDisease	D003117
2309698	1434	1437	ALD	Modifier	D000326
2309698	1656	1659	ALD	Modifier	D000326
2309698	1872	1875	AMN	SpecificDisease	D000326
2309698	1897	1900	ALD	Modifier	D000326
2309698	1901	1904	AMN	Modifier	D000326
2309698	1974	1996	color vision anomalies	DiseaseClass	D003117
2309698	2119	2141	color vision anomalies	DiseaseClass	D003117
2309698	2145	2148	AMN	SpecificDisease	D000326

10662807|t|Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C.
10662807|a|Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefevre syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction. Although both PLS and HMS share the cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS including arachnodactyly, acro-osteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers. While PLS cases have been identified throughout the world, HMS has only been described among descendants of a religious isolate originally from Cochin, India. Parental consanguinity is a characteristic of many cases of both conditions. Although autosomal recessive transmission of PLS is evident, a more " complex " autosomal recessive pattern of inheritance with phenotypic influences from a closely linked modifying locus has been hypothesised for HMS. Recently, mutations of the cathepsin C gene have been identified as the underlying genetic defect in PLS. To determine if a cathepsin C mutation is also responsible for HMS, we sequenced the gene in affected and unaffected subjects from the Cochin isolate in which both the PLS and HMS phenotypes appear. Here we report identification of a mutation of cathepsin C (exon 6, 2127A-- > G) that changes a highly conserved amino acid in the cathepsin C peptide. This mutation segregates with HMS in four nuclear families. Additionally, the existence of a shared common haplotype for genetic loci flanking the cathepsin C gene suggests that affected subjects descended from the Cochin isolate are homozygous for a mutation inherited " identical by descent " from a common ancestor. This finding supports simple autosomal recessive inheritance for HMS in these families. We also report a mutation of the same exon 6 CTSC codon (2126C-- > T) in a Turkish family with classical PLS. These findings provide evidence that PLS and HMS are allelic variants of cathepsin C gene mutations.. 
10662807	0	18	Haim-Munk syndrome	SpecificDisease	C537627
10662807	23	48	Papillon-Lefevre syndrome	SpecificDisease	D010214
10662807	99	140	palmoplantar keratoderma (PPK) conditions	DiseaseClass	D007645
10662807	147	172	Papillon-Lefevre syndrome	SpecificDisease	D010214
10662807	174	177	PLS	SpecificDisease	D010214
10662807	183	201	Haim-Munk syndrome	SpecificDisease	C537627
10662807	203	206	HMS	SpecificDisease	C537627
10662807	277	280	PLS	SpecificDisease	D010214
10662807	285	288	HMS	SpecificDisease	C537627
10662807	320	323	PPK	DiseaseClass	D007645
10662807	335	348	periodontitis	SpecificDisease	D010518
10662807	398	401	HMS	SpecificDisease	C537627
10662807	412	426	arachnodactyly	SpecificDisease	D054119
10662807	428	443	acro-osteolysis	SpecificDisease	D030981
10662807	445	474	atrophic changes of the nails	SpecificDisease	D009260
10662807	482	519	radiographic deformity of the fingers	SpecificDisease	D006226
10662807	527	530	PLS	Modifier	D010214
10662807	580	583	HMS	SpecificDisease	C537627
10662807	802	805	PLS	SpecificDisease	D010214
10662807	971	974	HMS	SpecificDisease	C537627
10662807	1059	1073	genetic defect	DiseaseClass	D030342
10662807	1077	1080	PLS	SpecificDisease	D010214
10662807	1145	1148	HMS	SpecificDisease	C537627
10662807	1250	1253	PLS	Modifier	D010214
10662807	1258	1261	HMS	Modifier	C537627
10662807	1463	1466	HMS	SpecificDisease	C537627
10662807	1817	1820	HMS	SpecificDisease	C537627
10662807	1945	1948	PLS	SpecificDisease	D010214
10662807	1987	1990	PLS	SpecificDisease	D010214
10662807	1995	1998	HMS	SpecificDisease	C537627

10377440|t|X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation.
10377440|a|A somatic mutation in the X linked PIGA gene is responsible for the deficiency of glycosyl phosphatidylinositol (GPI) -anchored proteins on blood cells from patients with paroxysmal nocturnal hemoglobinuria. No inherited form of GPI-anchor deficiency has been described. Because conventional Piga gene knockout is associated with high embryonic lethality in chimeric mice, we used the Cre/loxP system. We generated mice in which two loxP sites flank part of Piga exon 2. After crossbreeding with female mice of the EIIa-cre strain, the floxed allele undergoes Cre-mediated recombination with high efficiency during early embryonic development. Because of X chromosome inactivation, female offspring are mosaic for cells that express or lack GPI-linked proteins. Analysis of mosaic mice showed that in heart, lung, kidney, brain, and liver, mainly wild-type Piga is active, suggesting that these tissues require GPI-linked proteins. The salient exceptions were spleen, thymus, and red blood cells, which had almost equal numbers of cells expressing the wild-type or the recombined allele, implying that GPI-linked proteins are not essential for the derivation of these tissues. PIGA (-) cells had no growth advantage, suggesting that other factors are needed for their clonal dominance in patients with paroxysmal nocturnal hemoglobinuria.. 
10377440	160	228	deficiency of glycosyl phosphatidylinositol (GPI) -anchored proteins	DiseaseClass	C537277
10377440	263	298	paroxysmal nocturnal hemoglobinuria	SpecificDisease	D006457
10377440	321	342	GPI-anchor deficiency	SpecificDisease	C537277
10377440	427	446	embryonic lethality	SpecificDisease	D020964
10377440	1394	1429	paroxysmal nocturnal hemoglobinuria	SpecificDisease	D006457

1301161|t|The Norrie disease gene maps to a 150 kb region on chromosome Xp11.3.
1301161|a|Norrie disease is a human X-linked recessive disorder of unknown etiology characterized by congenital blindness, sensory neural deafness and mental retardation. This disease gene was previously linked to the DXS7 (L1. 28) locus and the MAO genes in band Xp11. 3 3. We report here fine physical mapping of the obligate region containing the Norrie disease gene (NDP) defined by a recombination and by the smallest submicroscopic chromosomal deletion associated with Norrie disease identified to date. Analysis, using in addition two overlapping YAC clones from this region, allowed orientation of the MAOA and MAOB genes in a 5-3-3-5 configuration. A recombination event between a (GT) n polymorphism in intron 2 of the MAOB gene and the NDP locus, in a family previously reported to have a recombination between DXS7 and NDP, delineates a flanking marker telomeric to this disease gene. An anonymous DNA probe, dc12, present in one of the YACs and in a patient with a submicroscopic deletion which includes MAOA and MAOB but not L1. 28, serves as a flanking marker centromeric to the disease gene. An Alu-PCR fragment from the right arm of the MAO YAC (YMAO. AluR) is not deleted in this patient and also delineates the centromeric extent of the obligate disease region. The apparent order of these loci is telomere. DXS7-MAOA-MAOB-NDP-dc12-YMAO DXS7-MAOA-MAOB-NDP-dc12-YMAO. AluR. centromere. Together these data define the obligate region containing the NDP gene to a chromosomal segment less than 150 kb.
1301161	4	18	Norrie disease	Modifier	C537849
1301161	70	84	Norrie disease	SpecificDisease	C537849
1301161	96	123	X-linked recessive disorder	DiseaseClass	D040181
1301161	161	181	congenital blindness	SpecificDisease	D057130
1301161	183	206	sensory neural deafness	SpecificDisease	D006319
1301161	211	229	mental retardation	DiseaseClass	D008607
1301161	410	424	Norrie disease	Modifier	C537849
1301161	535	549	Norrie disease	SpecificDisease	C537849

2393028|t|Molecular genetics of the glucose-6-phosphate dehydrogenase (G6PD) Mediterranean variant and description of a new G6PD mutant, G6PD Andalus1361A.
2393028|a|Glucose-6-phosphate dehydrogenase (G6PD; E. C. 1. 1. 1. 49) deficiency is the most common human enzymopathy; more than 300 different biochemical variants of the enzyme have been described. In many parts of the world the Mediterranean type of G6PD deficiency is prevalent. However, G6PD Mediterranean has come to be regarded as a generic term applied to similar G6PD mutations thought, however, to represent a somewhat heterogeneous group. A C----T mutation at nucleotide 563 of G6PD Mediterranean has been identified by Vulliamy et al., and the same mutation has been found by De Vita et al. in G6PD Mediterranean, G6PD Sassari, and G6PD Cagliari. The latter subjects had an additional mutation, at nucleotide 1311, that did not produce a coding change. We have examined genomic DNA of five patients--four of Spanish origin and one of Jewish origin--having enzymatically documented G6PD Mediterranean. All had both the mutation at nucleotide 563 and that at nucleotide 1311. A sixth sample, resembling G6PD Mediterranean kinetically but with a slightly rapid electrophoretic mobility, was designated G6PD Andalus and was found to have a different mutation, a G----A transition at nucleotide 1361, producing an arginine-to-histidine substitution. These studies suggest that G6PD Mediterranean is, after all, relatively homogeneous.
2393028	146	216	Glucose-6-phosphate dehydrogenase (G6PD; E. C. 1. 1. 1. 49) deficiency	SpecificDisease	D005955
2393028	242	253	enzymopathy	DiseaseClass	D008661
2393028	388	403	G6PD deficiency	SpecificDisease	D005955

1303277|t|Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader-Willi syndrome critical region.
1303277|a|Prader-Willi syndrome (PWS) is associated with paternally derived chromosomal deletions in region 15q11-13 or with maternal disomy for chromosome 15. Therefore, loss of the expressed paternal alleles of maternally imprinted genes must be responsible for the PWS phenotype. We have mapped the gene encoding the small nuclear RNA associated polypeptide SmN (SNRPN) to human chromosome 15q12 and a processed pseudogene SNRPNP1 to chromosome region 6pter-p21. Furthermore, SNRPN was mapped to the minimal deletion interval that is critical for PWS. The fact that the mouse Snrpn gene is maternally imprinted in brain suggests that loss of the paternally derived SNRPN allele may be involved in the PWS phenotype.. 
1303277	80	101	Prader-Willi syndrome	Modifier	D011218
1303277	119	140	Prader-Willi syndrome	SpecificDisease	D011218
1303277	142	145	PWS	SpecificDisease	D011218
1303277	234	267	maternal disomy for chromosome 15	SpecificDisease	C538037
1303277	377	380	PWS	Modifier	D011218
1303277	659	662	PWS	SpecificDisease	D011218
1303277	813	816	PWS	Modifier	D011218

10064668|t|Increased incidence of cancer in patients with cartilage-hair hypoplasia.
10064668|a|OBJECTIVE  Previous reports have suggested an increased risk of cancer among patients with cartilage-hair hypoplasia (CHH). This study was carried out to further evaluate this risk among patients with CHH and their first-degree relatives. STUDY DESIGN  One hundred twenty-two patients with CHH were identified through 2 countrywide epidemiologic surveys in 1974 and in 1986. Their parents and nonaffected siblings were identified through the Population Register Center. This cohort underwent follow-up for cancer incidence through the Finnish Cancer Registry to the end of 1995. RESULTS  A statistically significant excess risk of cancer was seen among the patients with CHH (standardized incidence ratio 6. 9, 95% confidence interval 2. 3 to 16), which was mainly attributable to non-Hodgkins lymphoma  (standardized incidence ratio 90, 95% confidence interval 18 to 264). In addition, a significant excess risk of basal cell carcinoma was seen (standardized incidence ratio 35, 95% confidence interval 7. 2 to 102). The cancer incidence among the siblings or the parents did not differ from the average cancer incidence in the Finnish population. CONCLUSIONS  This study confirms an increased risk of cancer, especially non-Hodgkins lymphoma, probably attributable to defective immunity, among patients with CHH.
10064668	23	29	cancer	DiseaseClass	D009369
10064668	47	72	cartilage-hair hypoplasia	SpecificDisease	C535916
10064668	138	144	cancer	DiseaseClass	D009369
10064668	165	190	cartilage-hair hypoplasia	SpecificDisease	C535916
10064668	192	195	CHH	SpecificDisease	C535916
10064668	275	278	CHH	SpecificDisease	C535916
10064668	364	367	CHH	SpecificDisease	C535916
10064668	580	586	cancer	Modifier	D009369
10064668	705	711	cancer	DiseaseClass	D009369
10064668	745	748	CHH	SpecificDisease	C535916
10064668	855	876	non-Hodgkins lymphoma	SpecificDisease	D008228
10064668	990	1010	basal cell carcinoma	SpecificDisease	D002280
10064668	1096	1102	cancer	Modifier	D009369
10064668	1179	1185	cancer	Modifier	D009369
10064668	1277	1283	cancer	DiseaseClass	D009369
10064668	1296	1317	non-Hodgkins lymphoma	SpecificDisease	D008228
10064668	1384	1387	CHH	SpecificDisease	C535916

6540752|t|Genetic polymorphism of G6PD in a Bulgarian population.
6540752|a|Considerable genetic heterogeneity in G6PD was found in the Bulgarian population-14 G6PD variants isolated from 117 hemizygous carriers of G6PD deficiency. Of these, G6PD Mediterranean type was a polymorphic variant and G6PD Corinth occurred with high frequency. Two new variants were identified-G6PD Rudosem and G6PD Nedelino. In a selected group of 78 subjects with clinical manifestations, four variants were established  G6PD Mediterranian, G6PD Corinth, G6PD Seattle and G6PD Ohut II.. 
6540752	195	210	G6PD deficiency	SpecificDisease	D005955

1349199|t|A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11.
1349199|a|DiGeorge syndrome (DGS), a developmental field defect of the third and fourth pharyngeal pouches, is characterized by aplasia or hypoplasia of the thymus and parathyroid glands and by conotruncal cardiac malformations. Cytogenetic studies support the presence of a DGS critical region in band 22q11. In the present study, we report the results of clinical, cytogenetic, and molecular studies of 14 patients with DGS. Chromosome analysis, utilizing high-resolution banding techniques, detected interstitial deletions in five probands and was inconclusive for a deletion in three probands. The remaining six patients had normal karyotypes. In contrast, molecular analysis detected DNA deletions in all 14 probands. Two of 10 loci tested, D22S75 and D22S259, are deleted in all 14 patients. A third locus, D22S66, is deleted in the eight DGS probands tested. Physical mapping using somatic cell hybrids places D22S66 between D22S75 and D22S259, suggesting that it should be deleted in the remaining six cases. Parent-of-origin studies were performed in five families. Four probands failed to inherit a maternal allele, and one failed to inherit a paternal allele. On the basis of these families, and of six maternally and five paternally derived unbalanced-translocation DGS probands in the literature, parent of origin or imprinting does not appear to play an important role in the pathogenesis of DGS. Deletion of the same three loci in all 14 DGS probands begins to delineate the region of chromosome 22 critical for DGS and confirms the hypothesis that submicroscopic deletions of 22q11 are etiologic in the vast majority of cases.. 
1349199	23	40	DiGeorge syndrome	SpecificDisease	D004062
1349199	92	109	DiGeorge syndrome	SpecificDisease	D004062
1349199	111	114	DGS	SpecificDisease	D004062
1349199	210	268	aplasia or hypoplasia of the thymus and parathyroid glands	CompositeMention	C536288|D007011
1349199	276	309	conotruncal cardiac malformations	SpecificDisease	C535464
1349199	357	360	DGS	Modifier	D004062
1349199	504	507	DGS	SpecificDisease	D004062
1349199	927	930	DGS	Modifier	D004062
1349199	1360	1363	DGS	Modifier	D004062
1349199	1488	1491	DGS	SpecificDisease	D004062
1349199	1535	1538	DGS	Modifier	D004062
1349199	1609	1612	DGS	SpecificDisease	D004062

1301146|t|Characterisation of a new rare fragile site easily confused with the fragile X.
1301146|a|A new fragile site (FRAXE) in Xq28 is described. It appears to be a typical folate sensitive fragile site. The fragile site is not associated with mental retardation, it does not give abnormal results when subjected to Southern analysis with probe pfxa3 which detects the unstable DNA sequence characteristic of fragile X syndrome. In situ hybridization mapping locates the fragile site between 150 kb and 600 kb distal to FRAXA. The distinction between the two fragile sites is important clinically since cytogenetic detection of FRAXE, without molecular analysis, could result in misdiagnosis of fragile X syndrome.. 
1301146	69	78	fragile X	SpecificDisease	D005600
1301146	227	245	mental retardation	DiseaseClass	D008607
1301146	392	410	fragile X syndrome	SpecificDisease	D005600
1301146	678	696	fragile X syndrome	SpecificDisease	D005600

7939630|t|BRCA1 mutations in primary breast and ovarian carcinomas.
7939630|a|Loss of heterozygosity data from familial tumors suggest that BRCA1, a gene that confers susceptibility to ovarian and early-onset breast cancer, encodes a tumor suppressor. The BRCA1 region is also subject to allelic loss in sporadic breast and ovarian cancers, an indication that BRCA1 mutations may occur somatically in these tumors. The BRCA1 coding region was examined for mutations in primary breast and ovarian tumors that show allele loss at the BRCA1 locus. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all four mutations were germline alterations and occurred in early-onset cancers. These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele.. 
7939630	27	56	breast and ovarian carcinomas	CompositeMention	D001943|D010051
7939630	91	106	familial tumors	DiseaseClass	D009386
7939630	165	188	ovarian and early-onset	CompositeMention	D010051
7939630	189	202	breast cancer	CompositeMention	D001943
7939630	214	219	tumor	Modifier	D009369
7939630	284	319	sporadic breast and ovarian cancers	SpecificDisease	D001943|D010051
7939630	387	393	tumors	DiseaseClass	D009369
7939630	457	482	breast and ovarian tumors	CompositeMention	D001943|D010051
7939630	579	597	ovarian carcinomas	SpecificDisease	D010051
7939630	672	679	cancers	DiseaseClass	D009369
7939630	784	810	breast and ovarian cancers	CompositeMention	D001943|D010051

8307570|t|Genomic structure of the EWS gene and its relationship to EWSR1, a site of tumor-associated chromosome translocation.
8307570|a|The EWS gene has been identified based on its location at the chromosome 22 breakpoint of the t (11; 22) (q24; q12) translocation that characterizes Ewing sarcoma and related neuroectodermal tumors. The EWS gene spans about 40 kb of DNA and is encoded by 17 exons. The nucleotide sequence of the exons is identical to that of the previously described cDNA. The first 7 exons encode the N-terminal domain of EWS, which consists of a repeated degenerated polypeptide of 7 to 12 residues rich in tyrosine, serine, threonine, glycine, and glutamine. Exons 11, 12, and 13 encode the putative RNA binding domain. The three glycine- and arginine-rich motifs of the gene are mainly encoded by exons 8-9, 14, and 16. The DNA sequence in the 5 region of the gene has features of a CpG-rich island and lacks canonical promoter elements, such as TATA and CCAAT consensus sequences. Positions of the chromosome 22 breakpoints were determined for 19 Ewing tumors. They were localized in introns 7 or 8 in 18 cases and in intron 10 in 1 case.. 
8307570	75	80	tumor	Modifier	D009369
8307570	267	280	Ewing sarcoma	SpecificDisease	D012512
8307570	293	315	neuroectodermal tumors	SpecificDisease	D017599
8307570	1054	1066	Ewing tumors	DiseaseClass	D012512

8364574|t|PAX6 mutations in aniridia.
8364574|a|Aniridia is a congenital malformation of the eye, chiefly characterised by iris hypoplasia, which can cause blindness. The PAX6 gene was isolated as a candidate aniridia gene by positional cloning from the smallest region of overlap of aniridia-associated deletions. Subsequently PAX6 intragenic mutations were demonstrated in Smalleye, a mouse mutant which is an animal model for aniridia, and six human aniridia patients. In this paper we describe four additional PAX6 point mutations in aniridia patients, both sporadic and familial. These mutations highlight regions of the gene which are essential for normal PAX6 function. In addition, the frequency at which we have found PAX6 mutations suggests that lesions in PAX6 will account for most cases of aniridia.. 
8364574	18	26	aniridia	SpecificDisease	D015783
8364574	28	36	Aniridia	SpecificDisease	D015783
8364574	42	76	congenital malformation of the eye	DiseaseClass	D005124
8364574	103	118	iris hypoplasia	SpecificDisease	D007499
8364574	136	145	blindness	SpecificDisease	D001766
8364574	189	197	aniridia	Modifier	D015783
8364574	264	272	aniridia	Modifier	D015783
8364574	409	417	aniridia	SpecificDisease	D015783
8364574	433	441	aniridia	Modifier	D015783
8364574	518	526	aniridia	Modifier	D015783
8364574	783	791	aniridia	SpecificDisease	D015783

8111379|t|Mutations in the PAX6 gene in patients with hereditary aniridia.
8111379|a|The 14 exons of the PAX6 gene have been analysed exon-by-exon using SSCP in 6 aniridia families. In each family band shifts were observed on the SSCP gels for only one exon and direct PCR-sequencing revealed mutations in each case. Two mutations involved C-- > T transitions in CGAarg codons in exons 9 and 11. Another C-- > T transition converted a CAG-glutamine to a TAG-stop in exon 7. Small insertions created frameshifts which produced downstream stop codons in another two patients and an A-- > T mutation disrupted the splice donor site of exon 5 in the remaining family. Thus, complete inactivation of the PAX6 gene is predicted in all cases. Analysis of other affected members of the families showed that, in each case, all affected individuals carried the same family-specific mutation. One polymorphism was found in exon 7. This data strongly supports the candidature of PAX6 as the gene responsible for hereditary aniridia.. 
8111379	55	63	aniridia	SpecificDisease	D015783
8111379	143	151	aniridia	Modifier	D015783
8111379	991	999	aniridia	SpecificDisease	D015783

10735274|t|Locus heterogeneity in Friedreich ataxia.
10735274|a|Friedreich ataxia (FRDA) is the most common form of autosomal recessive ataxia. The disease locus was assigned to chromosome 9 and the disease gene, STM7/X25, has been isolated. To date most data suggest locus homogeneity in FRDA. We now provide strong evidence of a second FRDA locus. Studying two siblings with FRDA from two families we did not detect a mutation in STM7/X25. Haplotype analysis of the STM7/X25 region of chromosome 9 demonstrated that the relevant portion of chromosome 9 differs in the patients. Although the patients studied had typical FRDA, one sibpair had the uncommon symptom of retained tendon reflexes. In order to investigate whether retained tendon reflexes are characteristic of FRDA caused by the second locus, FRDA2, we studied an unrelated FRDA patient with retained tendon reflexes. The observation of typical mutations in STM7/X25 (GAA expansions) in this patient demonstrates that the two genetically different forms of FRDA cannot be distinguished clinically.. 
10735274	23	40	Friedreich ataxia	SpecificDisease	D005621
10735274	42	59	Friedreich ataxia	SpecificDisease	D005621
10735274	61	65	FRDA	SpecificDisease	D005621
10735274	94	120	autosomal recessive ataxia	DiseaseClass	OMIM:610743
10735274	267	271	FRDA	SpecificDisease	D005621
10735274	316	320	FRDA	Modifier	D005621
10735274	355	359	FRDA	SpecificDisease	D005621
10735274	600	604	FRDA	SpecificDisease	D005621
10735274	751	755	FRDA	SpecificDisease	D005621
10735274	815	819	FRDA	Modifier	D005621
10735274	998	1002	FRDA	SpecificDisease	D005621

10767326|t|Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development.
10767326|a|Anterior segment developmental disorders, including Axenfeld-Rieger anomaly (ARA), variably associate with harmfully elevated intraocular pressure (IOP), which causes glaucoma. Clinically observed dysgenesis does not correlate with IOP, however, and the etiology of glaucoma development is not understood. The forkhead transcription factor genes Foxc1 (formerly Mf1) and Foxc2 (formerly Mfh1) are expressed in the mesenchyme from which the ocular drainage structures derive. Mutations in the human homolog of Foxc1, FKHL7, cause dominant anterior segment defects and glaucoma in various families. We show that Foxc1 (+/-) mice have anterior segment abnormalities similar to those reported in human patients. These abnormalities include small or absent Schlemms canal, aberrantly developed trabecular meshwork, iris hypoplasia, severely eccentric pupils and displaced Schwalbes line. The penetrance of clinically obvious abnormalities varies with genetic background. In some affected eyes, collagen bundles were half normal diameter, or collagen and elastic tissue were very sparse. Thus, abnormalities in extracellular matrix synthesis or organization may contribute to development of the ocular phenotypes. Despite the abnormalities in ocular drainage structures in Foxc1 (+/-) mice, IOP was normal in almost all mice analyzed, on all genetic backgrounds and at all ages. Similar abnormalities were found in Foxc2 (+/-) mice, but no disease-associated mutations were identified in the human homolog FKHL14 in 32 ARA patients. Foxc1 (+/-) and Foxc2 (+/-) mice are useful models for studying anterior segment development and its anomalies, and may allow identification of genes that interact with Foxc1 and Foxc2 (or FKHL7 and FKHL14) to produce a phenotype with elevated IOP and glaucoma.. 
10767326	0	63	Haploinsufficiency of the transcription factors FOXC1 and FOXC2	CompositeMention	OMIM:602482|OMIM:153400
10767326	104	144	Anterior segment developmental disorders	DiseaseClass	C537775
10767326	156	179	Axenfeld-Rieger anomaly	SpecificDisease	C535679
10767326	181	184	ARA	SpecificDisease	C535679
10767326	271	279	glaucoma	SpecificDisease	D005901
10767326	370	378	glaucoma	Modifier	D005901
10767326	642	666	anterior segment defects	DiseaseClass	C537775
10767326	671	679	glaucoma	SpecificDisease	D005901
10767326	736	766	anterior segment abnormalities	DiseaseClass	C537775
10767326	914	929	iris hypoplasia	SpecificDisease	D007499
10767326	1617	1620	ARA	Modifier	C535679
10767326	1883	1891	glaucoma	SpecificDisease	D005901

10446987|t|The dermatofibrosarcoma protuberans-associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB.
10446987|a|Dermatofibrosarcoma protuberans (DFSP) displays chromosomal rearrangements involving chromosome 17 and 22, which fuse the collagen type Ialpha1 (COLIA1) gene to the platelet-derived growth factor (PDGF) B-chain (PDGFB) gene. To characterize the functional and structural properties of the COLIA1/PDGFB fusion protein, we generated a stable NIH3T3 cell line that contained a tumor-derived chimeric gene resulting from a COIA1 intron 7-PDGFB intron 1 fusion. Expression of the fusion protein led to morphological transformation and increased growth rate of these cells. The PDGF receptor kinase inhibitor CGP57148B reversed the transformed phenotype and reduced the growth rate of COLIA1/PDGFB-expressing cells but had no effects on control cells. The presence of dimeric COLIA1/PDGFB precursors was demonstrated through PDGFB immunoprecipitations of metabolically labeled cells and also by PDGFB immunoprecipitations followed by immunoblotting with COLIA1 antibodies. Pulse-chase studies demonstrated that the COLIA1/PDGFB precursor was processed to an end product that was indistinguishable from wild-type PDGF-BB. Finally, COLIA1/PDGFB-expressing cells generated tumors after s. c c. injection into nude mice, and tumor growth was reduced by treatment with CGP57148B. We conclude that the COLIA1/PDGFB fusion associated with DFSP contributes to tumor development through ectopic production of PDGF-BB and the formation of an autocrine loop. Our findings, thus, suggest that PDGF receptors could be a target for pharmacological treatment of DFSP and giant cell fibroblastoma, e. g., through the use of PDGF receptor kinase inhibitors such as CGP57148B.
10446987	4	35	dermatofibrosarcoma protuberans	Modifier	C538219
10446987	201	232	Dermatofibrosarcoma protuberans	SpecificDisease	C538219
10446987	234	238	DFSP	SpecificDisease	C538219
10446987	1365	1371	tumors	DiseaseClass	D009369
10446987	1416	1421	tumor	Modifier	D009369
10446987	1527	1531	DFSP	SpecificDisease	C538219
10446987	1547	1552	tumor	Modifier	D009369
10446987	1742	1746	DFSP	SpecificDisease	C538219
10446987	1751	1775	giant cell fibroblastoma	SpecificDisease	C538219

2006152|t|Founder effect of a prevalent phenylketonuria mutation in the Oriental population.
2006152|a|A missense mutation has been identified in the human phenylalanine hydroxylase [PAH; phenylalanine 4-monooxygenase; L-phenylalanine, tetrahydrobiopterin  oxygen oxidoreductase (4-hydroxylating), EC 1. 14. 16. 1] gene in a Chinese patient with classic phenylketonuria (PKU). A G-to-C transition at the second base of codon 413 in exon 12 of the gene results in the substitution of Pro413 for Arg413 in the mutant protein. This mutation (R413P) results in negligible enzymatic activity when expressed in heterologous mammalian cells and is compatible with a classic PKU phenotype in the patient. Population genetic studies reveal that this mutation is tightly linked to restriction fragment length polymorphism haplotype 4, which is the predominant haplotype of the PAH locus in the Oriental population. It accounts for 13. 8% of northern Chinese and 27% of Japanese PKU alleles, but it is rare in southern Chinese (2. 2%) and is absent in the Caucasian population. The data demonstrate unambiguously that the mutation occurred after racial divergence of Orientals and Caucasians and suggest that the allele has spread throughout the Orient by a founder effect. Previous protein polymorphism studies in eastern Asia have led to the hypothesis that " northern Mongoloids " represented a founding population in Asia. Our results are compatible with this hypothesis in that the PKU mutation might have occurred in northern Mongoloids and subsequently spread to the Chinese and Japanese populations.
2006152	30	45	phenylketonuria	Modifier	D010661
2006152	334	349	phenylketonuria	SpecificDisease	D010661
2006152	351	354	PKU	SpecificDisease	D010661
2006152	647	650	PKU	Modifier	D010661
2006152	948	951	PKU	Modifier	D010661
2006152	1456	1459	PKU	Modifier	D010661

10528243|t|Late-onset familial Mediterranean fever (FMF): a subset with distinct clinical, demographic, and molecular genetic characteristics.
10528243|a|To determine the prevalence and characterize demographic, clinical, and genetic features of familial Mediterranean fever (FMF) of late onset, all patients experiencing their first FMF attack at age 40 years or more were identified using the computerized registry of our FMF clinic, and then thoroughly interviewed and examined. The control group consisted of 40 consecutive FMF patients, who arrived at the FMF clinic for their regular follow-up visit and were 40 years of age or older at the time of the examination. The severity of the disease in patients and controls was determined using a modified score, developed previously. Mutational analysis in the FMF gene was performed using a commercial kit. Only 20 of 4000 (0. 5%) patients had late-onset FMF. These patients were mostly men, of non-North African origin, P < 0. 05 compared to controls. All had abdominal attacks and in most these were the only manifestation of their disease, P < 0. 001 001. None had chronic or prolonged manifestations of FMF, for example, amyloidosis, chronic arthritis, or protracted myalgia, P < 0. 001. The response to treatment was good despite using low colchicine dose, P < 0. 05. The overall severity score indicated a mild disease, P < 0. 001. Mutational analysis revealed absence of M694V homozygosity, P < 0. 01, compared to our regular FMF population. We conclude that the onset of FMF in a late age defines a milder form of disease with typical clinical, demographic, and molecular genetic characteristics 
10528243	11	39	familial Mediterranean fever	SpecificDisease	D010505
10528243	41	44	FMF	SpecificDisease	D010505
10528243	224	252	familial Mediterranean fever	SpecificDisease	D010505
10528243	254	257	FMF	SpecificDisease	D010505
10528243	312	315	FMF	Modifier	D010505
10528243	402	405	FMF	Modifier	D010505
10528243	506	509	FMF	Modifier	D010505
10528243	539	542	FMF	Modifier	D010505
10528243	791	794	FMF	Modifier	D010505
10528243	886	889	FMF	SpecificDisease	D010505
10528243	1138	1141	FMF	SpecificDisease	D010505
10528243	1156	1167	amyloidosis	SpecificDisease	D000686
10528243	1169	1186	chronic arthritis	SpecificDisease	D001168
10528243	1202	1209	myalgia	SpecificDisease	D059352
10528243	1464	1467	FMF	Modifier	D010505
10528243	1510	1513	FMF	SpecificDisease	D010505

8195156|t|Structure of the human Na+/glucose cotransporter gene SGLT1.
8195156|a|Intestinal uptake of dietary glucose and galactose is mediated by the SGLT1 Na +/glucose cotransporter of the brush border. An SGLT1 missense mutation underlies hereditary glucose/galactose malabsorption, characterized by potentially fatal diarrhea; conversely, oral rehydration therapy exploits normal transport to alleviate life-threatening diarrhea of infectious origin. We have mapped the entire human SGLT1 Na +/glucose cotransporter gene from cosmid and lambda phage clones representing a genomic region of 112 kilobases. Transcription initiation occurred from a site 27 base pairs 3 of a TATAA sequence. All exon-flanking regions were sequenced, and the entire 112-kilobase region mapped with four restriction enzymes. SGLT1 is comprised of 15 exons (spanning 72 kilobases); a possible evolutionary origin from a six-membrane-span ancestral precursor via a gene duplication event is suggested from comparison of exons against protein secondary structure and from sequence considerations. A new missense mutation in exon 1 causing glucose/galactose malabsorption is also described. This is the first Na (+) -dependent cotransporter gene structure reported. These data facilitate the search for new glucose/galactose malabsorption-related mutations in this important gene and provide a basis for future evolutionary comparisons with other Na (+) -dependent cotransporters.. 
8195156	222	264	hereditary glucose/galactose malabsorption	SpecificDisease	OMIM:606824
8195156	301	309	diarrhea	SpecificDisease	D003967
8195156	404	412	diarrhea	SpecificDisease	D003967
8195156	1098	1129	glucose/galactose malabsorption	SpecificDisease	OMIM:606824
8195156	1265	1296	glucose/galactose malabsorption	Modifier	OMIM:606824

10766245|t|ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.
10766245|a|The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity and defects in cell-cycle checkpoints in response to ionizing radiation. The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs, whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks. Here, because of the similarities between AT and NBS, we evaluated the functional interactions between ATM and p95/nbs1. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not be required for signalling to ATM after ionizing radiation. However, p95/nbs1 was phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. A p95/nbs1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.. 
10766245	66	79	rare diseases	DiseaseClass	D035583
10766245	80	101	ataxia-telangiectasia	SpecificDisease	D001260
10766245	103	105	AT	SpecificDisease	D001260
10766245	149	175	Nijmegen breakage syndrome	SpecificDisease	D049932
10766245	177	180	NBS	SpecificDisease	D049932
10766245	239	263	phenotypic abnormalities	DiseaseClass	D004194
10766245	272	295	chromosomal instability	DiseaseClass	D043171
10766245	640	642	AT	SpecificDisease	D001260
10766245	647	650	NBS	SpecificDisease	D049932
10766245	814	817	NBS	Modifier	D049932
10766245	1239	1242	NBS	Modifier	D049932

1671881|t|Two distinct mutations at a single BamHI site in phenylketonuria.
1671881|a|Classical phenylketonuria is an autosomal recessive disease caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). The abolition of an invariant BamHI site located in the coding sequence of the PAH gene (exon 7) led to the recognition of two new point mutations at codon 272 and 273 (272gly----stop and 273ser----phe, respectively). Both mutations were detected in north eastern France or Belgium and occurred on the background of RFLP haplotype 7 alleles. The present study supports the view that the clinical heterogeneity in PKU is accounted for by the large variety of mutant genotypes associated with PAH deficiencies.. 
1671881	49	64	phenylketonuria	SpecificDisease	D010661
1671881	66	91	Classical phenylketonuria	SpecificDisease	D010661
1671881	98	125	autosomal recessive disease	DiseaseClass	D030342
1671881	138	185	deficiency of hepatic phenylalanine hydroxylase	SpecificDisease	OMIM:261600
1671881	606	609	PKU	SpecificDisease	D010661
1671881	684	700	PAH deficiencies	SpecificDisease	OMIM:261600

10839544|t|Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.
10839544|a|Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mrel1. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mrel1/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.. 
10839544	24	45	ataxia-telangiectasia	Modifier	D001260
10839544	50	76	Nijmegen breakage syndrome	Modifier	D049932
10839544	92	113	Ataxia-telangiectasia	SpecificDisease	D001260
10839544	115	118	A-T	SpecificDisease	D001260
10839544	124	150	Nijmegen breakage syndrome	SpecificDisease	D049932
10839544	152	155	NBS	SpecificDisease	D049932
10839544	161	188	recessive genetic disorders	DiseaseClass	D030342
10839544	212	218	cancer	DiseaseClass	D009369
10839544	300	303	A-T	SpecificDisease	D001260
10839544	493	519	Nijmegen breakage syndrome	SpecificDisease	D049932
10839544	1111	1149	hypersensitivity to ionizing radiation	DiseaseClass	D004194
10839544	1283	1299	genetic diseases	DiseaseClass	D030342

8499920|t|Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene.
8499920|a|The mutation causing myotonic dystrophy (DM) has recently been identified as an unstable CTG trinucleotide repeat located in the 3 untranslated region of a gene encoding for a protein with putative serine-threonine protein kinase activity. In this report we present the genomic sequences of the human and murine DM kinase gene. A comparison of these sequences with each other and with known cDNA sequences from both species, led us to predict a translation initiation codon, as well as determine the organization of the DM kinase gene. Several polymorphisms within the human DM kinase gene have been identified, and PCR assays to detect two of these are described. The complete sequence and characterization of the structure of the DM kinase gene, as well as the identification of novel polymorphisms within the gene, represent an important step in a further understanding of the genetics of myotonic dystrophy and the molecular biology of the gene.. 
8499920	38	56	myotonic dystrophy	Modifier	D009223
8499920	58	60	DM	Modifier	D009223
8499920	96	114	myotonic dystrophy	SpecificDisease	D009223
8499920	116	118	DM	SpecificDisease	D009223
8499920	387	389	DM	Modifier	D009223
8499920	595	597	DM	Modifier	D009223
8499920	650	652	DM	Modifier	D009223
8499920	807	809	DM	Modifier	D009223
8499920	967	985	myotonic dystrophy	SpecificDisease	D009223

10712201|t|Identification of novel imprinted transcripts in the Prader-Willi syndrome and Angelman syndrome deletion region: further evidence for regional imprinting control.
10712201|a|Deletions and other abnormalities of human chromosome 15q11-q13 are associated with two developmental disorders, Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Loss of expression of imprinted, paternally expressed genes has been implicated in PWS. However, the number of imprinted genes that contribute to PWS, and the range over which the imprinting signal acts to silence one copy of the gene in a parent-of-origin-specific manner, are unknown. To identify additional imprinted genes that could contribute to the PWS phenotype and to understand the regional control of imprinting in 15q11-q13, we have constructed an imprinted transcript map of the PWS-AS deletion interval. The imprinting status of 22 expressed sequence tags derived from the radiation-hybrid human transcript maps or physical maps was determined in a reverse transcriptase-PCR assay and correlated with the position of the transcripts on the physical map. Seven new paternally expressed transcripts localize to an approximately 1. 5-Mb domain surrounding the SNRPN-associated imprinting center, which already includes four imprinted, paternally expressed genes. All other tested new transcripts in the deletion region were expressed from both alleles. A domain of exclusive paternal expression surrounding the imprinting center suggests strong regional control of the imprinting process. This study provides the means for further investigation of additional genes that cause or modify the phenotypes associated with rearrangements of 15q11-q13. 
10712201	53	74	Prader-Willi syndrome	Modifier	D011218
10712201	79	96	Angelman syndrome	Modifier	D017204
10712201	277	298	Prader-Willi syndrome	SpecificDisease	D011218
10712201	300	303	PWS	SpecificDisease	D011218
10712201	309	326	Angelman syndrome	SpecificDisease	D017204
10712201	328	330	AS	SpecificDisease	D017204
10712201	416	419	PWS	SpecificDisease	D011218
10712201	479	482	PWS	SpecificDisease	D011218
10712201	688	691	PWS	Modifier	D011218

10441573|t|Penetrances of BRCA1 1675delA and 1135insA with respect to breast cancer and ovarian cancer.
10441573|a|For genetic counseling and predictive testing in families with inherited breast-ovarian cancer, penetrances and expressions of the underlying mutations should be known. We have previously reported two BRCA1 founder mutations in the Norwegian population. Index cases for the present study were found two different ways  through a series of consecutive ovarian cancers (n = 16) and through our family cancer clinic (n = 14). Altogether, 20 of the patients had BRCA1 1675delA, and 10 had 1135insA. Their relatives were described with respect to absence/presence of breast and/or ovarian cancer. Of 133 living female relatives, 83 (62%) were tested for the presence of a mutation. No difference, in penetrance and expression, between the two mutations were found, whereas differences according to method of ascertainment were seen. The overall findings were that disease started to occur at age 30 years and that by age 50 years 48% of the mutation-carrying women had experienced breast and/or ovarian cancer. More ovarian cancers than breast cancers were recorded. Both penetrance and expression (breast cancer vs. ovarian cancer) were different from those in reports of the Ashkenazi founder mutations. Whether the reported differences reflect true differences and/or methodological problems is discussed. An observed excess of mutation carriers could not be accounted for by methodological problems; possible explanations were a " true " low penetrance or preferential segregation.. 
10441573	59	72	breast cancer	SpecificDisease	D001943
10441573	77	91	ovarian cancer	SpecificDisease	D010051
10441573	156	187	inherited breast-ovarian cancer	CompositeMention	D061325
10441573	444	459	ovarian cancers	SpecificDisease	D010051
10441573	492	498	cancer	Modifier	D009369
10441573	655	683	breast and/or ovarian cancer	CompositeMention	D001943|D010051
10441573	1069	1097	breast and/or ovarian cancer	CompositeMention	D001943|D010051
10441573	1104	1119	ovarian cancers	SpecificDisease	D010051
10441573	1125	1139	breast cancers	SpecificDisease	D001943
10441573	1187	1200	breast cancer	SpecificDisease	D001943
10441573	1205	1219	ovarian cancer	SpecificDisease	D010051

7535801|t|Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6.
7535801|a|Individuals with subtotal complement C6 deficiency possess a C6 molecule that is 14% shorter than normal C6 and present in low but detectable concentrations (1-2% of the normal mean). We now show that this dysmorphic C6 is bactericidally active and lacks an epitope that was mapped to the most carboxy-terminal part of C6 using C6 cDNA fragments expressed as fusion proteins in the pUEX expression system. We thus predicted that the abnormal C6 molecule might be carboxy-terminally truncated and sought a mutation in an area approximately 14% from the carboxy-terminal end of the coding sequence. By sequencing PCR-amplified products from this region, we found, in three individuals from two families, a mutation that might plausibly be responsible for the defect. All three have an abnormal 5 splice donor site of intron 15, which would probably prevent splicing. An in-frame stop codon is found 17 codons downstream from the intron boundary, which would lead to a truncated polypeptide 13. 5% smaller than normal C6. This result was unexpected, as earlier studies mapped the C5b binding site, or a putative enzymatic region, to this part of C6. Interestingly, all three subjects were probably heterozygous for both subtotal C6 and complete C6 deficiency. 
7535801	19	52	subtotal complement C6 deficiency	SpecificDisease	OMIM:612446
7535801	130	163	subtotal complement C6 deficiency	SpecificDisease	OMIM:612446
7535801	1330	1368	subtotal C6 and complete C6 deficiency	CompositeMention	OMIM:612446

10408776|t|Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC.
10408776|a|To investigate the nature of somatic von Hippel-Lindau (VHL) mutations, we analyzed 173 primary sporadic human renal cell carcinomas for mutations of the VHL tumor suppressor gene, using polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis (SSCP) of DNA. We detected abnormal SSCP pattern in 73 samples. After sequencing, we identified microdeletions in 58% of cases, microinsertions in 17%, nonsense mutations in 8%, and missense mutations in 17%. Among these mutations, 50% correspond to new mutations. VHL mutations were found only in the nonpapillary renal cell carcinoma (RCC) subtype, as previously reported. To compare somatic and germline mutations, we used the VHL database, which includes 507 mutations. The study of mutational events revealed a significant difference between somatic and germline mutations with mutations leading to truncated proteins observed in 78% of somatic mutations vs only 37% in germline mutations (P < 0. 001). We postulated that a specific pattern of VHL mutations is associated with sporadic RCC. This pattern corresponds to mutations leading mainly to truncated proteins with few specific missense mutations. We then analyzed the occurrence of RCC in VHL families, based on the nature of mutations. We observed RCC in at least one member of the VHL families in 77% of cases with mutations leading to truncated proteins versus 55% in cases with missense mutations (P < 0. 05). Thus, mutations resulting in truncated proteins may lead to a higher risk of RCC in VHL patients 
10408776	17	20	VHL	Modifier	D006623
10408776	29	58	sporadic renal cell carcinoma	SpecificDisease	D002292
10408776	92	95	VHL	Modifier	D006623
10408776	119	122	RCC	SpecificDisease	D002292
10408776	161	178	von Hippel-Lindau	Modifier	D006623
10408776	180	183	VHL	Modifier	D006623
10408776	235	256	renal cell carcinomas	SpecificDisease	D002292
10408776	278	287	VHL tumor	Modifier	D006623
10408776	663	666	VHL	Modifier	D006623
10408776	700	733	nonpapillary renal cell carcinoma	Modifier	D002292
10408776	735	738	RCC	Modifier	D002292
10408776	828	831	VHL	Modifier	D006623
10408776	1147	1150	VHL	Modifier	D006623
10408776	1180	1192	sporadic RCC	SpecificDisease	D002292
10408776	1342	1345	RCC	SpecificDisease	D002292
10408776	1349	1352	VHL	Modifier	D006623
10408776	1409	1412	RCC	SpecificDisease	D002292
10408776	1443	1446	VHL	Modifier	D006623
10408776	1651	1654	RCC	SpecificDisease	D002292
10408776	1658	1661	VHL	Modifier	D006623

8528200|t|Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease.
8528200|a|The size of the (CAG)n repeat array in the 3' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD). Our data provide five novel observations. First, MJD is associated with expansion fo the array from the normal range of 14-37 repeats to 68-84 repeats in most Japanese and Caucasian subjects, but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups. Second, the expanded allele associated with MJD displays inter-generational instability, particularly in male meioses, and this instability was associated with the clinical phenomenon of anticipation. Third, the size of the expanded allele is not only inversely correlated with the age-of-onset of MJD (r = -0.738, p < 0.001), but is also correlated with the frequency of other clinical features [e.g. pseudoexophthalmos and pyramidal signs were more frequent in subjects with large repeats (p < 0.001 and p < 0.05 respectively)]. Fourth, the disease phenotype is significantly more severe and had an early age of onset (16 years) in a subject homozygous for the expanded allele, which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect (putatively excluded in HD) or by a gain of function effect as proposed for HD. Finally, Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene, which are uncommon in the normal Japanese and Caucasian population, and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene.
8528200	173	195	Machado-Joseph disease	SpecificDisease	D017827
8528200	427	449	Machado-Joseph disease	SpecificDisease	D017827
8528200	451	454	MJD	SpecificDisease	D017827
8528200	506	509	MJD	SpecificDisease	D017827
8528200	748	751	MJD	Modifier	D017827
8528200	813	816	MJD	SpecificDisease	D017827
8528200	1067	1070	MJD	SpecificDisease	D017827
8528200	1470	1488	Huntington disease	SpecificDisease	D006816
8528200	1628	1630	HD	SpecificDisease	D006816
8528200	1680	1682	HD	SpecificDisease	D006816
8528200	1739	1742	MJD	SpecificDisease	D017827

10911990|t|Myotonic dystrophy: the role of the CUG triplet repeats in splicing of a novel DMPK exon and altered cytoplasmic DMPK mRNA isoform ratios.
10911990|a|The mechanism by which (CTG) n expansion in the 3 UTR of the DMPK gene causes myotonic dystrophy (DM) is unknown. We identified four RNA splicing factors--hnRNP C, U2AF (U2 auxiliary factor), PTB (polypyrimidine tract binding protein), and PSF (PTB associated splicing factor) --that bind to two short regions 3 of the (CUG) n, and found a novel 3 DMPK exon resulting in an mRNA lacking the repeats. We propose that the (CUG) n is an essential cis acting element for this splicing event. In contrast to (CUG) n containing mRNAs, the novel isoform is not retained in the nucleus in DM cells, resulting in imbalances in relative levels of cytoplasmic DMPK mRNA isoforms and a new dominant effect of the mutation on DMPK.. 
10911990	0	18	Myotonic dystrophy	SpecificDisease	D009223
10911990	217	235	myotonic dystrophy	SpecificDisease	D009223
10911990	237	239	DM	SpecificDisease	D009223
10911990	720	722	DM	Modifier	D009223

10077651|t|Mechanism of increased iron absorption in murine model of hereditary hemochromatosis : increased duodenal expression of the iron transporter DMT1.
10077651|a|Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by tissue iron deposition secondary to excessive dietary iron absorption. We recently reported that HFE, the protein defective in HH, was physically associated with the transferrin receptor (TfR) in duodenal crypt cells and proposed that mutations in HFE attenuate the uptake of transferrin-bound iron from plasma by duodenal crypt cells, leading to up-regulation of transporters for dietary iron. Here, we tested the hypothesis that HFE-/- mice have increased duodenal expression of the divalent metal transporter (DMT1). By 4 weeks of age, the HFE-/- mice demonstrated iron loading when compared with HFE +/+ littermates, with elevated transferrin saturations (68. 4% vs. 49. 8%) and elevated liver iron concentrations (985 micrograms vs. 381 micrograms). By using Northern blot analyses, we quantitated duodenal expression of both classes of DMT1 transcripts  one containing an iron responsive element (IRE), called DMT1 (IRE), and one containing no IRE, called DMT1 (non-IRE). The positive control for DMT1 up-regulation was a murine model of dietary iron deficiency that demonstrated greatly increased levels of duodenal DMT1 (IRE) mRNA. HFE-/- mice also demonstrated an increase in duodenal DMT1 (IRE) mRNA (average 7. 7-fold), despite their elevated transferrin saturation and hepatic iron content. Duodenal expression of DMT1 (non-IRE) was not increased, nor was hepatic expression of DMT1 increased. These data support the model for HH in which HFE mutations lead to inappropriately low crypt cell iron, with resultant stabilization of DMT1 (IRE) mRNA, up-regulation of DMT1, and increased absorption of dietary iron.
10077651	58	84	hereditary hemochromatosis	SpecificDisease	D006432
10077651	147	173	Hereditary hemochromatosis	SpecificDisease	D006432
10077651	175	177	HH	SpecificDisease	D006432
10077651	191	219	autosomal recessive disorder	DiseaseClass	D030342
10077651	364	366	HH	SpecificDisease	D006432
10077651	1281	1304	dietary iron deficiency	SpecificDisease	D018798

1325652|t|Yeast artificial chromosomes for the molecular analysis of the familial polyposis APC gene region.
1325652|a|Two yeast artificial chromosomes (YACs) spanning a total distance of 1. 1 megabase pairs of DNA around the MCC (for mutated in colorectal carcinoma) and APC (for adenomatous polyposis coli) genes at 5q21 have been isolated and characterized. Starting from the MCC gene, a strategy was undertaken to identify constitutional submicroscopic deletions in familial adenomatous polyposis patients that might considerably narrow down the position of the APC gene. To this end, YACs identified by the MCC gene were screened across a chromosome 5-specific cosmid library to provide a source of DNA probes for genomic scanning. The cosmids isolated from these experiments were used to screen a panel of somatic cell hybrids containing chromosome 5 segregated from patients suspected to carry putative interstitial deletions. This screening approach led to the confirmation of a small heterozygous deletion in a polyposis patient that overlaps one of the two isolated YACs. This YAC has been shown to contain the entire APC gene, in addition to a significant portion of DNA flanking the 5 end of the gene, and should therefore prove a valuable resource for functional studies by transfer to colorectal tumor-derived cell lines. 
1325652	63	85	familial polyposis APC	Modifier	D011125
1325652	226	246	colorectal carcinoma	SpecificDisease	D015179
1325652	252	255	APC	Modifier	D011125
1325652	261	287	adenomatous polyposis coli	Modifier	D011125
1325652	450	480	familial adenomatous polyposis	Modifier	D011125
1325652	546	549	APC	Modifier	D011125
1325652	1000	1009	polyposis	Modifier	D011125
1325652	1108	1111	APC	Modifier	D011125
1325652	1279	1295	colorectal tumor	Modifier	D015179

1269174|t|Analbuminemia in an American Indian girl.
1269174|a|Analbuminemia was fortuitously detected in a nonedematous 12-year-old American Indian girl with atopic dermatitis, mild bronchial asthma, a mild seizure disorder, and hyperlipoproteinemia with a corneal arcus. Immunologic methods revealed trace amounts (17 mg/100 ml) of apparently normal serum albumin. The patients parents were remotely related. The pedigree and clinical findings were compatible with autosomal recessive transmission of analbuminemia. Heterozygotes had subnormal levels of serum albumin. The Gc-locus is closely linked to the structural albumin locus. Gc-protein levels were normal in the patient and together with normal chromosomal banding studies make it unlikely that a chromosomal deletion caused analbuminemia. Gc-types in the family were compatible with, but did not prove, linkage of analbuminemia to the Gc-locus. These findings suggest a " thalassemia " -like mutation for this disorder.. 
1269174	0	13	Analbuminemia	SpecificDisease	OMIM:103600
1269174	42	55	Analbuminemia	SpecificDisease	OMIM:103600
1269174	138	155	atopic dermatitis	SpecificDisease	D003876
1269174	162	178	bronchial asthma	SpecificDisease	D001249
1269174	187	203	seizure disorder	SpecificDisease	D004827
1269174	209	229	hyperlipoproteinemia	SpecificDisease	D006951
1269174	237	250	corneal arcus	SpecificDisease	D001112
1269174	482	495	analbuminemia	SpecificDisease	OMIM:103600
1269174	764	777	analbuminemia	SpecificDisease	OMIM:103600
1269174	854	867	analbuminemia	SpecificDisease	OMIM:103600
1269174	912	923	thalassemia	Modifier	D013789

3524231|t|Treatment of Duchenne muscular dystrophy with growth hormone inhibitors.
3524231|a|A controlled, double-blind therapeutic trial with the drug mazindol, a growth hormone inhibitor, was performed in a pair of 7 1/2 year-old monozygotic twins, with Duchenne muscular dystrophy (DMD). The rationale for this trial was based on a patient (reported previously) affected simultaneously with DMD and growth hormone (GH) deficiency, who is showing a benign course of the dystrophic process and is still walking at 18 years. One of the twins received 2 mg of mazindol daily, while the other received a placebo. The assessment, repeated every 2 months, included weight and height measurements, functional and motor ability tests, ergometry and determinations of serum enzymes and GH levels. After one year of trial the code was broken and it was seen that the twin under placebo treatment was strikingly worse than his brother, the progression of whose condition was practically arrested. These results strongly suggest that treatment with a GH inhibitor is beneficial for DMD patients.. 
3524231	13	40	Duchenne muscular dystrophy	SpecificDisease	D020388
3524231	236	263	Duchenne muscular dystrophy	SpecificDisease	D020388
3524231	265	268	DMD	SpecificDisease	D020388
3524231	374	377	DMD	SpecificDisease	D020388
3524231	382	412	growth hormone (GH) deficiency	SpecificDisease	OMIM:262400
3524231	452	470	dystrophic process	DiseaseClass	D009136
3524231	1052	1055	DMD	Modifier	D020388

8528198|t|Identification of WASP mutations in patients with Wiskott-Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus.
8528198|a|Mutation in the gene encoding the recently isolated WASP protein has now been identified as the genetic defect responsible for the X-linked Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disease associated with extensive phenotypic variability. To elucidate the range of WASP mutations responsible for WAS, we used PCR-SSCP analysis to screen for WASP gene mutation in 19 unrelated boys with the diagnosis of classical or attenuated WAS or isolated thrombocytopenia. All 19 patients had WASP mutations, each of which localized to the initial three or terminal three exons of the gene, and the majority of which were unique in each case. However, a missense mutation which results in substitution of the arginine at WAS codon 86 was identified in three boys with severe WAS as well as in one boy presenting with thrombocytopenia alone. While the three mutations found in the isolated thrombocytopenia patients leave the reading frame intact, about one-half of the gene alterations detected in both severe and attenuated WAS patients result in frameshifted transcript and premature translation termination. These findings therefore confirm the association of WAS with WASP mutation and identify WASP mutation as a cause for isolated congenital thrombocytopenia in males. While the WASP gene defects responsible for isolated thrombocytopenia and other mild presentations of WAS do not appear distinct from those resulting in severe WAS, these data indicate that analysis of WASP gene mutation provides a valuable tool for distinguishing the spectrum of WAS patients and the subset of males with isolated thrombocytopenia who represent mild cases of WAS.. 
8528198	50	74	Wiskott-Aldrich syndrome	SpecificDisease	D014923
8528198	79	104	isolated thrombocytopenia	SpecificDisease	OMIM:313900
8528198	142	145	WAS	Modifier	D014923
8528198	249	263	genetic defect	DiseaseClass	D030342
8528198	284	317	X-linked Wiskott-Aldrich syndrome	SpecificDisease	D014923
8528198	319	322	WAS	SpecificDisease	D014923
8528198	335	359	immunodeficiency disease	DiseaseClass	D007153
8528198	467	470	WAS	SpecificDisease	D014923
8528198	598	601	WAS	SpecificDisease	D014923
8528198	605	630	isolated thrombocytopenia	SpecificDisease	OMIM:313900
8528198	880	883	WAS	Modifier	D014923
8528198	934	937	WAS	SpecificDisease	D014923
8528198	976	992	thrombocytopenia	SpecificDisease	D013921
8528198	1039	1064	isolated thrombocytopenia	Modifier	OMIM:313900
8528198	1184	1187	WAS	SpecificDisease	D014923
8528198	1322	1325	WAS	SpecificDisease	D014923
8528198	1396	1423	congenital thrombocytopenia	SpecificDisease	OMIM:313900
8528198	1478	1503	isolated thrombocytopenia	SpecificDisease	OMIM:313900
8528198	1536	1539	WAS	SpecificDisease	D014923
8528198	1594	1597	WAS	SpecificDisease	D014923
8528198	1715	1718	WAS	Modifier	D014923
8528198	1757	1782	isolated thrombocytopenia	SpecificDisease	OMIM:313900
8528198	1811	1814	WAS	SpecificDisease	D014923

8178825|t|Huntington disease without CAG expansion: phenocopies or errors in assignment?
8178825|a|Huntington disease (HD) has been shown to be associated with an expanded CAG repeat within a novel gene on 4p16. 3 (IT15). A total of 30 of 1, 022 affected persons (2. 9% of our cohort) did not have an expanded CAG in the disease range. The reasons for not observing expansion in affected individuals are important for determining the sensitivity of using repeat length both for diagnosis of affected patients and for predictive testing programs and may have biological relevance for the understanding of the molecular mechanism underlying HD. Here we show that the majority (18) of the individuals with normal sized alleles represent misdiagnosis, sample mix-up, or clerical error. The remaining 12 patients represent possible phenocopies for HD. In at least four cases, family studies of these phenocopies excluded 4p16. 3 as the region responsible for the phenotype. Mutations in the HD gene that are other than CAG expansion have not been excluded for the remaining eight cases; however, in as many as seven of these persons, retrospective review of these patients clinical features identified characteristics not typical for HD. This study shows that on rare occasions mutations in other, as-yet-undefined genes can present with a clinical phenotype very similar to that of HD 
8178825	0	18	Huntington disease	SpecificDisease	D006816
8178825	79	97	Huntington disease	SpecificDisease	D006816
8178825	99	101	HD	SpecificDisease	D006816
8178825	619	621	HD	SpecificDisease	D006816
8178825	823	825	HD	SpecificDisease	D006816
8178825	966	968	HD	Modifier	D006816
8178825	1209	1211	HD	SpecificDisease	D006816
8178825	1358	1360	HD	SpecificDisease	D006816

6101415|t|Allelic exclusion of glucose-6-phosphate dehydrogenase in platelets and T lymphocytes from a Wiskott-Aldrich syndrome carrier.
6101415|a|An obligate carrier of the Wiskott-Aldrich syndrome (WAS) who was also heterozygous for the A and B types of X-linked glucose-6-phosphate dehydrogenase was found. With her it became possible to determine whether allelic exclusion occurs in particular cell-types of the WAS carrier. If so, the remaining cells of a particular cell-type would express only the normal X chromosome and only one glucose-6-phosphate dehydrogenase isoenzyme would be demonstrable. This carrier had only the B isoenzyme of glucose-6-phosphate dehydrogenase in platelets and thymus-derived T lymphocytes, although both isoenzymes A and B were present in erythrocytes and neutrophils. These findings suggest that selection against the WAS gene occurs in platelets and thymus-derived T lymphocytes and that the defects associated with WAS expressed in these cell-types may be implicated in the genesis of the Wiskott-Aldrich syndrome.. 
6101415	93	117	Wiskott-Aldrich syndrome	Modifier	D014923
6101415	154	178	Wiskott-Aldrich syndrome	SpecificDisease	D014923
6101415	180	183	WAS	SpecificDisease	D014923
6101415	396	399	WAS	Modifier	D014923
6101415	836	839	WAS	Modifier	D014923
6101415	935	938	WAS	SpecificDisease	D014923
6101415	1009	1033	Wiskott-Aldrich syndrome	SpecificDisease	D014923

10487695|t|A novel mutation in the sodium/iodide symporter gene in the largest family with iodide transport defect.
10487695|a|We previously reported nine children with an autosomally recessive form of congenital hypothyroidism due to an iodide transport defect in a large Hutterite family with extensive consanguinity living in central Canada. Since the original report, we have diagnosed congenital hypothyroidism by newborn TSH screening in 9 additional children from the family. We performed direct sequencing of the PCR products of each NIS (sodium/iodide symporter) gene exon with flanking introns amplified from genomic DNA extracted from peripheral blood cells of the patients. We identified a novel NIS gene mutation, G395R (Gly395-- > Arg; GGA-- > AGA), in 10 patients examined in the present study. All of the parents tested were heterozygous for the mutation, suggesting that the patients were homozygous. The mutation was located in the 10th transmembrane helix. Expression experiments by transfection of the mutant NIS complimentary DNA into COS-7 cells showed no perchlorate-sensitive iodide uptake, confirming that the mutation is the direct cause of the iodide transport defect in these patients. A patient who showed an intermediate saliva/serum technetium ratio (14. 0; normal, > or = 20) and was considered to have a partial or less severe defect in the previous report (IX-24) did not have a NIS gene mutation. It is now possible to use gene diagnostics of this unique NIS mutation to identify patients with congenital hypothyroidism due to an iodide transport defect in this family and to determine the carrier state of potential parents for genetic counseling and arranging rapid and early diagnosis of their infants. 
10487695	80	103	iodide transport defect	DiseaseClass	OMIM:274400
10487695	180	205	congenital hypothyroidism	SpecificDisease	D003409
10487695	216	239	iodide transport defect	DiseaseClass	OMIM:274400
10487695	368	393	congenital hypothyroidism	SpecificDisease	D003409
10487695	1149	1172	iodide transport defect	DiseaseClass	OMIM:274400
10487695	1507	1532	congenital hypothyroidism	SpecificDisease	D003409
10487695	1543	1566	iodide transport defect	DiseaseClass	OMIM:274400

2071157|t|Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects.
2071157|a|Hypoxanthine--guanine phosphoribosyltransferase (HPRT) is a purine salvage enzyme that catalyzes the conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. Previous studies of mutant HPRT proteins analyzed at the molecular level have shown a significant heterogeneity. This investigation further verifies this heterogeneity and identifies insertions, deletions, and point mutations. The direct sequencing of the polymerase chain reaction-amplified product of reverse-transcribed HPRT mRNA enabled the rapid identification of the mutations found in 17 previously uncharacterized cell lines derived from patients with the Lesch-Nyhan syndrome.. 
2071157	51	71	Lesch-Nyhan syndrome	SpecificDisease	D007926
2071157	745	765	Lesch-Nyhan syndrome	SpecificDisease	D007926

7444053|t|A new CT pattern in adrenoleukodystrophy.
7444053|a|A new CT pattern was observed in 2 patients with adrenoleukodystrophy (ALD). This pattern, which the authors call Type II, is characterized by the absence of posterior periventricular areas of decreased attenuation around the trigone on non-contrast scans  after contrast infusion, however, there is striking enhancement of various white-matter structures (tracts or fiber systems) such as the internal capsules, corpus callosum, corona radiata, forceps major, and cerebral peduncles. This is different from numerous previous descriptions of the CT pattern in ALD. Type II ALD does not appear to have been seen in any other leukoencephalopathy and is probably specific for a phenotypic variant or an evolving stage of ALD.. 
7444053	20	40	adrenoleukodystrophy	SpecificDisease	D000326
7444053	91	111	adrenoleukodystrophy	SpecificDisease	D000326
7444053	113	116	ALD	SpecificDisease	D000326
7444053	602	605	ALD	SpecificDisease	D000326
7444053	607	618	Type II ALD	SpecificDisease	D000326
7444053	666	685	leukoencephalopathy	DiseaseClass	D056784
7444053	760	763	ALD	SpecificDisease	D000326

10706858|t|Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S.
10706858|a|Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1 gene defect (sensitivity 97. 7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5. 0-fold higher risk of thrombosis (95% confidence interval, 1. 5-16. 8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons with PROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency. (Blood. 2000; 95  1935-1941).
10706858	52	69	venous thrombosis	SpecificDisease	D020246
10706858	97	122	deficiencies of protein S	SpecificDisease	D018455
10706858	124	144	Protein S deficiency	SpecificDisease	D018455
10706858	177	194	venous thrombosis	SpecificDisease	D020246
10706858	217	241	thrombophilic conditions	DiseaseClass	D019851
10706858	533	553	protein S deficiency	SpecificDisease	D018455
10706858	560	577	PROS1 gene defect	SpecificDisease	OMIM:612336
10706858	854	871	PROS1 gene defect	SpecificDisease	OMIM:612336
10706858	942	959	PROS1 gene defect	SpecificDisease	OMIM:612336
10706858	991	1001	thrombosis	SpecificDisease	D013927
10706858	1100	1120	thrombophilic defect	SpecificDisease	D019851
10706858	1167	1173	trauma	SpecificDisease	D014947
10706858	1215	1225	thrombosis	SpecificDisease	D013927
10706858	1318	1343	defects in the PROS1 gene	SpecificDisease	OMIM:612336
10706858	1530	1548	PROS1 gene defects	SpecificDisease	OMIM:612336
10706858	1553	1573	protein S deficiency	SpecificDisease	D018455
10706858	1599	1609	thrombosis	SpecificDisease	D013927

10382910|t|Severe clinical expression in X-linked Emery-Dreifuss muscular dystrophy.
10382910|a|X-linked Emery-Dreifuss muscular dystrophy (EDMD) is a relatively rare benign neuromuscular disorder which can vary remarkably in onset, course and severity. In the present study, a TCTAC deletion spanning the nucleotides 631-635 of the emerin gene caused an unusually severe disease phenotype including loss of ambulation and severe muscle wasting in two affected brothers. The same mutation has been reported previously in an unrelated family showing a significantly milder phenotype. The interfamilial heterogeneity in distribution and in severity of the features in the two families point to environmental or genetic modification as the cause of clinical variability in Emery-Dreifuss muscular dystrophy.. 
10382910	30	72	X-linked Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10382910	74	116	X-linked Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10382910	118	122	EDMD	SpecificDisease	D020389
10382910	145	174	benign neuromuscular disorder	DiseaseClass	D009468
10382910	378	396	loss of ambulation	DiseaseClass	D051346
10382910	408	422	muscle wasting	DiseaseClass	D009133
10382910	748	781	Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389

7825578|t|The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24.3-q32.2.
7825578|a|SCA3, the gene for spinal cerebellar ataxia 3, was recently mapped to a 15-cM interval between D14S67 and D14S81 on chromosome 14q, by linkage analysis in two families of French ancestry. The SCA3 candidate region has now been refined by linkage analysis with four new microsatellite markers (D14S256, D14S291, D14S280, and AFM343vf1) in the same two families, in which 19 additional individuals were genotyped, and in a third French family. Combined two-point linkage analyses show that the new markers, D14S280 and AFM343vf1, are tightly linked to the SCA3 locus, with maximal lod scores, at recombination fraction, (theta) =. 00, of 7. 05 and 13. 70, respectively. Combined multipoint and recombinant haplotype analyses localize the SCA3 locus to a 3-cM interval flanked by D14S291 and D14S81. The same allele for D14S280 segregates with the disease locus in the three kindreds. This allele is frequent in the French population, however, and linkage disequilibrium is not clearly established. The SCA3 locus remains within the 29-cM region on 14q24. 3-q32. 2 containing the gene for the Machado-Joseph disease, which is clinically related to the phenotype determined by SCA3, but it cannot yet be concluded that both diseases result from alterations of the same gene 
7825578	13	37	spinal cerebellar ataxia	Modifier	D013132
7825578	140	164	spinal cerebellar ataxia	Modifier	D013132
7825578	1211	1233	Machado-Joseph disease	SpecificDisease	D017827

1831007|t|Huntington disease and childhood-onset Tourette syndrome.
1831007|a|A 40-year-old man with childhood-onset Tourette syndrome (TS) developed Huntington disease (HD). We believe this to be the first reported case of childhood-onset TS with adult onset HD. Discovery of other cases with both disorders may provide clues to the pathophysiology of both conditions.. 
1831007	0	18	Huntington disease	SpecificDisease	D006816
1831007	39	56	Tourette syndrome	SpecificDisease	D005879
1831007	97	114	Tourette syndrome	SpecificDisease	D005879
1831007	116	118	TS	SpecificDisease	D005879
1831007	130	148	Huntington disease	SpecificDisease	D006816
1831007	150	152	HD	SpecificDisease	D006816
1831007	220	222	TS	SpecificDisease	D005879
1831007	240	242	HD	SpecificDisease	D006816

7761412|t|The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase.
7761412|a|Lowe syndrome, also known as oculocerebrorenal syndrome, is caused by mutations in the X chromosome-encoded OCRL gene. The OCRL protein is 51% identical to inositol polyphosphate 5-phosphatase II (5-phosphatase II) from human platelets over a span of 744 aa, suggesting that OCRL may be a similar enzyme. We engineered a construct of the OCRL cDNA that encodes amino acids homologous to the platelet 5-phosphatase for expression in baculovirus-infected Sf9 insect cells. This cDNA encodes aa 264-968 of the OCRL protein. The recombinant protein was found to catalyze the reactions also carried out by platelet 5-phosphatase II. Thus OCRL converts inositol 1, 4, 5-trisphosphate to inositol 1, 4-bisphosphate, and it converts inositol 1, 3, 4, 5-tetrakisphosphate to inositol 1, 3, 4-trisphosphate. Most important, the enzyme converts phosphatidylinositol 4, 5-bisphosphate to phosphatidylinositol 4-phosphate. The relative ability of OCRL to catalyze the three reactions is different from that of 5-phosphatase II and from that of another 5-phosphatase isoenzyme from platelets, 5-phosphatase I. The recombinant OCRL protein hydrolyzes the phospholipid substrate 10- to 30-fold better than 5-phosphatase II, and 5-phosphatase I does not cleave the lipid at all. We also show that OCRL functions as a phosphatidylinositol 4, 5-bisphosphate 5-phosphatase in OCRL-expressing Sf9 cells. These results suggest that OCRL is mainly a lipid phosphatase that may control cellular levels of a critical metabolite, phosphatidylinositol 4, 5-bisphosphate. Deficiency of this enzyme apparently causes the protean manifestations of Lowe syndrome.. 
7761412	25	38	Lowe syndrome	SpecificDisease	D009800
7761412	97	110	Lowe syndrome	SpecificDisease	D009800
7761412	126	152	oculocerebrorenal syndrome	SpecificDisease	D009800
7761412	1715	1728	Lowe syndrome	SpecificDisease	D009800

10323740|t|Microdeletions at chromosome bands 1q32-q41 as a cause of Van der Woude syndrome.
10323740|a|Van der Woude syndrome (VWS) is an autosomal dominant disorder comprising cleft lip and/or cleft palate and lip pits. We reported previously a family whose underlying mutation is a 500-800 kb deletion localized to chromosome bands 1q32-q41 [Sander et al., 1994  Hum Mol Genet 3  576-578]. Along with cleft lip/palate and lip pits, affected relatives exhibit developmental delays, suggesting that the function of a gene nearby may also be disrupted. To further localize the VWS gene we searched for other deletions that cause VWS. An allele loss assay was performed using a novel highly polymorphic marker, D1S3753. From a panel of 37 unrelated individuals, we detected an allele loss in one family, indicating the presence of a deletion. In this family, the phenotype in three generations of affected individuals was confined to the cardinal signs of VWS. Surprisingly, mapping of the new deletion showed that it extended 0. 2-1 Mb beyond the proximal breakpoint for the deletion described previously. No deletions were detected in seven cases of popliteal pterygia syndrome, 76 cases of mixed syndromic forms of cleft lip and palate, and 178 cases of nonsyndromic cleft lip and palate. 
10323740	58	80	Van der Woude syndrome	SpecificDisease	C536528
10323740	82	104	Van der Woude syndrome	SpecificDisease	C536528
10323740	106	109	VWS	SpecificDisease	C536528
10323740	117	144	autosomal dominant disorder	DiseaseClass	D030342
10323740	156	165	cleft lip	SpecificDisease	D002971
10323740	173	185	cleft palate	SpecificDisease	D002972
10323740	190	198	lip pits	SpecificDisease	C536528
10323740	382	398	cleft lip/palate	CompositeMention	D002971|D002972
10323740	403	411	lip pits	SpecificDisease	C536528
10323740	440	460	developmental delays	DiseaseClass	D006130
10323740	555	558	VWS	Modifier	C536528
10323740	607	610	VWS	SpecificDisease	C536528
10323740	933	936	VWS	SpecificDisease	C536528
10323740	1129	1156	popliteal pterygia syndrome	SpecificDisease	OMIM:119500
10323740	1176	1215	syndromic forms of cleft lip and palate	CompositeMention	D002971|D002972
10323740	1234	1267	nonsyndromic cleft lip and palate	CompositeMention	OMIM:119530

7607677|t|Mucopolysaccharidosis type IVA: common double deletion in the N-acetylgalactosamine-6-sulfatase gene (GALNS).
7607677|a|Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency in N-acetylgalactosamine-6-sulfatase (GALNS). We found two separate deletions of nearly 8. 0 and 6. 0 kb in the GALNS gene, including some exons. There are Alu repetitive elements near the breakpoints of the 8. 0-kb deletion, and this deletion resulted from an Alu-Alu recombination. The other 6. 0-kb deletion involved illegitimate recombinational events between incomplete short direct repeats of 8 bp at deletion breakpoints. The same rearrangement has been observed in a heteroallelic state in four unrelated patients. This is the first documentation of a common double deletion a gene that is not a member of a gene cluster.
7607677	0	30	Mucopolysaccharidosis type IVA	SpecificDisease	OMIM:253000
7607677	110	135	Mucopolysaccharidosis IVA	SpecificDisease	OMIM:253000
7607677	137	144	MPS IVA	SpecificDisease	OMIM:253000
7607677	152	180	autosomal recessive disorder	DiseaseClass	D030342
7607677	193	240	deficiency in N-acetylgalactosamine-6-sulfatase	SpecificDisease	D009085

2995231|t|Segregation analysis of a marker localised Xp21.2-Xp21.3 in Duchenne and Becker muscular dystrophy families.
2995231|a|A DNA marker C7, localised Xp21. 1-Xp21. 3, has been studied in kindreds segregating for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). In DMD families four crossovers were observed in 38 informative meioses between C7 and the DMD locus (theta = 0. 12, z max = + 2. 72). In BMD families no recombinants were observed in the 16 informative meioses studied. These data are consistent with the localisation of the mutations in these disorders being in the same region of Xp21. Studies in families also segregating for the DNA marker 754 support the previously reported physical order of these loci as X centromere-754-DMD-BMD-C7-X telomere. A recombination fraction of 0. 11 (z max = + 5. 58) was found between DMD-754 by combining our previously published data with the data presented here. C7 and 754 thus provide good bridging markers for the diagnosis of DMD and BMD 
2995231	60	98	Duchenne and Becker muscular dystrophy	CompositeMention	D020388|C537666
2995231	198	225	Duchenne muscular dystrophy	SpecificDisease	D020388
2995231	227	230	DMD	SpecificDisease	D020388
2995231	236	261	Becker muscular dystrophy	SpecificDisease	C537666
2995231	263	266	BMD	SpecificDisease	C537666
2995231	272	275	DMD	Modifier	D020388
2995231	360	363	DMD	Modifier	D020388
2995231	407	410	BMD	Modifier	C537666
2995231	989	992	DMD	SpecificDisease	D020388
2995231	997	1000	BMD	SpecificDisease	C537666

8281142|t|Genetic analysis of the BRCA1 region in a large breast/ovarian family: refinement of the minimal region containing BRCA1.
8281142|a|We have analyzed a single multi-affected breast/ovarian cancer pedigree (BOV3) and have shown consistent inheritance of markers on chromosome 17q with the disease confirming that this family is due to the BRCA1 gene. Analysis of 17q haplotypes shows a recombination event in a bilateral breast cancer case which suggests that the BRCA1 gene lies distal to D17S857; D17S857 is thus the new proximal boundary for the region containing BRCA1. Combining this information with previously published mapping information suggests that BRCA1 is contained in a region estimated at 1-1. 5 Mb in length. All seven breast tumour/blood pairs examined from this family show loss of heterozygosity in the tumours. The allel retained in each tumour was from the disease-bearing chromosome implicating BRCA1 as a tumour suppressor gene. We have sequenced the 17 beta-oestradiol dehydrogenase genes (EDH17B1 and EDH17B2) which have been suggested as candidate genes for BRCA1 in four members of this family. No germline mutations were detected. 
8281142	163	184	breast/ovarian cancer	Modifier	D061325
8281142	409	422	breast cancer	Modifier	D001943
8281142	724	737	breast tumour	Modifier	D001943
8281142	811	818	tumours	DiseaseClass	D009369
8281142	847	853	tumour	DiseaseClass	D009369
8281142	917	923	tumour	Modifier	D009369

10590055|t|A point mutation Thr(799)Met on the alpha(2) integrin leads to the formation of new human platelet alloantigen Sit(a) and affects collagen-induced aggregation.
10590055|a|A new platelet-specific alloantigen, termed Sit (a), was identified in a severe case of neonatal alloimmune thrombocytopenia. The Sit (a) alloantigen is of low frequency (1/400) in the German population. Immunochemical studies demonstrated that the Sit (a) epitopes reside on platelet glycoprotein (GP) Ia. Nucleotide sequence analysis of GPIa cDNA derived from Sit (a) -positive platelets showed C (2531) -- > T (2531) point mutation, resulting in Thr (799) Met dimorphism. Analysis of genomic DNA from 22 Sit (a) -negative normal individuals showed that the Thr (799) is encoded by ACG (2532) (90. 9%) or ACA (2532) (9. 1%). To establish a DNA typing technique, we elucidated the organization of the GPIa gene adjacent to the polymorphic bases. The introns (421 bp and 1. 2 kb) encompass a 142-bp exon with the 2 polymorphic bases 2531 and 2532. Polymerase chain reaction-restriction fragment length polymorphism analysis on DNA derived from 100 donors using the restriction enzyme Mae III showed that the Met (799) form of GPIa is restricted to Sit (a) (+) phenotype. Analysis of stable Chinese hamster ovary transfectants expressing allele-specific recombinant forms of GPIa showed that anti-Sit (a) exclusively reacted with the Glu (505) Met (799), but not with the Glu (505) Thr (799) and the Lys (505) Thr (799) isoforms. In contrast, anti-Br (a) (HPA-5b) only recognized the Lys (505) Thr (799) form, whereas anti-Br (b) (HPA-5a) reacted with both Glu (505) Thr (799) and Glu (505) Met (799) isoforms. These results demonstrated that the Met (799) is responsible for formation of the Sit (a) alloantigenic determinants, whereas amino acid 505 (Lys or Glu) specifically controls the expression of Br (a) and Br (b) epitopes, respectively. Platelet aggregation responses of Sit (a) (+) individuals were diminished in response to collagen, indicating that the Thr (799) Met mutation affects the function of the GPIa/IIa complex 
10590055	248	284	neonatal alloimmune thrombocytopenia	SpecificDisease	D054098

3464560|t|Estimation of the male to female ratio of mutation rates from the segregation of X-chromosomal DNA haplotypes in Duchenne muscular dystrophy families.
3464560|a|A novel procedure is presented to estimate the ratio of male to female mutation rates for Duchenne muscular dystrophy (DMD). X-specific restriction fragment length polymorphisms are used to establish DNA haplotypes in three-generation DMD families. From the proportion of DMD patients who have inherited their maternal grandfathers X chromosome, the ratio of mutation rates can be calculated. In contrast to classical methods, the proposed procedure is not restricted to sporadic or familiar cases nor is any information on the carrier status of female relatives required.. 
3464560	113	140	Duchenne muscular dystrophy	Modifier	D020388
3464560	241	268	Duchenne muscular dystrophy	SpecificDisease	D020388
3464560	270	273	DMD	SpecificDisease	D020388
3464560	386	389	DMD	Modifier	D020388
3464560	423	426	DMD	Modifier	D020388

3789016|t|Genetic analysis of an inherited deficiency of the third component of complement in Brittany spaniel dogs.
3789016|a|Genetically determined C3 deficiency in Brittany spaniel dogs shares a number of biochemical and clinical characteristics with the human disorder. In humans, the gene for C3 deficiency is a null gene that is allelic to the structural gene for C3 and is not linked to the major histocompatibility locus. The current study used allotype analysis of canine C3 in order to demonstrate that the gene for C3 deficiency in these dogs is also a null gene allelic to the structural gene for C3. In addition, preliminary pedigree analysis suggests that the gene for canine C3 deficiency is apparently not closely linked to the major histocompatibility complex of the dog. Thus, it appears that C3 deficiency in Brittany spaniel dogs not only shares biochemical and clinical features with C3 deficiency in humans, but also shares some genetic characteristics with the human disorder.. 
3789016	33	80	deficiency of the third component of complement	SpecificDisease	OMIM:613779
3789016	130	143	C3 deficiency	SpecificDisease	OMIM:613779
3789016	278	291	C3 deficiency	SpecificDisease	OMIM:613779
3789016	506	519	C3 deficiency	SpecificDisease	OMIM:613779
3789016	670	683	C3 deficiency	SpecificDisease	OMIM:613779
3789016	791	804	C3 deficiency	SpecificDisease	OMIM:613779
3789016	885	898	C3 deficiency	SpecificDisease	OMIM:613779

10426139|t|A novel frameshift mutation in the McLeod syndrome gene in a Japanese family.
10426139|a|We report a novel mutation in the XK gene (XK) in a Japanese patient with McLeod syndrome. A 50-year-old man showed progressive muscular atrophy, choreic movement, elevated level of serum creatinine kinase, and acanthocytosis. The expression level of all the Kell antigens in erythrocyte was decreased and molecular analysis revealed a single-base (T) deletion at the nucleotide position 1095 in XK. This deletion caused a frameshift in translation, leading to a premature stop codon at the amino acid position 408. We conclude this single-base deletion causes defective Kx protein, which is responsible for the McLeod phenotype in this patient.. 
10426139	35	50	McLeod syndrome	Modifier	OMIM:300842
10426139	152	167	McLeod syndrome	SpecificDisease	OMIM:300842
10426139	206	222	muscular atrophy	DiseaseClass	D009133
10426139	224	240	choreic movement	DiseaseClass	D002819
10426139	289	303	acanthocytosis	SpecificDisease	D000012
10426139	690	696	McLeod	Modifier	OMIM:300842

10330430|t|Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy.
10330430|a|We identified the alpha-cardiac actin gene (ACTC) as a novel disease gene in a pedigree suffering from familial hypertrophic cardiomyopathy (FHC). Linkage analyses excluded all the previously reported FHC loci as possible disease loci in the family studied, with lod scores varying between -2. 5 and -6. 0 0. Further linkage analyses of plausible candidate genes highly expressed in the adult human heart identified ACTC as the most likely disease gene, showing a maximal lod score of 3. 6 6. Mutation analysis of ACTC revealed an Ala295Ser mutation in exon 5 close to 2 missense mutations recently described to cause the inherited form of idiopathic dilated cardiomyopathy (IDC). 
10330430	47	83	familial hypertrophic cardiomyopathy	SpecificDisease	D024741
10330430	188	224	familial hypertrophic cardiomyopathy	SpecificDisease	D024741
10330430	226	229	FHC	SpecificDisease	D024741
10330430	286	289	FHC	Modifier	D024741
10330430	725	758	idiopathic dilated cardiomyopathy	SpecificDisease	C536277
10330430	760	763	IDC	SpecificDisease	C536277

8084618|t|The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains.
8084618|a|The EWS gene, which maps to band q12 of human chromosome 22, is involved in a wide variety of human solid tumors including Ewing sarcoma, related primitive neuroectodermal tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors. In these tumors, the EWS is fused to genes encoding transcriptional activators/repressors, like Fli-1 or erg or ATF 1 or wt1. To better understand the function of the EWS protein, we cloned the EWS cDNA. Sequence analysis of this cDNA revealed differential splicing involving two exons encoding 72 amino acids. Both alternatively spliced transcripts, EWS and EWS-b, are expressed in a variety of cells. Because EWS proteins contain putative conserved RNA binding motifs, we studied the RNA binding properties of the EWS protein. The EWS-b protein binds to RNA in vitro and, specifically, to poly G and poly U. The RNA binding activity was localized to the carboxy terminal 86 amino acids, which constitute RGG box. Thus the amino terminal domain of EWS (NTD-EWS), which is involved in chromosome translocation may regulate the specificity of RNA binding activity of EWS. An EWS-erg chimeric protein, which is found in Ewings sarcoma cells, functions as a transcriptional activator. Mutational analysis of EWS-erg chimeric protein revealed that NTD-EWS functions as a regulatory domain for the transcriptional activation properties of EWS-erg chimeric protein.. 
8084618	26	48	Ewing family of tumors	DiseaseClass	D012512
8084618	50	82	malignant melanoma of soft parts	DiseaseClass	D008545
8084618	87	123	desmoplastic small round cell tumors	SpecificDisease	D058405
8084618	289	301	solid tumors	DiseaseClass	D009369
8084618	312	325	Ewing sarcoma	SpecificDisease	D012512
8084618	345	367	neuroectodermal tumors	DiseaseClass	D017599
8084618	369	401	malignant melanoma of soft parts	DiseaseClass	D008545
8084618	406	442	desmoplastic small round cell tumors	DiseaseClass	D058405
8084618	453	459	tumors	DiseaseClass	D009369
8084618	1362	1376	Ewings sarcoma	Modifier	D012512

1301938|t|A mutation common in non-Jewish Tay-Sachs disease: frequency and RNA studies.
1301938|a|Tay-Sachs disease (TSD) is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, beta-N-acetylhexosaminidase A (Hex A). We have discovered that a Tay-Sachs mutation, IVS-9 + 1 G-- > A, first detected by Akli et al. (Genomics 11  124-134, 1991), is a common disease allele in non-Jewish Caucasians (10/58 alleles examined). A PCR-based diagnostic test, which detects an NlaIII site generated by the mutation, revealed a frequency among enzyme-defined carriers of 9/64 (14%). Most of those carrying the allele trace their origins to the United Kingdom, Ireland, or Western Europe. It was not identified among 12 Black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers who did not carry any of the mutations common to this population. No normally spliced RNA was detected in PCR products generated from reverse transcription of RNA carrying the IVS-9 mutation. Instead, the low levels of mRNA from this allele were comprised of aberrant species resulting from the use of either of two cryptic donor sites, one truncating exon 9 and the other within IVS-9, spliced to exon 10. Numerous additional splice products were detected, most involving skipping of one or more surrounding exons. Together with a recently identified allele responsible for Hex A pseudodeficiency (Triggs-Raine et al. Am J Hum Genet, 1992), these two alleles accounted for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening tests in non-Jewish Caucasians.. 
1301938	32	49	Tay-Sachs disease	SpecificDisease	D013661
1301938	78	95	Tay-Sachs disease	SpecificDisease	D013661
1301938	97	100	TSD	SpecificDisease	D013661
1301938	108	144	autosomal recessive genetic disorder	DiseaseClass	D030342
1301938	303	312	Tay-Sachs	Modifier	D013661
1301938	782	785	TSD	Modifier	D013661
1301938	1548	1551	TSD	Modifier	D013661

1302022|t|Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs.
1302022|a|The mutation underlying myotonic dystrophy (DM) has been identified as an expansion of a polymorphic CTG-repeat in a gene encoding protein kinase activity. Brain and heart transcripts of the DM-kinase (DMR-B15) gene are subject to alternative RNA splicing in both human and mouse. The unstable [CTG] 5-30 motif is found uniquely in humans, although the flanking nucleotides are also present in mouse. Characterization of the DM region of both species reveals another active gene (DMR-N9) in close proximity to the kinase gene. DMR-N9 transcripts, mainly expressed in brain and testis, possess a single, large open reading frame, but the function of its protein product is unknown. Clinical manifestation of DM may be caused by the expanded CTG-repeat compromising the (alternative) expression of DM-kinase or DMR-N9 proteins.. 
1302022	24	42	myotonic dystrophy	Modifier	D009223
1302022	124	142	myotonic dystrophy	SpecificDisease	D009223
1302022	144	146	DM	SpecificDisease	D009223
1302022	525	527	DM	Modifier	D009223
1302022	807	809	DM	SpecificDisease	D009223

2310692|t|Paroxysmal nocturnal haemoglobinuria with coexisting deficiency of the ninth component of complement: lack of massive haemolytic attack.
2310692|a|A 47-year-old woman with paroxysmal nocturnal haemoglobinuria (PNH) was found to have an inherited deficiency in the ninth complement component (C9). In complement-sensitivity lysis tests, 80% of her erythrocytes were markedly complement-sensitive (PNH-III). Laser cytofluorimetry with a monoclonal antibody against decay-accelerating factor (DAF) revealed that 95% of her erythrocytes were DAF-negative. Surprisingly, she has suffered only mild haemolysis and has never experienced massive spontaneous haemolysis. Gross haemoglobinuria and jaundice occurred only after receiving postoperative transfusion of whole blood. In her serum, C9 was not detectable either by immunological or by functional assays. Both the Ham test and the sugar water test using normal human serum or plasma yielded marked haemolysis of the patients erythrocytes. When the patients serum or plasma was used, only a trace of lysis was detected. Addition of purified human C9 to her plasma fully restored haemolysis. These observations indicated that C9 may play a critical role in haemolytic attacks in patients with PNH and that characteristic haemolysis in PNH may be tempered by coexisting C9 deficiency.. 
2310692	0	36	Paroxysmal nocturnal haemoglobinuria	SpecificDisease	D006457
2310692	53	100	deficiency of the ninth component of complement	SpecificDisease	OMIM:613825
2310692	118	135	haemolytic attack	SpecificDisease	D006461
2310692	162	198	paroxysmal nocturnal haemoglobinuria	SpecificDisease	D006457
2310692	200	203	PNH	SpecificDisease	D006457
2310692	226	280	inherited deficiency in the ninth complement component	SpecificDisease	OMIM:613825
2310692	583	593	haemolysis	SpecificDisease	D006461
2310692	640	650	haemolysis	SpecificDisease	D006461
2310692	658	673	haemoglobinuria	SpecificDisease	D006456
2310692	678	686	jaundice	SpecificDisease	D007565
2310692	1194	1212	haemolytic attacks	DiseaseClass	D006461
2310692	1230	1233	PNH	SpecificDisease	D006457
2310692	1258	1268	haemolysis	SpecificDisease	D006461
2310692	1272	1275	PNH	SpecificDisease	D006457
2310692	1306	1319	C9 deficiency	SpecificDisease	OMIM:613825

10943845|t|BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer.
10943845|a|Germline mutations in the tumor suppressor gene, BRCA1, predispose individuals to breast and ovarian cancers. Using a combination of affinity- and conventional chromatographic techniques, we have isolated a predominant form of a multiprotein BRCA1-containing complex from human cells displaying chromatin-remodeling activity. Mass spectrometric sequencing of components of this complex indicated that BRCA1 is associated with a SWI/SNF-related complex. We show that BRCA1 can directly interact with the BRG1 subunit of the SWI/SNF complex. Moreover, p53-mediated stimulation of transcription by BRCA1 was completely abrogated by either a dominant-negative mutant of BRG1 or the cancer-causing deletion in exon 11 of BRCA1. These findings reveal a direct function for BRCA1 in transcriptional control through modulation of chromatin structure.. 
10943845	90	103	breast cancer	SpecificDisease	D001943
10943845	131	136	tumor	Modifier	D009369
10943845	187	213	breast and ovarian cancers	CompositeMention	D010051|D001943
10943845	783	789	cancer	DiseaseClass	D009369

8375105|t|Germinal mosaicism in a Duchenne muscular dystrophy family: implications for genetic counselling.
8375105|a|In this study we describe a three-generation family in which two siblings were affected by Duchenne muscular dystrophy (DMD). Immunohistochemical analysis of muscle dystrophin and haplotype analysis of the DMD locus revealed that the X chromosome carrying the DMD gene was transmitted from the healthy maternal grandfather to his three daughters, including the probands mother. These findings indicate that the grandfather was a germinal mosaic for the DMD gene. The definition of the carrier status in two possible carriers led us to give accurate genetic counselling and to prevent the birth of an affected boy. The results of this study demonstrate the usefulness of haplotype analysis and immunohistochemical muscle dystrophin studies to detect hidden germinal mosaicism and to improve genetic counselling.. 
8375105	24	51	Duchenne muscular dystrophy	Modifier	D020388
8375105	189	216	Duchenne muscular dystrophy	SpecificDisease	D020388
8375105	218	221	DMD	SpecificDisease	D020388
8375105	304	307	DMD	Modifier	D020388
8375105	358	361	DMD	Modifier	D020388
8375105	551	554	DMD	Modifier	D020388

10198641|t|Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells.
10198641|a|Germline mutations of the Brca1 tumor suppressor gene predispose women to breast and ovarian cancers. To study mechanisms underlying BRCA1-related tumorigenesis, we derived mouse embryonic fibroblast cells carrying a targeted deletion of exon 11 of the Brca1 gene. We show that the mutant cells maintain an intact G1-S cell cycle checkpoint and proliferate poorly. However, a defective G2-M checkpoint in these cells is accompanied by extensive chromosomal abnormalities. Mutant fibroblasts contain multiple, functional centrosomes, which lead to unequal chromosome segregation, abnormal nuclear division, and aneuploidy. These data uncover an essential role of BRCA1 in maintaining genetic stability through the regulation of centrosome duplication and the G2-M checkpoint and provide a molecular basis for the role of BRCA1 in tumorigenesis.. 
10198641	169	174	tumor	Modifier	D009369
10198641	211	237	breast and ovarian cancers	CompositeMention	D061325
10198641	582	607	chromosomal abnormalities	DiseaseClass	D002869
10198641	747	757	aneuploidy	SpecificDisease	D000782

1769645|t|Aberrant splicing of phenylalanine hydroxylase mRNA: the major cause for phenylketonuria in parts of southern Europe.
1769645|a|We report a mutation within the phenylalanine hydroxylase (PAH) gene that causes aberrant splicing of the mRNA and that is in tight association with chromosomal haplotypes 6, 10, and 36. Because of the high frequency of these particular haplotypes in Bulgaria, Italy, and Turkey, it appears to be one of the more frequent defects in the PAH gene causing classical phenylketonuria in this part of Europe. The mutation is a G to A transition at position 546 in intron 10 of the PAH gene, 11 bp upstream from the intron 10/exon 11 boundary. It activates a cryptic splice site and results in an in-frame insertion of 9 nucleotides between exon 10 and exon 11 of the processed mRNA. Normal amounts of liver PAH protein are present in homozygous patients, but no catalytic activity can be detected. This loss of enzyme activity is probably caused by conformational changes resulting from the insertion of three additional amino acids (Gly-Leu-Gln) between the normal sequences encoded by exon 10 and exon 11.. 
1769645	73	88	phenylketonuria	SpecificDisease	D010661
1769645	482	497	phenylketonuria	SpecificDisease	D010661

10814710|t|Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes.
10814710|a|Mucopolysaccharidosis IVA (MPS IVA; OMIM # 253000), a lysosomal storage disorder caused by a deficiency of N -acetylgalactosamine-6-sulfate sulfatase (GALNS), has variable clinical phenotypes. To date we have identified 65 missense mutations in the GALNS gene from MPS IVA patients, but the correlation between genotype and phenotype has remained unclear. We studied 17 missense mutations using biochemical approaches and 32 missense mutations, using structural analyses. Fifteen missense mutations and two newly engineered active site mutations (C79S, C79T) were characterized by transient expression analysis. Mutant proteins, except for C79S and C79T, were destabilized and detected as insoluble precursor forms while the C79S and C79T mutants were of a soluble mature size. Mutants found in the severe phenotype had no activity. Mutants found in the mild phenotype had a considerable residual activity (1. 3-13. 3% of wild-type GALNS activity). Sulfatases, including GALNS, are members of a highly conserved gene family sharing an extensive sequence homology. Thus, a tertiary structural model of human GALNS was constructed from the X-ray crystal structure of N -acetylgalacto-samine-4-sulfatase and arylsulfatase A, using homology modeling, and 32 missense mutations were investigated. Consequently, we propose that there are at least three different reasons for the severe phenotype  (i) destruction of the hydrophobic core or modification of the packing; (ii) removal of a salt bridge to destabilize the entire conformation; (iii) modification of the active site. In contrast, mild mutations were mostly located on the surface of the GALNS protein. These studies shed further light on the genotype-phenotype correlation of MPS IVA and structure-function relationship in the sulfatase family.
10814710	111	136	mucopolysaccharidosis IVA	Modifier	OMIM:253000
10814710	149	174	Mucopolysaccharidosis IVA	SpecificDisease	OMIM:253000
10814710	176	183	MPS IVA	SpecificDisease	OMIM:253000
10814710	203	229	lysosomal storage disorder	DiseaseClass	D016464
10814710	242	298	deficiency of N -acetylgalactosamine-6-sulfate sulfatase	SpecificDisease	OMIM:253000
10814710	414	421	MPS IVA	Modifier	OMIM:253000
10814710	1880	1887	MPS IVA	SpecificDisease	OMIM:253000

7437512|t|Wiskott-Aldrich syndrome: cellular impairments and their implication for carrier detection.
7437512|a|A family in which two male siblings were affected with Wiskott-Aldrich syndrome (WAS) was studied using G-6-PD isoenzymes as an X-linked marker in order to investigate the nature of cellular abnormalities. Isolated peripheral blood cell types from the doubly heterozygous mother of the affected males seemingly failed to express the G-6-PD allele in cis position with the WAS allele while her cultured skin fibroblasts expressed both G-6-PD alleles. Additionally, a histogram analysis of platelet size revealed a single population of abnormally small platelets in the affected propositus, whereas the heterozygous mother had no appreciable small platelet subpopulation. In vitro culture of hemopoietic progenitor cells of the heterozygous mother showed that the majority of progenitor cells did not express the WAS allele. However, a small number of cells expressing the G-6-PD type linked with the WAS allele were detected. The proportion of the latter progenitors was significantly higher among more primitive progenitors (those giving rise to later appearing colonies). This observation suggests that selection against cells expressing the Wiskott-Aldrich defect takes place in the hemopoietic system of the heterozygous female and offers a possible means of carrier detection in some women. Linkage studies in this family revealed one example of probable recombination between the loci for WAS and G-6-PD among three informative subjects, suggesting that these two loci may not be closely linked on the X-chromosome.. 
7437512	0	24	Wiskott-Aldrich syndrome	SpecificDisease	D014923
7437512	147	171	Wiskott-Aldrich syndrome	SpecificDisease	D014923
7437512	173	176	WAS	SpecificDisease	D014923
7437512	464	467	WAS	Modifier	D014923
7437512	903	906	WAS	Modifier	D014923
7437512	991	994	WAS	Modifier	D014923
7437512	1235	1257	Wiskott-Aldrich defect	SpecificDisease	D014923
7437512	1486	1489	WAS	SpecificDisease	D014923

2792129|t|Familial deficiency of the seventh component of complement associated with recurrent meningococcal infections.
2792129|a|We describe an 11-year-old girl suffering from recurrent meningitis with a complete absence of the seventh component of complement (C7). Diagnosis was established by haemolytic titration and western blotting. The patients serum lacked the 85 kDa C7 chain. Haemolytic activity of serum was reconstituted with either pooled normal human serum or with purified C7. The relatives (parents and one sister) had half-normal levels of both immunochemically and functionally determined C7, indicating a heterozygous state for C7 deficiency.. 
2792129	0	58	Familial deficiency of the seventh component of complement	SpecificDisease	OMIM:610102
2792129	85	109	meningococcal infections	SpecificDisease	D008589
2792129	158	178	recurrent meningitis	SpecificDisease	D008581+D012008
2792129	195	240	absence of the seventh component of complemen	SpecificDisease	OMIM:610102
2792129	628	641	C7 deficiency	SpecificDisease	OMIM:610102

10190331|t|Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.
10190331|a|Enlarged vestibular aqueduct (EVA), known as the most common form of inner ear abnormality, has recently been of particular genetic interest because this anomaly is inherited in a recessive manner. The locus for non-syndromic sensorineural hearing loss with EVA has been mapped to the same chromosomal region, 7q31, as the Pendred syndrome locus. In the present study, seven mutations in the PDS gene (PDS), the gene responsible for Pendred syndrome, have been found in families of non-syndromic sensorineural hearing loss with EVA. One family is homozygous, three families are compound heterozygotes, and two families are heterozygous but with no other mutation detected. The present results provide evidence that mutations in PDS cause both syndromic and non-syndromic hearing loss.. 
10190331	0	26	Non-syndromic hearing loss	SpecificDisease	C537845
10190331	43	71	enlarged vestibular aqueduct	SpecificDisease	OMIM:600791
10190331	85	88	PDS	Modifier	C536648
10190331	100	128	Enlarged vestibular aqueduct	SpecificDisease	OMIM:600791
10190331	130	133	EVA	SpecificDisease	OMIM:600791
10190331	169	190	inner ear abnormality	DiseaseClass	D007759
10190331	312	352	non-syndromic sensorineural hearing loss	SpecificDisease	C537845
10190331	358	361	EVA	SpecificDisease	OMIM:600791
10190331	423	439	Pendred syndrome	Modifier	C536648
10190331	492	495	PDS	Modifier	C536648
10190331	533	549	Pendred syndrome	SpecificDisease	C536648
10190331	582	622	non-syndromic sensorineural hearing loss	SpecificDisease	C537845
10190331	628	631	EVA	SpecificDisease	OMIM:600791
10190331	843	883	syndromic and non-syndromic hearing loss	CompositeMention	D034381|C537845

3480530|t|Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: organization of the sequence and its encoded protein.
3480530|a|Retinoblastoma is a childhood tumor that can arise because of mutant alleles acquired as somatic or germinal mutations. The mutant allele can be carried in the germ line. The mutations creating these alleles act by inactivating copies of a recessive oncogene located within band q14 of chromosome 13 and termed the RB1 locus. We have reported isolation of a cDNA fragment that recognizes chromosomal sequences possessing many of the attributes of the retinoblastoma gene associated with the RB1 locus. We now report that this segment is additionally the target of somatic mutations in mesenchymal tumors among patients having no apparent predisposition to retinoblastoma and no previous evidence of retinoblastoma. These tumors provide additional evidence that the cloned sequences are representative of a gene that is a frequent target of inactivation during tumorigenesis. Sequence analysis of this cDNA provides little insight into its normal functional role.. 
3480530	31	46	retinoblastomas	SpecificDisease	D012175
3480530	51	69	mesenchymal tumors	DiseaseClass	C535700
3480530	125	139	Retinoblastoma	SpecificDisease	D012175
3480530	145	160	childhood tumor	DiseaseClass	D009369
3480530	576	590	retinoblastoma	Modifier	D012175
3480530	710	728	mesenchymal tumors	DiseaseClass	C535700
3480530	781	795	retinoblastoma	SpecificDisease	D012175
3480530	824	838	retinoblastoma	SpecificDisease	D012175
3480530	846	852	tumors	DiseaseClass	D009369

2862466|t|Genetically determined low C4: a predisposing factor to autoimmune chronic active hepatitis.
2862466|a|Of 26 patients with autoimmune chronic active hepatitis (CAH) starting in childhood 18 (69%) had low C4 and 5 (19%) had low C3 serum levels. Impaired hepatic synthesis and immune-consumption were unlikely since transferrin levels were normal in all patients, albumin levels were persistently low in only 3, and only 3 had raised levels of activation fragment C3d. C4d was normal in all patients studied. In the families of 12 probands with low C4, 7 parents had low C4 and 2 had levels which were at the lower limit of normal. 5 of 10 siblings from 5 families had low C4. These results suggest that low C4 levels in CAH are genetically determined. C4 phenotyping in 20 patients and in 26 parents showed that 90% and 81%, respectively, had null allotypes at either the C4A or C4B locus compared with 59% in controls, indicating that defective expression of structural genes may contribute to the observed C4 deficiency.. 
2862466	56	91	autoimmune chronic active hepatitis	SpecificDisease	D006521
2862466	113	148	autoimmune chronic active hepatitis	SpecificDisease	D006521
2862466	150	153	CAH	SpecificDisease	D006521
2862466	709	712	CAH	SpecificDisease	D006521
2862466	997	1010	C4 deficiency	SpecificDisease	OMIM:614380+OMIM:614379

3417303|t|Tight linkage between myotonic dystrophy and apolipoprotein E genes revealed with allele-specific oligonucleotides.
3417303|a|In 16 families with myotonic dystrophy (DM) a novel approach based on use of allele-specific oligonucleotides has been employed to study the linkage relationship between the apolipoprotein E (APOE) gene and DM. Synthetic oligonucleotides, designed to discriminate between APOE alleles epsilon 3 and epsilon 4, enabled us to distinguish heterozygous carriers in a hybridization assay. In a subset of families, the relevant segment of the APOE gene was enzymatically amplified to increase the sensitivity of the method. For DM and APOE, a maximum lod score (zmax of 7. 47 was obtained at a recombination frequency (theta) of 0. 047 (male theta = female theta). No recombination (maximum lod score of 5. 61 at theta = 0. 0) was found between APOE and the apolipoprotein CII (APOC2) gene. These results suggest that, in addition to APOC2, APOE is a useful marker for presymptomatic DM diagnosis.
3417303	22	40	myotonic dystrophy	Modifier	D009223
3417303	136	154	myotonic dystrophy	SpecificDisease	D009223
3417303	156	158	DM	SpecificDisease	D009223
3417303	323	325	DM	SpecificDisease	D009223
3417303	994	996	DM	Modifier	D009223

7894493|t|Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.
7894493|a|We provide genetic evidence supporting the identity of the candidate gene for BRCA1 through the characterization of germline mutations in 63 breast cancer patients and 10 ovarian cancer patients in ten families with cancer linked to chromosome 17q21. Nine different mutations were detected by screening BRCA1 DNA and RNA by single-strand conformation polymorphism analysis and direct sequencing. Seven mutations lead to protein truncations at sites throughout the gene. One missense mutation (which occurred independently in two families) leads to loss of a cysteine in the zinc binding domain. An intronic single basepair substitution destroys an acceptor site and activates a cryptic splice site, leading to a 59 basepair insertion and chain termination. The four families with both breast and ovarian cancer had chain termination mutations in the N-terminal half of the protein.. 
7894493	66	91	breast and ovarian cancer	CompositeMention	D061325
7894493	250	263	breast cancer	Modifier	D001943
7894493	280	294	ovarian cancer	Modifier	D010051
7894493	325	331	cancer	DiseaseClass	D009369
7894493	894	919	breast and ovarian cancer	CompositeMention	D061325

7937795|t|Genetic instability in human ovarian cancer cell lines.
7937795|a|We have analyzed the stability of microsatellites in cell lines derived from human ovarian cancers and found that 5 out of 10 of the ovarian tumor cell lines are genetically unstable at the majority of the loci analyzed. In clones and subclones derived serially from one of these cell lines (2774; serous cystadenocarcinoma), a very high proportion of microsatellites distributed in many different regions of the genome change their size in a mercurial fashion. We conclude that genomic instability in ovarian tumors is a dynamic and ongoing process whose high frequency may have been previously underestimated by PCR-based allelotyping of bulk tumor tissue. We have identified the source of the genetic instability in one ovarian tumor as a point mutation (R524P) in the human mismatch-repair gene MSH2 (Salmonella MutS homologue), which has recently been shown to be involved in hereditary nonpolyposis colorectal cancer. Patient 2774 was a 38-year-old heterozygote, and her normal tissue carried both mutant and wild-type alleles of the human MSH2 gene. However the wild-type allele was lost at some point early during tumorigenesis so that DNA isolated either from the patients ovarian tumor or from the 2774 cell line carries only the mutant allele of the human MSH2 gene. The genetic instability observed in the tumor and cell line DNA, together with the germ-line mutation in a mismatch-repair gene, suggest that the MSH2 gene is involved in the onset and/or progression in a subset of ovarian cancer.. 
7937795	29	43	ovarian cancer	Modifier	D010051
7937795	139	154	ovarian cancers	SpecificDisease	D010051
7937795	189	202	ovarian tumor	Modifier	D010051
7937795	354	379	serous cystadenocarcinoma	SpecificDisease	D018284
7937795	558	572	ovarian tumors	SpecificDisease	D010051
7937795	701	706	tumor	Modifier	D009369
7937795	779	792	ovarian tumor	SpecificDisease	D010051
7937795	937	978	hereditary nonpolyposis colorectal cancer	SpecificDisease	D003123
7937795	1238	1251	ovarian tumor	SpecificDisease	D010051
7937795	1374	1379	tumor	DiseaseClass	D009369
7937795	1549	1563	ovarian cancer	SpecificDisease	D010051

3455778|t|Retroviral-mediated gene transfer of human phenylalanine hydroxylase into NIH 3T3 and hepatoma cells.
3455778|a|Phenylketonuria (PKU) is caused by deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). A full-length human PAH cDNA sequence has been inserted into pzip-neoSV (X), which is a retroviral vector containing the bacterial neo gene. The recombinant has been transfected into psi 2 cells, which provide synthesis of the retroviral capsid. Recombinant virus was detected in the culture medium of the transfected psi 2 cells, which is capable of transmitting the human PAH gene into mouse NIH 3T3 cells by infection leading to stable incorporation of the recombinant provirus. Infected cells express PAH mRNA, immunoreactive PAH protein, and exhibit pterin-dependent phenylalanine hydroxylase activity. The recombinant virus is also capable of infecting a mouse hepatoma cell line that does not normally synthesize PAH. PAH activity is present in the cellular extracts and the entire hydroxylation system is reconstituted in the hepatoma cells infected with the recombinant viruses. Thus, recombinant viruses containing human PAH cDNA provide a means for introducing functional PAH into mammalian cells of hepatic origin and can potentially be introduced into whole animals as a model for somatic gene therapy for PKU.. 
3455778	86	94	hepatoma	Modifier	D006528
3455778	102	117	Phenylketonuria	SpecificDisease	D010661
3455778	119	122	PKU	SpecificDisease	D010661
3455778	137	195	deficiency of the hepatic enzyme phenylalanine hydroxylase	SpecificDisease	OMIM:261600
3455778	870	878	hepatoma	Modifier	D006528
3455778	1037	1045	hepatoma	Modifier	D006528
3455778	1322	1325	PKU	SpecificDisease	D010661

7599636|t|Characterisation of molecular defects in X-linked amelogenesis imperfecta (AIH1).
7599636|a|Amelogenins are an heterogenous family of proteins produced by ameloblasts of the enamel organ during tooth development. Disturbances of enamel formation occur in amelogenesis imperfecta, a clinically heterogenous group of inherited disorders characterised by defective enamel biomineralisation. An amelogenin gene, AMGX, has been mapped to the short of the X chromosome (Xp22. 1-p22. 3) and has been implicated in the molecular pathology of X-linked amelogenesis imperfecta (AIH1). We have identified three families exhibiting AIH1 and screened the AMGX gene for mutations using single-strand conformational polymorphism analysis and DNA sequencing. Three novel mutations were identified  a C-T substitution in exon 5, and a G-T substitution and single cytosine deletion in exon 6, confirming the existence of extensive allelic heterogeneity in this condition. The identification of family-specific mutations will enable early identification of affected individuals and correlation of clinical phenotype with genotype will facilitate an objective system of disease classification. 
7599636	41	73	X-linked amelogenesis imperfecta	SpecificDisease	C538243
7599636	245	268	amelogenesis imperfecta	DiseaseClass	D000567
7599636	305	324	inherited disorders	DiseaseClass	D030342
7599636	524	556	X-linked amelogenesis imperfecta	SpecificDisease	C538243
7599636	558	562	AIH1	SpecificDisease	C538243
7599636	610	614	AIH1	SpecificDisease	C538243

10192399|t|The Pendred syndrome gene encodes a chloride-iodide transport protein.
10192399|a|Pendred syndrome is the most common form of syndromic deafness and characterized by congenital sensorineural hearing loss and goitre. This disorder was mapped to chromosome 7 and the gene causing Pendred syndrome (PDS) was subsequently identified by positional cloning. PDS encodes a putative transmembrane protein designated pendrin. Pendrin is closely related to a family of sulfate transport proteins that includes the rat sulfate-anion transporter (encoded by Sat-1; 29% amino acid sequence identity), the human diastrophic dysplasia sulfate transporter (encoded by DTD; 32%) and the human sulfate transporter downregulated in adenoma (encoded by DRA; 45%). On the basis of this homology and the presence of a slightly modified sulfate-transporter signature sequence comprising its putative second transmembrane domain, pendrin has been proposed to function as a sulfate transporter. We were unable to detect evidence of sulfate transport following the expression of pendrin in Xenopus laevis oocytes by microinjection of PDS cRNA or in Sf9 cells following infection with PDS-recombinant baculovirus. The rates of transport for iodide and chloride were significantly increased following the expression of pendrin in both cell systems. Our results demonstrate that pendrin functions as a transporter of chloride and iodide, but not sulfate, and may provide insight into thyroid physiology and the pathophysiology of Pendred syndrome.. 
10192399	4	20	Pendred syndrome	Modifier	C536648
10192399	71	87	Pendred syndrome	SpecificDisease	C536648
10192399	115	133	syndromic deafness	DiseaseClass	D003638
10192399	166	192	sensorineural hearing loss	SpecificDisease	D006319
10192399	197	203	goitre	SpecificDisease	D006042
10192399	267	283	Pendred syndrome	SpecificDisease	C536648
10192399	285	288	PDS	SpecificDisease	C536648
10192399	587	608	diastrophic dysplasia	Modifier	C536170
10192399	702	709	adenoma	DiseaseClass	D000236
10192399	1490	1506	Pendred syndrome	SpecificDisease	C536648

161677|t|Linkage relationship of C2 deficiency, HLA and glyoxalase I loci.
161677|a|Immunogenetic analysis of a homozygous C2-deficient individual and family members demonstrated linkage of HLA-A25, B18 and C2o. HLA-D typing showed that 5 members typed with homozygous Dw2 typing cells from an individual with C2 deficiency but not with Dw2 typing cells from 2 individuals with normal C2. The homozygous C2-deficient propositus and brother were HLA-A and B homozygous but heterozygous at the HLA-D and glyoxalase I loci. Therefore, in this family, the C2o gene is linked with two distinct haplotypes  HLA-A25, B18, Dw2, GLO1 and HLA-A25, B18, D unknown, GL02. These results could be explained by an ancestral recombinant event, which occurred between the C2o locus and HLA-D locus in which C2o segregated with HLA-B. This would suggest that the locus for the C2o gene maps between HLA-B and HLA-D on the sixth chromosome.. 
161677	24	37	C2 deficiency	SpecificDisease	OMIM:217000
161677	105	117	C2-deficient	Modifier	OMIM:217000
161677	292	305	C2 deficiency	SpecificDisease	OMIM:217000
161677	386	398	C2-deficient	Modifier	OMIM:217000

1319059|t|A 71-kilodalton protein is a major product of the Duchenne muscular dystrophy gene in brain and other nonmuscle tissues.
1319059|a|The known Duchenne muscular dystrophy (DMD) gene products, the muscle- and brain-type dystrophin isoforms, are 427-kDa proteins translated from 14-kilobase (kb) mRNAs. Recently we described a 6. 5-kb mRNA that also is transcribed from the DMD gene. Cloning and in vitro transcription and translation of the entire coding region show that the 6. 5-kb mRNA encodes a 70. 8-kDa protein that is a major product of the DMD gene. It contains the C-terminal and the cysteine-rich domains of dystrophin, seven additional amino acids at the N terminus, and some modifications formed by alternative splicing in the C-terminal domain. It lacks the entire large domain of spectrin-like repeats and the actin-binding N-terminal domain of dystrophin. This protein is the major DMD gene product in brain and other nonmuscle tissues but is undetectable in skeletal muscle extracts.
1319059	50	77	Duchenne muscular dystrophy	Modifier	D020388
1319059	131	158	Duchenne muscular dystrophy	Modifier	D020388
1319059	160	163	DMD	Modifier	D020388
1319059	360	363	DMD	Modifier	D020388
1319059	535	538	DMD	Modifier	D020388
1319059	884	887	DMD	Modifier	D020388

1146783|t|Histidinemia. Classical and atypical form in siblings.
1146783|a|Two brothers, 6 and 13 years old, had histidinemia. On the basis of clinical and biochemical observations, the younger boy was considered to have a classical type of the disease, while the older boy had an atypical form characterized by partial impairment of the skin histidase activity and a moderately prolonged half-life of blood histidine. The mother is a heterozygous carrier, while the father and sister seem to be normal.. 
1146783	0	12	Histidinemia	SpecificDisease	C538320
1146783	93	105	histidinemia	SpecificDisease	C538320

1937471|t|Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification.
1937471|a|The Lesch-Nyhan syndrome is a severe X chromosome-linked human disease caused by a virtual absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. A partial deficiency in the activity of this enzyme can result in gouty arthritis. To determine the genetic basis for reduction or loss of enzyme activity, we have amplified and sequenced the coding region of HPRT cDNA from four patients  one with Lesch-Nyhan syndrome (HPRTPerth) and three with partial deficiencies of HPRT activity, which have been designated HPRTUrangan, HPRTSwan and HPRTToowong. In all four patients, the only mutation identified was a single base substitution in exons 2 or 3 of the coding region, which in each case predicts a single amino acid substitution in the translated protein. Each base change was confirmed by allele-specific amplification of the patients genomic DNA. It is interesting to note that the mutation found for HPRTPerth is identical to that reported for HPRTFlint. It appears that the two mutations are de novo events.. 
1937471	0	57	Hypoxanthine-guanine phosphoribosyltransferase deficiency	SpecificDisease	OMIM:300323
1937471	146	166	Lesch-Nyhan syndrome	SpecificDisease	D007926
1937471	179	212	X chromosome-linked human disease	DiseaseClass	D040181
1937471	233	306	absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity	SpecificDisease	D007926
1937471	374	389	gouty arthritis	SpecificDisease	D015210
1937471	556	576	Lesch-Nyhan syndrome	SpecificDisease	D007926
1937471	604	641	partial deficiencies of HPRT activity	DiseaseClass	OMIM:300323

3343337|t|Sjogren-Larsson syndrome. Impaired fatty alcohol oxidation in cultured fibroblasts due to deficient fatty alcohol:nicotinamide adenine dinucleotide oxidoreductase activity.
3343337|a|Lipid metabolism was studied in cultured skin fibroblasts from patients with the inherited disorder, Sjogren-Larsson syndrome (SLS). Intact SLS fibroblasts incubated in the presence of [1-14C] palmitate accumulated more radioactive hexadecanol than did normal cells, whereas incorporation of radioactivity into other cellular lipids was unaltered. The hexadecanol content of SLS fibroblasts was abnormally elevated. Hexadecanol accumulation was not due to increased fatty alcohol synthesis nor its deficient utilization for glycerol ether synthesis. The half-life of intracellular hexadecanol loaded into SLS fibroblasts was increased (70 min) compared with normal (15 min), and intact SLS fibroblasts showed impaired oxidation of [14C] -hexadecanol to fatty acid. Fatty alcohol  NAD + oxidoreductase, the enzyme catalyzing this reaction, was deficient in SLS fibroblasts. Mean total activity in SLS fibroblasts (n = 5) was 13% of that in normal fibroblasts, and palmitoyl CoA-inhibitable activity was 1% of normal. Fibroblasts from two obligate SLS heterozygotes had enzyme activities intermediate between that in normal fibroblasts and individuals with SLS. These results suggest that the primary defect in SLS is deficiency of fatty alcohol  NAD + oxidoreductase. SLS represents the first inherited disorder in man associated with an isolated abnormality in fatty alcohol metabolism.. 
3343337	0	24	Sjogren-Larsson syndrome	SpecificDisease	D016111
3343337	254	272	inherited disorder	DiseaseClass	D030342
3343337	274	298	Sjogren-Larsson syndrome	SpecificDisease	D016111
3343337	300	303	SLS	SpecificDisease	D016111
3343337	313	316	SLS	Modifier	D016111
3343337	548	551	SLS	Modifier	D016111
3343337	778	781	SLS	Modifier	D016111
3343337	859	862	SLS	Modifier	D016111
3343337	1029	1032	SLS	Modifier	D016111
3343337	1069	1072	SLS	Modifier	D016111
3343337	1219	1222	SLS	Modifier	D016111
3343337	1328	1331	SLS	SpecificDisease	D016111
3343337	1382	1385	SLS	SpecificDisease	D016111
3343337	1389	1438	deficiency of fatty alcohol  NAD + oxidoreductase	SpecificDisease	D016111
3343337	1440	1443	SLS	SpecificDisease	D016111
3343337	1465	1483	inherited disorder	DiseaseClass	D030342
3343337	1519	1558	abnormality in fatty alcohol metabolism	DiseaseClass	D005235

10736265|t|Glycerol as a correlate of impaired glucose tolerance: dissection of a complex system by use of a simple genetic trait.
10736265|a|Glycerol kinase (GK) represents the primary entry of glycerol into glucose and triglyceride metabolism. Impaired glucose tolerance (IGT) and hypertriglyceridemia are associated with an increased risk of diabetes mellitus and cardiovascular disease. The relationship between glycerol and the risk of IGT, however, is poorly understood. We therefore undertook the study of fasting plasma glycerol levels in a cohort of 1, 056 unrelated men and women of French-Canadian descent. Family screening in the initial cohort identified 18 men from five families with severe hyperglycerolemia (values above 2. 0 mmol/liter) and demonstrated an X-linked pattern of inheritance. Linkage analysis of the data from 12 microsatellite markers surrounding the Xp21. 3 GK gene resulted in a peak LOD score of 3. 46, centered around marker DXS8039. In addition, since all of the families originated in a population with a proven founder effect-the Saguenay Lac-St. -Jean region of Quebec-a common disease haplotype was sought. Indeed, a six-marker haplotype extending over a region of 5. 5 cM was observed in all families. Resequencing of the GK gene in family members led to the discovery of a N288D missense mutation in exon 10, which resulted in the substitution of a highly conserved asparagine residue by a negatively charged aspartic acid. 
10736265	27	53	impaired glucose tolerance	SpecificDisease	D018149
10736265	224	250	Impaired glucose tolerance	SpecificDisease	D018149
10736265	252	255	IGT	SpecificDisease	D018149
10736265	261	281	hypertriglyceridemia	SpecificDisease	D015228
10736265	323	340	diabetes mellitus	SpecificDisease	D003920
10736265	345	367	cardiovascular disease	SpecificDisease	D002318
10736265	419	422	IGT	SpecificDisease	D018149
10736265	684	701	hyperglycerolemia	SpecificDisease	C538138

1505217|t|Assignment of the aspartylglucosaminidase gene (AGA) to 4q33----q35 based on decreased activity in a girl with a 46,XX,del(4)(q33) karyotype.
1505217|a|Aspartylglucosaminuria (AGU) is a recessive autosomally inherited lysosomal storage disorder due to deficiency of the enzyme aspartylglucosaminidase (AGA). The structural gene for this human enzyme (AGA) has been assigned to the region 4q21----qter. We determined the AGA activity in cultured fibroblasts of a girl with a 46, XX, del (4) (q33) karyotype. The results indicate that the girl is a hemizygote for AGA, permitting the assignment of human AGA to the region 4q33----qter.. 
1505217	142	164	Aspartylglucosaminuria	SpecificDisease	D054880
1505217	166	169	AGU	SpecificDisease	D054880
1505217	208	234	lysosomal storage disorder	DiseaseClass	D016464
1505217	242	290	deficiency of the enzyme aspartylglucosaminidase	SpecificDisease	D054880

10891444|t|Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia.
10891444|a|Congenital afibrinogenemia is a rare, autosomal, recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations in a nonconsanguineous Swiss family; the 4 affected persons have homozygous deletions of approximately 11 kb of the fibrinogen alpha (FGA) gene. Haplotype data implied that these deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. We subsequently showed that all the deletions were identical to the base pair and probably resulted from a nonhomologous recombination mediated by 7-bp direct repeats. In this study, we have collected data on 13 additional unrelated patients to identify the causative mutations and to determine the prevalence of the 11-kb deletion. A common recurrent mutation, at the donor splice site of FGA intron 4 (IVS4 + 1 G > T), accounted for 14 of the 26 (54%) alleles. One patient was heterozygous for the previously identified deletion. Three more frameshift mutations, 2 nonsense mutations, and a second splice site mutation were also identified. Consequently, 86% of afibrinogenemia alleles analyzed to date have truncating mutations of FGA, though mutations in all 3 fibrinogen genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrinogenemia.. 
10891444	77	103	congenital afibrinogenemia	SpecificDisease	C531603
10891444	105	131	Congenital afibrinogenemia	SpecificDisease	C531603
10891444	143	172	autosomal, recessive disorder	DiseaseClass	D030342
10891444	1271	1286	afibrinogenemia	Modifier	D000347
10891444	1437	1463	congenital afibrinogenemia	SpecificDisease	C531603

523196|t|Utilization of purines by an HPRT variant in an intelligent, nonmutilative patient with features of the Lesch-Nyhan syndrome.
523196|a|The patient, H. Chr. B., was among the first reported with hyperuricemia and central nervous system symptoms. He has been found to have a variant of hypoxanthine guanine phosphoribosyl transferase (HPRT; E. C. 2. 4. 2. 8) distinct from the enzyme present in patients with the Lesch-Nyhan syndrome. The patient had chroeoathetosis, spasticity, dysarthric speech, and hyperuricemia. However, his intelligence was normal and he had no evidence of self-mutilation. There was no activity of HPRT in the lysates of erythrocytes and cultured fibroblasts when analyzed in the usual manner. Using a newly developed method for the study of purine metabolism in intact cultured cells, this patient was found to metabolize some 9% of 8-14C-hypoxanthine, and 90% of the isotope utilized was converted to adenine and guanine nucleotides. In contrast, cells from patients with the Lesch-Nyhan syndrome were virtually completely unable to convert hypoxanthine to nucleotides. The patients fibroblasts were even more efficient in the metabolism of 8-14C-guanine, which was utilized to the extent of 27%, over 80% of which was converted to guanine and adenine nucleotides. The growth of the cultured fibroblasts of this patient was intermediate in media containing hypoxanthine aminopterin thymidine (HAT), whereas the growth of Lesch-Nyhan cells was inhibited and normal cells grew normally. Similarly in 8-azaguanine, 6-thioguanine, and 8-azahypoxanthine, the growth of the patients cells was intermediate between normal and Lesch-Nyhan cells. These observations provide further evidence for genetic heterogeneity among patients with disorders in purine metabolism involving the HPRT gene. They document that this famous patient did not have the Lesch-Nyhan syndrome 
523196	104	124	Lesch-Nyhan syndrome	SpecificDisease	D007926
523196	185	198	hyperuricemia	SpecificDisease	D033461
523196	203	234	central nervous system symptoms	DiseaseClass	D002493
523196	402	422	Lesch-Nyhan syndrome	SpecificDisease	D007926
523196	440	455	chroeoathetosis	SpecificDisease	C537181
523196	457	467	spasticity	SpecificDisease	D009128
523196	469	486	dysarthric speech	SpecificDisease	D004401
523196	492	505	hyperuricemia	SpecificDisease	D033461
523196	992	1012	Lesch-Nyhan syndrome	SpecificDisease	D007926
523196	1437	1448	Lesch-Nyhan	Modifier	D007926
523196	1635	1646	Lesch-Nyhan	Modifier	D007926
523196	1856	1876	Lesch-Nyhan syndrome	SpecificDisease	D007926

8023850|t|Canavan disease: mutations among Jewish and non-Jewish patients.
8023850|a|Canavan disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Sixty-four probands were analyzed for mutations in the ASPA gene. Three point mutations--693C-- > A, 854A-- > C, and 914C-- > A--were identified in the coding sequence. The 693C-- > A and 914C-- > A base changes, resulting in nonsense tyr231-- > ter and missense ala305-- > glu mutations, respectively, lead to complete loss of ASPA activity in in vitro expression studies. The 854A-- > C transversion converted glu to ala in codon 285. The glu285-- > ala mutant ASPA has 2. 5% of the activity expressed by the wild-type enzyme. A fourth mutation, 433 --2 (A-- > G) transition, was identified at the splice-acceptor site in intron 2. The splice-site mutation would lead to skipping of exon 3, accompanied by a frameshift, and thus would produce aberrant ASPA. Of the 128 unrelated Canavan chromosomes analyzed, 88 were from probands of Ashkenazi Jewish descent. The glu285-- > ala mutation was predominant (82. 9%) in this population, followed by the tyr231-- > ter (14. 8%) and 433 --2 (A-- > G) (1. 1%) mutations. The three mutations account for 98. 8% of the Canavan chromosomes of Ashkenazi Jewish origin. The ala305-- > glu mutation was found exclusively in non-Jewish probands of European descent and constituted 60% of the 40 mutant chromosomes. Predominant occurrence of certain mutations among Ashkenazi Jewish and non-Jewish patients with Canavan disease would suggest a founding-father effect in propagation of these mutant chromosomes 
8023850	0	15	Canavan disease	SpecificDisease	D017825
8023850	65	80	Canavan disease	SpecificDisease	D017825
8023850	87	121	autosomal recessive leukodystrophy	DiseaseClass	D007966
8023850	136	164	deficiency of aspartoacylase	SpecificDisease	D017825
8023850	954	961	Canavan	Modifier	D017825
8023850	1235	1242	Canavan	Modifier	D017825
8023850	1522	1537	Canavan disease	SpecificDisease	D017825

1678319|t|Identification of deletion mutations and three new genes at the familial polyposis locus.
1678319|a|Small (100-260 kb), nested deletions were characterized in DNA from two unrelated patients with familial adenomatous polyposis coli (APC). Three candidate genes located within the deleted region were ascertained and a previous candidate gene, MCC, was shown to be located outside the deleted region. One of the new genes contained sequence identical to SRP19, the gene coding for the 19 kd component of the ribosomal signal recognition particle. The second, provisionally designated DP1 (deleted in polyposis 1), was found to be transcribed in the same orientation as MCC. Two other cDNAs, DP2 and DP3, were found to overlap, forming a single gene, DP2. 5, that is transcribed in the same orientation as SRP19. 
1678319	64	82	familial polyposis	Modifier	D011125
1678319	186	221	familial adenomatous polyposis coli	SpecificDisease	D011125
1678319	223	226	APC	SpecificDisease	D011125

10830910|t|Genotype-phenotype correlations in families with deletions in the von Hippel-Lindau (VHL) gene.
10830910|a|Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome characterized by predisposition for bilateral and multi-centric hemangioblastoma in the retina and central nervous system, pheochromocytoma, renal cell carcinoma, and cysts in the kidney, pancreas, and epididymis. We describe five families for which direct sequencing of the coding region of the VHL gene had failed to identify the family-specific mutation. Further molecular analysis revealed deletions involving the VHL gene in each of these families. In four families, partial deletions of one or more exons were detected by Southern blot analysis. In the fifth family, FISH analysis demonstrated the deletion of the entire VHL gene. Our results show that (quantitative) Southern blot analysis is a sensitive method for detecting germline deletions of the VHL gene and should be implemented in routine DNA diagnosis for VHL disease. Our data support the previously established observation that families with a germline deletion have a low risk for pheochromocytoma. Further unraveling of genotype-phenotype correlations in VHL disease has revealed that families with a full or partial deletion of the VHL gene exhibit a phenotype with a preponderance of central nervous system hemangioblastoma.. 
10830910	66	83	von Hippel-Lindau	Modifier	D006623
10830910	85	88	VHL	Modifier	D006623
10830910	96	127	Von Hippel-Lindau (VHL) disease	SpecificDisease	D006623
10830910	133	158	hereditary tumor syndrome	DiseaseClass	D009386
10830910	195	239	bilateral and multi-centric hemangioblastoma	CompositeMention	D018325
10830910	282	298	pheochromocytoma	SpecificDisease	D010673
10830910	300	320	renal cell carcinoma	SpecificDisease	D002292
10830910	326	371	cysts in the kidney, pancreas, and epididymis	CompositeMention	D052177|D010181|D013088
10830910	455	458	VHL	Modifier	D006623
10830910	577	580	VHL	Modifier	D006623
10830910	786	789	VHL	Modifier	D006623
10830910	918	921	VHL	Modifier	D006623
10830910	982	993	VHL disease	SpecificDisease	D006623
10830910	1110	1126	pheochromocytoma	SpecificDisease	D010673
10830910	1185	1196	VHL disease	SpecificDisease	D006623
10830910	1263	1266	VHL	Modifier	D006623
10830910	1316	1355	central nervous system hemangioblastoma	SpecificDisease	D018325

10767313|t|Understanding the molecular basis of fragile X syndrome.
10767313|a|Fragile X syndrome, a common form of inherited mental retardation, is mainly caused by massive expansion of CGG triplet repeats located in the 5-untranslated region of the fragile X mental retardation-1 (FMR1) gene. In patients with fragile X syndrome, the expanded CGG triplet repeats are hypermethylated and the expression of the FMR1 gene is repressed, which leads to the absence of FMR1 protein (FMRP) and subsequent mental retardation. FMRP is an RNA-binding protein that shuttles between the nucleus and cytoplasm. This protein has been implicated in protein translation as it is found associated with polyribosomes and the rough endoplasmic reticulum. We discuss here the recent progress made towards understanding the molecular mechanism of CGG repeat expansion and physiological function (s) of FMRP. These studies will not only help to illuminate the molecular basis of the general class of human diseases with trinucleotide repeat expansion but also provide an avenue to understand aspects of human cognition and intelligence.. 
10767313	37	55	fragile X syndrome	SpecificDisease	D005600
10767313	57	75	Fragile X syndrome	SpecificDisease	D005600
10767313	94	122	inherited mental retardation	DiseaseClass	D038901
10767313	229	257	fragile X mental retardation	Modifier	OMIM:300624
10767313	290	308	fragile X syndrome	SpecificDisease	D005600
10767313	478	496	mental retardation	DiseaseClass	D008607

7076260|t|Glucose-6-phosphate dehydrogenase deficiency in Papua New Guinea. The description of 13 new variants.
7076260|a|A total of 362 males from various regions of Papua New Guinea were screened for red cell glucose-6-phosphate dehydrogenase (G6PD) activity. Twenty-six G6PD deficient individuals were identified. Biochemical characterization of G6PD purified from these subjects has revealed 13 new variants and several copies of previously described forms of G6PD. This study illustrates the extreme heterogeneity of G6PD deficiency among the people of Papua New Guinea.. 
7076260	0	44	Glucose-6-phosphate dehydrogenase deficiency	SpecificDisease	D005955
7076260	253	267	G6PD deficient	Modifier	D005955
7076260	502	517	G6PD deficiency	SpecificDisease	D005955

3862128|t|Regional mapping of the phenylalanine hydroxylase gene and the phenylketonuria locus in the human genome.
3862128|a|Phenylketonuria (PKU) is an autosomal recessive disorder of amino acid metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH; phenylalanine 4-monooxygenase, EC 1. 14. 16. 1). A cDNA clone for human PAH has previously been used to assign the corresponding gene to human chromosome 12. To define the regional map position of the disease locus and the PAH gene on human chromosome 12, DNA was isolated from human-hamster somatic cell hybrids with various deletions of human chromosome 12 and was analyzed by Southern blot analysis using the human cDNA PAH clone as a hybridization probe. From these results, together with detailed biochemical and cytogenetic characterization of the hybrid cells, the region on chromosome 12 containing the human PAH gene has been defined as 12q14. 3----qter 3----qter. The PAH map position on chromosome 12 was further localized by in situ hybridization of 125I-labeled human PAH cDNA to chromosomes prepared from a human lymphoblastoid cell line. Results of these experiments demonstrated that the region on chromosome 12 containing the PAH gene and the PKU locus in man is 12q22----12q24. 1. These results not only provide a regionalized map position for a major human disease locus but also can serve as a reference point for linkage analysis with other DNA markers on human chromosome 12 
3862128	63	78	phenylketonuria	Modifier	D010661
3862128	106	121	Phenylketonuria	SpecificDisease	D010661
3862128	123	126	PKU	SpecificDisease	D010661
3862128	134	162	autosomal recessive disorder	DiseaseClass	D030342
3862128	200	258	deficiency of the hepatic enzyme phenylalanine hydroxylase	SpecificDisease	OMIM:261600
3862128	1225	1228	PKU	Modifier	D010661

2390095|t|Total deficiency of plasma cholesteryl ester transfer protein in subjects homozygous and heterozygous for the intron 14 splicing defect.
2390095|a|The molecular basis of cholesteryl ester transfer protein (CETP) deficiency was investigated in 4 unrelated CETP-deficient families. The high density lipoprotein-cholesterol levels of the probands exceeded 150 mg/dl. The plasma of the probands was totally deficient in CETP activity and mass. The genomic DNA of the patients was amplified by polymerase chain reaction, using two oligonucleotide primers located in the intron 12 and 14 of the CETP gene, and the amplified products were directly sequenced. Two patients were homozygous for a G-to-A change at the 5-splice donor site of the intron 14. The G-to-A change would cause impaired splicing of pre-messenger RNA. The other two probands were heterozygous for the mutation, but totally lacked CETP. Their lipoprotein patterns were also similar to those of the two homozygotes. Thus, other genetic defects or metabolic factors influencing CETP expression are implicated. The data suggest that the G-to-A mutation may be common in human plasma CETP deficiency. Furthermore, there could be compound heterozygotes who totally lack plasma CETP and have lipoprotein profiles similar to those of homozygotes.. 
2390095	0	61	Total deficiency of plasma cholesteryl ester transfer protein	SpecificDisease	OMIM:143470
2390095	160	212	cholesteryl ester transfer protein (CETP) deficiency	SpecificDisease	OMIM:143470
2390095	245	259	CETP-deficient	Modifier	OMIM:143470
2390095	980	995	genetic defects	DiseaseClass	D030342
2390095	1133	1148	CETP deficiency	SpecificDisease	OMIM:143470

3876122|t|Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor.
3876122|a|Type I von Willebrand disease (vWD) is characterized by equally low plasma concentrations of von Willebrand factor antigen (vWF  Ag) and ristocetin cofactor (RiCof) and by the presence of all vWF multimers in sodium dodecyl sulfate (SDS) -agarose gel electrophoresis. For 17 patients (13 kindreds) diagnosed with these criteria, we have studied the platelet contents of vWF  Ag and RiCof and the changes of these in plasma after DDAVP infusion. Platelet vWF  Ag and RiCof were normal in four kindreds (called " platelet normal " subgroup); following 1-deamino-8-D-arginine vasopressin; plasma vWF  Ag, RiCof and the bleeding time (BT) became normal. In six kindreds, platelet vWF  Ag and RiCof were equally low (platelet low); after DDAVP, plasma vWF  Ag and RiCof remained low, and the BT was prolonged. In three additional kindreds, platelets contained normal concentrations of vWF  Ag, but RiCof was very low (platelet discordant); even though a complete set of multimers was found in plasma and platelets, there was a relatively small amount of large multimers. After DDAVP, plasma vWF  Ag became normal, but RiCof remained low and the BT was very prolonged. These findings demonstrated that there can be an abnormal vWF (RiCof less than vWF  Ag) even in type I vWD, coexisting with a complete set of vWF multimers (platelet discordant); that the abnormal vWF can be shown more clearly in platelets than in plasma or else in plasma after DDAVP infusion; and that DDAVP normalizes the BT only in those patients with normal platelet levels of both vWF  Ag and RiCof (platelet normal).. 
3876122	17	46	type I von Willebrand disease	SpecificDisease	D056725
3876122	89	103	von Willebrand	Modifier	D014842
3876122	112	141	Type I von Willebrand disease	SpecificDisease	D056725
3876122	143	146	vWD	SpecificDisease	D014842
3876122	205	219	von Willebrand	Modifier	D014842
3876122	1371	1381	type I vWD	SpecificDisease	D056725

1303171|t|Characterization of a YAC containing part or all of the Norrie disease locus.
1303171|a|It has been shown from pulsed-field gel electrophoresis (PFGE) that the monoamine oxidase genes A and B (MAOA & MAOB) and DXS7 loci are physically very close. We have therefore extended studies on their relationship through the characterisation of a 650 kb YAC isolated using L1. 28 (recognising the DXS7 locus) as a probe. Restriction mapping of the YAC indicates that it contains both MAOA and MAOB genes in addition to the DXS7 locus. The map derived from the YL1. 28-YAC is compatible both with the map from an independently derived YAC carrying MAOA and B genes and with the long range genomic map for the region. A series of subclones prepared from a phage library (lambda DASH II) of the YAC have been characterised and have been employed to determine the end point of the deletion of a Norrie disease (NDP) patient who has been shown to lack both DXS7 and MAO coding sequences. The pattern of retention of subclones in the deletion patient place the end point of the deletion within 30-130 kb of the proximal end of the YAC. By combining the data with established recombination analysis, we provide evidence that all or part of the NDP lies in the interval of approximately 250kb within the YAC.
1303171	56	70	Norrie disease	Modifier	C537849
1303171	872	886	Norrie disease	Modifier	C537849
1303171	888	891	NDP	Modifier	C537849

8477262|t|Identification of mutations in Danish choroideremia families.
8477262|a|We have searched for mutations in the choroideremia gene (CHM) in patients from 12 Danish families in which CHM is segregating. Employing polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP) analysis, and direct DNA sequencing, different mutations have been identified in 6 patients. All the mutations will interfere with the correct translation of the mRNA predicting a truncated protein or no gene product at all.. 
8477262	38	51	choroideremia	Modifier	D015794
8477262	100	113	choroideremia	Modifier	D015794
8477262	120	123	CHM	Modifier	D015794
8477262	170	173	CHM	SpecificDisease	D015794

10543403|t|G130V, a common FRDA point mutation, appears to have arisen from a common founder.
10543403|a|Friedreich ataxia (FRDA) is the most common inherited ataxia. About 98% of mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of the affected gene, FRDA. The other 2% are point mutations. Of the 17 point mutations so far described, three appear to be more common. One of these is the G130V mutation in exon 4 of FRDA. G130V, when present with an expanded GAA repeat on the other allele, is associated with an atypical FRDA phenotype. Haplotype analysis was undertaken on the four families who have been described with this mutation. The results suggest a common founder for this mutation. Although marked differences in extragenic marker haplotypes were seen in one family, similar intragenic haplotyping suggests the same mutation founder for this family with the differences explicable by two recombination events.. 
10543403	16	20	FRDA	Modifier	D005621
10543403	83	100	Friedreich ataxia	SpecificDisease	D005621
10543403	102	106	FRDA	SpecificDisease	D005621
10543403	127	143	inherited ataxia	DiseaseClass	D013132
10543403	525	529	FRDA	Modifier	D005621

7605382|t|Frequency of exon 15 missense mutation (442D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects.
7605382|a|Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester from high density lipoprotein (HDL) to apo B-containing lipoproteins. The hyperalphalipoproteinemia caused by CETP deficiency is fairly common in Japan and one of the most common mutations in the CETP gene is the splicing defect of the intron 14, the allelic frequency of which has been shown to be 0. 0049 in the Japanese general population. Recently, we have reported a missense mutation in exon 15 of the CETP gene (442D  G), showing a dominant effect on the CETP activity and HDL-cholesterol level. In the current study, we determined the frequency of this new mutation in Japanese hyperalphalipoproteinemic (HDL-cholesterol > or = 100 mg/dl) subjects. A rapid and easy screening method for this new mutation was developed using a polymerase chain reaction (PCR) -mediated site-directed mutagenesis. Among 117 Japanese hyperalphalipoproteinemic subjects (HDL-cholesterol; 116. 7 +/- 16. 5 mg/dl, mean +/- S. D.) without the intron 14 splice defect, three homozygotes (2. 5%) and 34 heterozygotes (29. 1%) were found to have the 442D  G mutation. The relative allelic frequency of this mutation was calculated to be 0. 17. One of the homozygotes for the 442D  G mutation was the patient previously described by us as having hyperalphalipoproteinemia with corneal opacity and coronary heart disease. This was the first reported subject homozygous for the CETP deficiency who also demonstrated atherosclerotic symptoms. In homozygous subjects, CETP activity ranged from 37% to 62% of the normal value, which was consistent with the results obtained from the transient expression experiment previously reported; however, the specific activity of CETP was not as low as expected. (ABSTRACT TRUNCATED AT 250 WORDS) 
7605382	94	119	hyperalphalipoproteinemic	Modifier	OMIM:143470
7605382	283	308	hyperalphalipoproteinemia	SpecificDisease	OMIM:143470
7605382	319	334	CETP deficiency	SpecificDisease	OMIM:143470
7605382	795	820	hyperalphalipoproteinemic	Modifier	OMIM:143470
7605382	1032	1057	hyperalphalipoproteinemic	Modifier	OMIM:143470
7605382	1436	1461	hyperalphalipoproteinemia	SpecificDisease	OMIM:143470
7605382	1467	1482	corneal opacity	SpecificDisease	D003318
7605382	1487	1509	coronary heart disease	SpecificDisease	D003327
7605382	1566	1581	CETP deficiency	SpecificDisease	OMIM:143470
7605382	1604	1628	atherosclerotic symptoms	DiseaseClass	D050197

10071193|t|Fibroblast growth factor homologous factor 2 (FHF2): gene structure, expression and mapping to the Borjeson-Forssman-Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a BFLS-like patient.
10071193|a|Borjeson-Forssman-Lehmann syndrome (BFLS) is a syndromal X-linked mental retardation, which maps by linkage to the q26 region of the human X chromosome. We have identified a male patient with BFLS-like features and a duplication, 46, Y, dup (X) (q26q28), inherited from his phenotypically normal mother. Fluorescence in situ hybridisation using yeast artificial chromosome clones from Xq26 localised the duplication breakpoint to an approximately 400-kb interval in the Xq26. 3 region between DXS155 and DXS294/DXS730. Database searches and analysis of available genomic DNA sequence from the region revealed the presence of the fibroblast growth factor homologous factor gene, FHF2, within the duplication breakpoint interval. The gene structure of FHF2 was determined and two new exons were identified, including a new 5 end exon, 1B. FHF2 is a large gene extending over approximately 200 kb in Xq26. 3 and is composed of at least seven exons. It shows tissue-specific alternative splicing and alternative transcription starts. Northern blot hybridisation showed highest expression in brain and skeletal muscle. The FHF2 gene localisation and tissue-specific expression pattern suggest it to be a candidate gene for familial cases of the BFLS syndrome and other syndromal and non-specific forms of X-linked mental retardation mapping to the region.
10071193	99	133	Borjeson-Forssman-Lehmann syndrome	Modifier	C536575
10071193	193	197	BFLS	Modifier	C536575
10071193	212	246	Borjeson-Forssman-Lehmann syndrome	SpecificDisease	C536575
10071193	248	252	BFLS	SpecificDisease	C536575
10071193	269	296	X-linked mental retardation	DiseaseClass	D038901
10071193	404	408	BFLS	Modifier	C536575
10071193	1452	1465	BFLS syndrome	SpecificDisease	C536575
10071193	1512	1539	X-linked mental retardation	DiseaseClass	D038901

8098245|t|Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria.
8098245|a|Taking advantage of the illegitimate transcription of the phenylalanine hydroxylase (PAH) gene, we have been able to analyse the PAH cDNA sequence of hyperphenylalaninemic children in circulating lymphocytes. Using this approach, we have also identified 3 novel mutations in cDNA from liver and lymphocytes of two patients. One mutation, detected by the abnormal pattern of migration of an amplified fragment, is a C to T transition in the splice acceptor site of intron 10, which resulted in the skipping of exon 11 with the premature termination of RNA translation downstream from exon 12 (-3 IVS10). The other two mutations are missense mutations in exons 10 and 11 (respectively, L333F and E390G). The present study supports the view that circulating lymphocytes give easy access to PAH gene transcripts whose nucleotide sequence is identical to that reported in liver and therefore represent a useful tool for molecular genetic studies in phenylketonuria.. 
8098245	115	130	phenylketonuria	SpecificDisease	D010661
8098245	282	303	hyperphenylalaninemic	Modifier	D010661
8098245	1076	1091	phenylketonuria	SpecificDisease	D010661

10958786|t|Function of an axonal chemoattractant modulated by metalloprotease activity.
10958786|a|The axonal chemoattractant netrin-1 guides spinal commissural axons by activating its receptor DCC (Deleted in Colorectal Cancer ). We have found that chemical inhibitors of metalloproteases potentiate netrin-mediated axon outgrowth in vitro. We have also found that DCC is a substrate for metalloprotease-dependent ectodomain shedding, and that the inhibitors block proteolytic processing of DCC and cause an increase in DCC protein levels on axons within spinal cord explants. Thus, potentiation of netrin activity by inhibitors may result from stabilization of DCC on the axons, and proteolytic activity may regulate axon migration by controlling the number of functional extracellular axon guidance receptors.. 
10958786	188	205	Colorectal Cancer	SpecificDisease	D015179

2886237|t|Choroideremia: close linkage to DXYS1 and DXYS12 demonstrated by segregation analysis and historical-genealogical evidence.
2886237|a|Linkage studies using restriction fragment length polymorphisms were conducted in the X-linked disorder, choroideremia, designated TCD for Progressive Tapeto-Choroidal Dystrophy. Previously demonstrated close linkage with locus DXYS1 was confirmed (lod 11. 44 at 0 recombination distance). In addition, locus DXYS12 was found to be closely linked with TCD (lod 3. 31 at 0 recombination distance). The disease mainly occurs in three large kindreds in remote Northern Finland. While formal genealogical proof is lacking, all presently living (more than 80 affected males and 120 carrier females) probably originate from a common founder couple born in 1644 and 1646, twelve generations ago. All 36 patients and 48 carriers tested from the three kindreds had the same haplotype (TCD/DXYS1, 11kb/DXYS12, 1. 6kb). Given that at least 105 female meioses transmitting TCD have occurred since 1650 in these kindreds, extremely close linkage between TCD, DXYS1 and DXYS12 is suggested. The above haplotype is a very useful diagnostic tool in these TCD families. We suggest that our historical-genealogical approach to linkage analysis may be possible elsewhere in similar isolated populations 
2886237	0	13	Choroideremia	SpecificDisease	D015794
2886237	210	227	X-linked disorder	DiseaseClass	D040181
2886237	229	242	choroideremia	SpecificDisease	D015794
2886237	255	258	TCD	SpecificDisease	C531652
2886237	263	301	Progressive Tapeto-Choroidal Dystrophy	SpecificDisease	C531652
2886237	476	479	TCD	SpecificDisease	C531652
2886237	900	903	TCD	SpecificDisease	C531652
2886237	985	988	TCD	SpecificDisease	C531652
2886237	1065	1068	TCD	SpecificDisease	C531652
2886237	1163	1166	TCD	Modifier	C531652

10369870|t|Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies.
10369870|a|The early growth response 2 gene (EGR2) is a Cys2His2zinc finger transcription factor which is thought to play a role in the regulation of peripheral nervous system myelination. This idea is based partly on the phenotype of homozygous Krox20 (Egr2) knockout mice, which display hypomyelination of the PNS and a block of Schwann cells at an early stage of differentiation. Mutations in the human EGR2 gene have recently been associated with the inherited peripheral neuropathies Charcot-Marie-Tooth type 1, Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy. Three of the four EGR2 mutations are dominant and occur within the zinc finger DNA-binding domain. The fourth mutation is recessive and affects the inhibitory domain (R1) that binds the NAB transcriptional co-repressors. A combination of DNA-binding assays and transcriptional analysis was used to determine the functional consequences of these mutations. The zinc finger mutations affect DNA binding and the amount of residual binding directly correlates with disease severity. The R1 domain mutation prevents interaction of EGR2 with the NAB co-repressors and thereby increases transcriptional activity. These data provide insight into the possible disease mechanisms underlying EGR2 mutations and the reason for varying severity and differences in inheritance patterns.. 
10369870	113	127	myelinopathies	DiseaseClass	D011115
10369870	407	433	hypomyelination of the PNS	DiseaseClass	D010523
10369870	573	606	inherited peripheral neuropathies	DiseaseClass	C548028
10369870	607	633	Charcot-Marie-Tooth type 1	SpecificDisease	D002607
10369870	635	659	Dejerine-Sottas syndrome	SpecificDisease	C538392
10369870	664	701	congenital hypomyelinating neuropathy	SpecificDisease	OMIM:605253

2786201|t|Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA.
2786201|a|von Willebrand disease (vWD), the most common inherited bleeding disorder in humans, can result from either a quantitative or a qualitative defect in the adhesive glycoprotein, von Willebrand factor (vWF). Molecular studies of vWD have been limited by the large size of the vWF gene and difficulty in obtaining the vWF mRNA from patients. By use of an adaptation of the polymerase chain reaction, vWF mRNA was amplified and sequenced from peripheral blood platelets. A silent vWF allele was identified, resulting from a cis defect in vWF mRNA transcription or processing. In two type IIA vWD patients, two different but adjacent missense mutations were identified, the locations of which may identify an important vWF functional domain. Expression in heterologous cells of recombinant vWF containing one of these latter mutations reproduced the characteristic structural abnormality seen in type IIA vWD plasma.. 
2786201	25	47	von Willebrand disease	SpecificDisease	D014842
2786201	70	84	von Willebrand	Modifier	D014842
2786201	98	120	von Willebrand disease	SpecificDisease	D014842
2786201	122	125	vWD	SpecificDisease	D014842
2786201	144	171	inherited bleeding disorder	DiseaseClass	D025861
2786201	275	289	von Willebrand	Modifier	D014842
2786201	325	328	vWD	SpecificDisease	D014842
2786201	677	689	type IIA vWD	Modifier	D056728
2786201	989	1001	type IIA vWD	Modifier	D056728

10430930|t|A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and angelman syndromes.
10430930|a|Prader-Willi syndrome (PWS) and Angelman syndrome (AS) result from the loss of function of imprinted genes in human chromosome 15q11-q13. The central part of mouse chromosome 7 is homologous to human 15q11-q13, with conservation of both gene order and imprinted features. We report here the characterization of a transgene insertion (Epstein-Barr virus Latent Membrane Protein 2A, LMP2A) into mouse chromosome 7C, which has resulted in mouse models for PWS and AS dependent on the sex of the transmitting parent. Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridization analyses indicate that the transgene-induced mutation has generated a complete deletion of the PWS/AS-homologous region but has not deleted flanking loci. Because the intact chromosome 7, opposite the deleted homolog, maintains the correct imprint in somatic cells of PWS and AS mice and establishes the correct imprint in male and female germ cells of AS mice, homologous association and replication asynchrony are not part of the imprinting mechanism. This heritable-deletion mouse model will be particularly useful for the identification of the etiological genes and mechanisms, phenotypic basis, and investigation of therapeutic approaches for PWS.. 
10430930	78	113	Prader-Willi and angelman syndromes	CompositeMention	D011218|D017204
10430930	115	136	Prader-Willi syndrome	SpecificDisease	D011218
10430930	138	141	PWS	SpecificDisease	D011218
10430930	147	164	Angelman syndrome	SpecificDisease	D017204
10430930	166	168	AS	SpecificDisease	D017204
10430930	568	571	PWS	SpecificDisease	D011218
10430930	576	578	AS	SpecificDisease	D017204
10430930	815	818	PWS	Modifier	D011218
10430930	819	821	AS	Modifier	D017204
10430930	988	991	PWS	Modifier	D011218
10430930	996	998	AS	Modifier	D017204
10430930	1073	1075	AS	Modifier	D017204
10430930	1368	1371	PWS	SpecificDisease	D011218

10747931|t|Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas.
10747931|a|Chromosomal translocations in human lipomas frequently create fusion transcripts encoding high mobility group (HMG) I-C DNA-binding domains and C-terminal sequences from different presumed transcription factors, suggesting a potential role for HMG I-C in the development of lipomas. To evaluate the role of the HMG I-C component, the three DNA-binding domains of HMG I-C have now been expressed in transgenic mice. Despite the ubiquitous expression of the truncated HMG I-C protein, the transgenic mice develop a selective abundance of fat tissue early in life, show marked adipose tissue inflammation, and have an abnormally high incidence of lipomas. These findings demonstrate that the DNA-binding domains of HMG I-C, in the absence of a C-terminal fusion partner, are sufficient to perturb adipogenesis and predispose to lipomas. We provide data supporting the central utility of this animal model as a tool to understand the molecular mechanisms underlying the development of one of the most common kind of human benign tumors.. 
10747931	138	145	lipomas	DiseaseClass	D008067
10747931	183	190	lipomas	DiseaseClass	D008067
10747931	421	428	lipomas	DiseaseClass	D008067
10747931	721	748	adipose tissue inflammation	SpecificDisease	D007249
10747931	791	798	lipomas	DiseaseClass	D008067
10747931	972	979	lipomas	DiseaseClass	D008067
10747931	1165	1178	benign tumors	DiseaseClass	D009369

10051005|t|A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer.
10051005|a|The frequency, origin, and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated. The mutation (A-- > T at nt943 + 3) disrupts the 3 splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported. Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England, more extensive analysis has reduced the frequency to four of 52 (8%) English HNPCC kindreds analysed. In contrast, the MSH2 mutation was identified in 10 of 20 (50%) separately identified colorectal families from Newfoundland. To investigate the origin of this mutation in colorectal cancer families from England (n = 4), Newfoundland (n = 10), and the United States (n = 3), haplotype analysis using microsatellite markers linked to MSH2 was performed. Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families. In contrast, a common haplotype was identified at the two flanking markers (CA5 and D2S288) in eight of the Newfoundland families. These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families. We calculated age related risks of all, colorectal, endometrial, and ovarian cancers in nt943 + 3 A-- > T MSH2 mutation carriers (n = 76) for all patients and for men and women separately. For both sexes combined, the penetrances at age 60 years for all cancers  and for colorectal cancer were 0. 86 and 0. 57, respectively. The risk of colorectal cancer was significantly higher (p < 0. 01) in males than females (0. 63 v 0. 30 and 0. 84 v 0. 44 at ages 50 and 60 years, respectively). For females there was a high risk of endometrial cancer (0. 5 at age 60 years) and premenopausal ovarian cancer (0. 2 at 50 years). These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers.
10051005	53	58	HNPCC	Modifier	D003123
10051005	132	149	colorectal cancer	SpecificDisease	D015179
10051005	278	318	hereditary non-polyposis cancer syndrome	SpecificDisease	D003123
10051005	320	325	HNPCC	SpecificDisease	D003123
10051005	594	611	colorectal cancer	Modifier	D015179
10051005	729	734	HNPCC	Modifier	D003123
10051005	840	850	colorectal	Modifier	D015179
10051005	925	942	colorectal cancer	Modifier	D015179
10051005	1507	1512	HNPCC	Modifier	D003123
10051005	1563	1607	colorectal, endometrial, and ovarian cancers	CompositeMention	D010051|D016889|D015179
10051005	1777	1784	cancers	DiseaseClass	D009369
10051005	1794	1811	colorectal cancer	SpecificDisease	D015179
10051005	1860	1877	colorectal cancer	SpecificDisease	D015179
10051005	2047	2065	endometrial cancer	SpecificDisease	D016889
10051005	2093	2121	premenopausal ovarian cancer	SpecificDisease	D010051
10051005	2172	2189	colorectal cancer	Modifier	D015179
10051005	2268	2285	colorectal cancer	Modifier	D015179

7814011|t|Novel mutation at the initiation codon in the Norrie disease gene in two Japanese families.
7814011|a|We have identified a new mutation of Norrie disease (ND) gene in two Japanese males from unrelated families; they showed typical ocular features of ND but no mental retardation or hearing impairment. A mutation was found in both patients at the initiation codon of exon 2 of the ND gene (ATG to GTG), with otherwise normal nucleotide sequences. Their mothers had the normal and mutant types of the gene, which was expected for heterozygotes of the disease. The mutation of the initiation codon would cause the failure of ND gene expression or a defect in translation thereby truncating the amino terminus of ND protein. In view of the rarity and marked heterogeneity of mutations in the ND gene, the present apparently unrelated Japanese families who have lived in the same area for over two centuries presumably share the origin of the mutation.. 
7814011	46	60	Norrie disease	Modifier	C537849
7814011	129	143	Norrie disease	Modifier	C537849
7814011	145	147	ND	Modifier	C537849
7814011	240	242	ND	SpecificDisease	C537849
7814011	250	268	mental retardation	DiseaseClass	D008607
7814011	272	290	hearing impairment	DiseaseClass	D034381
7814011	371	373	ND	Modifier	C537849
7814011	613	615	ND	Modifier	C537849
7814011	700	702	ND	Modifier	C537849
7814011	779	781	ND	Modifier	C537849

8571953|t|Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.
8571953|a|Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations. Tests of both mutations and family-specific differences in age at diagnosis were not significant. A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P =. 069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1. For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago. In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events. 
8571953	196	221	breast and ovarian cancer	Modifier	D061325
8571953	427	448	breast/ovarian cancer	Modifier	D061325
8571953	688	713	breast and ovarian cancer	CompositeMention	D061325
8571953	839	853	ovarian cancer	SpecificDisease	D010051

7166314|t|A new glucose-6-phosphate dehydrogenase variant (G6PD Nagano) associated with congenital hemolytic anemia.
7166314|a|A new glucose-6-phosphate dehydrogenase (G6PD) variant associated with chronic nonspherocytic hemolytic anemia was reported. The patient, a 6-year-old Japanese male, was noticed to have hemolytic anemia soon after birth, and a diagnosis of G6PD deficiency was made at the age of 2. He had episodes of hemolytic crisis several times after upper respiratory infection. G6PD activity of the patient was 5. 5% of normal. The enzymatic characteristics were examined when he was 5 years old, and his G6PD showed faster-than-normal electrophoretic mobility, low Km G6P, high Km NADP, low Ki NADPH, normal utilization of substrate analogues, heat instability, and a normal pH optimum curve. From these results, this was considered to be a new variant and was designated G6PD Nagano. Infection-induced hemolysis and chronic hemolytic anemia seem to be due to markedly impaired enzyme activity and thermal instability. 
7166314	78	105	congenital hemolytic anemia	SpecificDisease	D000745
7166314	178	217	chronic nonspherocytic hemolytic anemia	SpecificDisease	D000746
7166314	293	309	hemolytic anemia	SpecificDisease	D000743
7166314	347	362	G6PD deficiency	SpecificDisease	D005955
7166314	408	424	hemolytic crisis	DiseaseClass	D006461
7166314	445	472	upper respiratory infection	SpecificDisease	D012141
7166314	900	909	hemolysis	SpecificDisease	D006461
7166314	914	938	chronic hemolytic anemia	SpecificDisease	D000745

1468459|t|Craniofrontonasal dysplasia.
1468459|a|We report on nine patients with craniofrontonasal dysplasia (CFND). Seven classical cases had facial features suggestive of frontonasal dysplasia and coronal craniosynostosis. Extracranial abnormalities such as brittle nails with prominent longitudinal grooves or syndactyly of fingers and toes were observed in individual patients. In two families the father of classical cases showed a milder pattern of abnormalities, consistent with the diagnosis. We present a 2- to 13-year follow-up on our patients. Hypotonia and laxity of joints are common and may necessitate supportive measures. Mild developmental delay was noted in three out of six classical cases studied in detail. Unlike almost all other X-linked disorders, clinical expression in CFND is generally much more severe in females than in males. In contrast to previous reports of this condition, one of our severely affected cases is a male.. 
1468459	0	27	Craniofrontonasal dysplasia	SpecificDisease	C536456
1468459	61	88	craniofrontonasal dysplasia	SpecificDisease	C536456
1468459	90	94	CFND	SpecificDisease	C536456
1468459	153	174	frontonasal dysplasia	SpecificDisease	C538065
1468459	179	203	coronal craniosynostosis	SpecificDisease	C537369
1468459	205	231	Extracranial abnormalities	DiseaseClass	D009139
1468459	240	289	brittle nails with prominent longitudinal grooves	SpecificDisease	D009260
1468459	293	323	syndactyly of fingers and toes	CompositeMention	D013576
1468459	535	544	Hypotonia	SpecificDisease	D009123
1468459	549	565	laxity of joints	SpecificDisease	C535884
1468459	623	642	developmental delay	DiseaseClass	D002658
1468459	732	750	X-linked disorders	DiseaseClass	D040181
1468459	775	779	CFND	SpecificDisease	C536456

1707231|t|A new mutation in the proteolipid protein (PLP) gene in a German family with Pelizaeus-Merzbacher disease.
1707231|a|A C-to-T transition in exon 4 of the PLP gene was found in 2 affected males and two obligate carriers in a German family with Pelizaeus-Merzbacher disease. The mutation, which causes loss of an HphI site and changes amino acid 155 from threonine to isoleucine, was absent from 108 normal chromosomes. There are 5 concordances and 1 discrepancy between these results and those obtained by magnetic resonance imaging in this family.. 
1707231	77	105	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
1707231	233	261	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080

7579347|t|The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene.
7579347|a|The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency. Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency. Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations.. 
7579347	4	28	Wiskott-Aldrich syndrome	SpecificDisease	D014923
7579347	33	69	X-linked congenital thrombocytopenia	SpecificDisease	OMIM:313900
7579347	116	140	Wiskott-Aldrich syndrome	SpecificDisease	D014923
7579347	142	145	WAS	SpecificDisease	D014923
7579347	153	180	X-linked recessive disorder	DiseaseClass	D040181
7579347	198	214	thrombocytopenia	SpecificDisease	D013921
7579347	233	239	eczema	SpecificDisease	D004485
7579347	267	283	immunodeficiency	DiseaseClass	D007153
7579347	305	308	WAS	Modifier	D014923
7579347	354	390	congenital X-linked thrombocytopenia	SpecificDisease	OMIM:313900
7579347	392	395	XLT	SpecificDisease	OMIM:313900
7579347	441	447	eczema	SpecificDisease	D004485
7579347	469	486	immune deficiency	DiseaseClass	D007153
7579347	521	524	WAS	SpecificDisease	D014923
7579347	578	581	WAS	Modifier	D014923
7579347	598	601	WAS	Modifier	D014923
7579347	733	736	WAS	Modifier	D014923
7579347	929	932	WAS	Modifier	D014923
7579347	1113	1116	XLT	Modifier	OMIM:313900
7579347	1243	1246	WAS	SpecificDisease	D014923
7579347	1387	1390	XLT	SpecificDisease	OMIM:313900
7579347	1395	1398	WAS	SpecificDisease	D014923

1709636|t|A 3-base pair in-frame deletion of the phenylalanine hydroxylase gene results in a kinetic variant of phenylketonuria.
1709636|a|Phenylketonuria (PKU) is an autosomal recessive disease due to deficiency of a hepatic enzyme, phenylalanine hydroxylase (PAH). The absence of PAH activity results in typical PKU while persistence of a residual enzyme activity gives rise to variant forms of the disease. We report here a 3-base pair in-frame deletion of the PAH gene (delta 194) in a mild variant, with markedly reduced affinity of the enzyme for phenylalanine (Km = 160 nM), and we provide functional evidence for responsibility of the deletion in the mutant phenotype. Since the deletion was located in the third exon of the gene, which presents no homology with other hydroxylases, we suggest that exon 3 is involved in the specificity of the enzyme for phenylalanine. Finally, since none of the 98 PKU patients tested were found to carry this particular deletion, our study suggests that this molecular event probably occurred recently on the background of a haplotype 2 gene in Portugal.. 
1709636	102	117	phenylketonuria	SpecificDisease	D010661
1709636	119	134	Phenylketonuria	SpecificDisease	D010661
1709636	136	139	PKU	SpecificDisease	D010661
1709636	147	174	autosomal recessive disease	DiseaseClass	D030342
1709636	182	239	deficiency of a hepatic enzyme, phenylalanine hydroxylase	SpecificDisease	OMIM:261600
1709636	294	297	PKU	SpecificDisease	D010661
1709636	888	891	PKU	Modifier	D010661

10633128|t|Friedreich ataxia: an overview.
10633128|a|Friedreich ataxia, an autosomal recessive neurodegenerative disease, is the most common of the inherited ataxias. The recent discovery of the gene that is mutated in this condition, FRDA, has led to rapid advances in the understanding of the pathogenesis of Friedreich ataxia. About 98% of mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of the gene. This leads to reduced levels of the protein, frataxin. There is mounting evidence to suggest that Friedreich ataxia is the result of accumulation of iron in mitochondria leading to excess production of free radicals, which then results in cellular damage and death. Currently there is no known treatment that alters the natural course of the disease. The discovery of the FRDA gene and its possible function has raised hope that rational therapeutic strategies will be developed.. 
10633128	0	17	Friedreich ataxia	SpecificDisease	D005621
10633128	32	49	Friedreich ataxia	SpecificDisease	D005621
10633128	54	99	autosomal recessive neurodegenerative disease	DiseaseClass	D020271
10633128	127	144	inherited ataxias	SpecificDisease	D013132
10633128	290	307	Friedreich ataxia	SpecificDisease	D005621
10633128	508	525	Friedreich ataxia	SpecificDisease	D005621
10633128	782	786	FRDA	Modifier	D005621

10737119|t|Clinical and molecular genetics of primary dystonias.
10737119|a|Primary dystonias are movement disorders with dystonia as a major symptom. They are frequently inherited as Mendelian traits. There are at least eight clinically distinct autosomal dominant and two X-linked recessive forms. In addition, pedigree analyses suggest the occurrence of an autosomal recessive variant. The clinical classification is increasingly being replaced by a genetic one. To date gene loci have been identified in at least six autosomal dominant forms, i. e., in idiopathic torsion dystonia (9q34), focal dystonia (18p), adult-onset idiopathic torsion dystonia of mixed type (8p21-q22), dopa-responsive dystonia (14q22. 1-q22. 2), and paroxysmal dystonic choreoathetosis (2q25-q33; 1p21-p13. 3). Gene loci in the X-linked recessive  forms have been assigned to Xq13. 1 in the X-linked dystonia parkinsonism syndrome and to Xq22 in X-linked sensorineural deafness, dystonia, and mental retardation. The disease genes have been identified in two autosomal dominant forms and in one X-linked recessive form. Mutations in a gene coding for an ATP-binding protein were detected in idiopathic torsion dystonia (DYT1), and the GTP cyclohydrolase 1 gene is mutated in dopa-responsive dystonia (DYT5). In sensorineural deafness, dystonia, and mental retardation , mutations were found in the gene DDP coding for a polypeptide of unknown function. This article reviews the clinical and molecular genetics of primary dystonias, critically discusses present findings, and proposes referring to the known forms, most of which can be distinguished by genetic criteria, as dystonias 1-12.
10737119	35	52	primary dystonias	DiseaseClass	D020821
10737119	54	71	Primary dystonias	DiseaseClass	D020821
10737119	76	94	movement disorders	DiseaseClass	D009069
10737119	100	108	dystonia	DiseaseClass	D004421
10737119	535	562	idiopathic torsion dystonia	SpecificDisease	D004422
10737119	571	585	focal dystonia	SpecificDisease	D020821
10737119	605	632	idiopathic torsion dystonia	SpecificDisease	D004422
10737119	659	683	dopa-responsive dystonia	SpecificDisease	C538007
10737119	707	742	paroxysmal dystonic choreoathetosis	SpecificDisease	C537181
10737119	848	887	X-linked dystonia parkinsonism syndrome	SpecificDisease	OMIM:314250
10737119	903	934	X-linked sensorineural deafness	DiseaseClass	OMIM:304500
10737119	936	944	dystonia	DiseaseClass	D004421
10737119	950	968	mental retardation	DiseaseClass	D008607
10737119	1148	1175	idiopathic torsion dystonia	SpecificDisease	D004422
10737119	1232	1256	dopa-responsive dystonia	SpecificDisease	C538007
10737119	1268	1290	sensorineural deafness	DiseaseClass	D006319
10737119	1292	1300	dystonia	DiseaseClass	D004421
10737119	1306	1324	mental retardation	DiseaseClass	D008607
10737119	1470	1487	primary dystonias	DiseaseClass	D020821
10737119	1630	1644	dystonias 1-12	CompositeMention	D020821

10533031|t|Clinical and genetic study of Friedreich ataxia in an Australian population.
10533031|a|Friedreich ataxia is an autosomal recessive disorder caused by mutations in the FRDA gene that encodes a 210-amino acid protein called frataxin. An expansion of a GAA trinucleotide repeat in intron 1 of the gene is present in more than 95% of mutant alleles. Of the 83 people we studied who have mutations in FRDA, 78 are homozygous for an expanded GAA repeat; the other five patients have an expansion in one allele and a point mutation in the other. Here we present a detailed clinical and genetic study of a subset of 51 patients homozygous for an expansion of the GAA repeat. We found a correlation between the size of the smaller of the two expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity. There was no significant correlation between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms. The larger allele size correlated with bladder symptoms and the presence of foot deformity. The duration of disease is correlated with wheelchair use and the presence of diabetes, scoliosis, bladder symptoms and impaired proprioception, and vibration sense but no other complications studied.. 
10533031	30	47	Friedreich ataxia	SpecificDisease	D005621
10533031	77	94	Friedreich ataxia	SpecificDisease	D005621
10533031	101	129	autosomal recessive disorder	DiseaseClass	D030342
10533031	157	161	FRDA	Modifier	D005621
10533031	779	788	scoliosis	DiseaseClass	D012600
10533031	836	850	foot deformity	DiseaseClass	D005530
10533031	932	946	cardiomyopathy	SpecificDisease	D009202
10533031	948	965	diabetes mellitus	SpecificDisease	D003920
10533031	967	989	loss of proprioception	DiseaseClass	D020886
10533031	994	1010	bladder symptoms	DiseaseClass	D001745
10533031	1051	1067	bladder symptoms	DiseaseClass	D001745
10533031	1088	1102	foot deformity	DiseaseClass	D005530
10533031	1182	1190	diabetes	DiseaseClass	D003920
10533031	1192	1201	scoliosis	DiseaseClass	D012600
10533031	1203	1219	bladder symptoms	DiseaseClass	D001745
10533031	1224	1247	impaired proprioception	DiseaseClass	D020886

492812|t|Recurrent meningococcal meningitis with absence of the sixth component of complement: an evaluation of underlying immunologic mechanisms.
492812|a|A 51/2-year-old black girl with recurrent meningococcal meningitis and absence of the sixth component of complement (C6) is reported. To explore the pathogenesis of recurrent neisserial infections in C6 deficiency, a detailed analysis of her immune competence was conducted. Her serum had normal chemotactic, opsonic, alternative complement pathway, and specific antibody activity, but lacked complement-mediated bacteriolytic activity. In addition, her C6-deficient serum was indistinguishable from normal serum in a complement-dependent assay of phagocyte bactericidal activity. Absent bacteriolysis remains the only consistent defect associated with recurrent neisserial infections and absence of one of the late-acting complement components.. 
492812	10	34	meningococcal meningitis	SpecificDisease	D008585
492812	40	84	absence of the sixth component of complement	SpecificDisease	OMIM:612446
492812	180	204	meningococcal meningitis	SpecificDisease	D008585
492812	209	253	absence of the sixth component of complement	SpecificDisease	OMIM:612446
492812	313	334	neisserial infections	SpecificDisease	D016870
492812	338	351	C6 deficiency	SpecificDisease	OMIM:612446
492812	592	604	C6-deficient	Modifier	OMIM:612446
492812	801	822	neisserial infections	SpecificDisease	D016870

10519880|t|Mutation of the sterol 27-hydroxylase gene (CYP27) results in truncation of mRNA expressed in leucocytes in a Japanese family with cerebrotendinous xanthomatosis.
10519880|a|OBJECTIVES  A Japanese family with cerebrotendinous xanthomatosis (CTX) was investigated for a sequence alteration in the sterol 27-hydroxylase gene (CYP27). The expression of CYP27 has been mostly explored using cultured fibroblasts, prompting the examination of the transcripts from blood leucocytes as a simple and rapid technique. METHODS  An alteration in CYP27 of the proband was searched for by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and subsequent sequencing. Samples of RNA were subjected to reverse transcription PCR (RT-PCR) and the product of the proband was amplified with nested primers and sequenced. RESULTS  A homozygous G to A transition at the 5 end of intron 7 was detected in the patient. In RT-PCR analysis, only a truncated transcript was detected in the patient, whereas both normal and truncated transcripts were detected in the siblings. The sequencing of the patients cDNA fragment disclosed a direct conjuction of exon 6 and exon 8. CONCLUSION  The mutation at splice donor site and the truncation of mRNA were identical with those of a recently reported Italian patient, although different in symptomatology. The application of blood leucocytes can be a simple technique on analysing a constructive abnormality of CYP27 mRNA.. 
10519880	131	161	cerebrotendinous xanthomatosis	SpecificDisease	D019294
10519880	198	228	cerebrotendinous xanthomatosis	SpecificDisease	D019294
10519880	230	233	CTX	SpecificDisease	D019294
10519880	1438	1458	abnormality of CYP27	SpecificDisease	OMIM:213700

8187068|t|Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers.
8187068|a|Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone-binding domain of the androgen receptor (AR) gene. Direct sequencing of the polymerase chain reaction-derived DNAs of 6 of 24 specimens revealed a codon 877 mutation (ACT-- > GCT, Thr-- > Ala) in the hormone-binding domain of the AR gene. This same AR mutation has been reported previously in a metastatic prostate cancer cell line, LNCaP, where this mutation confers upon the AR an altered ligand-binding specificity which is stimulated by estrogens, progestagens, and antiandrogens. It is possible that analogous to an activated/altered growth factor receptor oncogene, codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. Although estrogens are used infrequently, antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer. The stimulatory effect of these therapeutic agents on the codon 877 mutant AR further suggests that this frequently observed AR mutation may contribute to the treatment refractory disease.. 
8187068	74	99	advanced prostate cancers	SpecificDisease	D011471
8187068	183	209	metastatic prostate cancer	SpecificDisease	D011471
8187068	558	584	metastatic prostate cancer	Modifier	D011471
8187068	954	978	advanced prostate cancer	SpecificDisease	D011471
8187068	1096	1120	advanced prostate cancer	SpecificDisease	D011471

10802669|t|ATM-dependent phosphorylation of nibrin in response to radiation exposure.
10802669|a|Mutations in the gene ATM are responsible for the genetic disorder ataxia-telangiectasia (A-T), which is characterized by cerebellar dysfunction, radiosensitivity, chromosomal instability and cancer predisposition. Both the A-T phenotype and the similarity of the ATM protein to other DNA-damage sensors suggests a role for ATM in biochemical pathways involved in the recognition, signalling and repair of DNA double-strand breaks (DSBs). There are strong parallels between the pattern of radiosensitivity, chromosomal instability and cancer predisposition in A-T patients and that in patients with Nijmegen breakage syndrome (NBS). The protein defective in NBS, nibrin (encoded by NBS1), forms a complex with MRE11 and RAD50 (refs 1, 2). This complex localizes to DSBs within 30 minutes after cellular exposure to ionizing radiation (IR) and is observed in brightly staining nuclear foci after a longer period of time. The overlap between clinical and cellular phenotypes in A-T and NBS suggests that ATM and nibrin may function in the same biochemical pathway. Here we demonstrate that nibrin is phosphorylated within one hour of treatment of cells with IR. This response is abrogated in A-T cells that either do not express ATM protein or express near full-length mutant protein. We also show that ATM physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association as revealed by radiation-induced foci formation. Our data provide a biochemical explanation for the similarity in phenotype between A-T and NBS.. 
10802669	125	141	genetic disorder	DiseaseClass	D030342
10802669	142	163	ataxia-telangiectasia	SpecificDisease	D001260
10802669	165	168	A-T	SpecificDisease	D001260
10802669	197	219	cerebellar dysfunction	DiseaseClass	D002526
10802669	267	273	cancer	Modifier	D009369
10802669	299	302	A-T	Modifier	D001260
10802669	610	616	cancer	Modifier	D009369
10802669	635	638	A-T	SpecificDisease	D001260
10802669	674	700	Nijmegen breakage syndrome	SpecificDisease	D049932
10802669	702	705	NBS	SpecificDisease	D049932
10802669	733	736	NBS	SpecificDisease	D049932
10802669	1051	1054	A-T	SpecificDisease	D001260
10802669	1059	1062	NBS	SpecificDisease	D049932
10802669	1265	1268	A-T	Modifier	D001260
10802669	1621	1624	NBS	Modifier	D049932
10802669	1841	1844	A-T	SpecificDisease	D001260
10802669	1849	1852	NBS	SpecificDisease	D049932

1346924|t|Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy.
1346924|a|Myotonic dystrophy (DM) is the most common form of adult muscular dystrophy, with a prevalence of 2-14 per 100, 000 individuals. The disease is characterized by progressive muscle weakness and sustained muscle contraction, often with a wide range of accompanying symptoms. The age at onset and severity of the disease show extreme variation, both within and between families. Despite its clinical variability, this dominant condition segregates as a single locus at chromosome 19q13. 3 in every population studied. It is flanked by the tightly linked genetic markers ERCC1 proximally and D19S51 distally; these define the DM critical region. We report the isolation of an expressed sequence from this region which detects a DNA fragment that is larger in affected individuals than in normal siblings or unaffected controls. The size of this fragment varies between affected siblings, and increases in size through generations in parallel with increasing severity of the disease. We postulate that this unstable DNA sequence is the molecular feature that underlies DM. 
1346924	70	88	myotonic dystrophy	SpecificDisease	D009223
1346924	90	108	Myotonic dystrophy	SpecificDisease	D009223
1346924	110	112	DM	SpecificDisease	D009223
1346924	147	165	muscular dystrophy	SpecificDisease	D009136
1346924	263	278	muscle weakness	DiseaseClass	D018908
1346924	283	311	sustained muscle contraction	DiseaseClass	D009120
1346924	712	714	DM	Modifier	D009223
1346924	1154	1156	DM	SpecificDisease	D009223

10987655|t|Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM.
10987655|a|Mutations in the brain specific P/Q type Ca2 + channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, viz. episodic ataxia type 2 (EA-2), familial hemiplegic migraine (FHM) and spinocerebellar ataxia 6 (SCA6). For individuals with EA-2, the mutations described thus far are presumed to result in a truncated protein product. Several different missense mutations have been identified in patients with FHM. At least two of these mutations have been identified on two different chromosome 19p13 haplotypes and thus represent recurrent mutations. In the present study, we have screened several individuals for mutations in all 47 exons in the CACNA1A gene by single-strand conformation analysis. We have characterised a novel missense mutation, G5260A, in exon 32 in a family segregating for EA-2. The consequence of this mutation is an amino acid substitution at a highly conserved position within the CACNA1A gene. This represents the first point mutation not resulting in a proposed truncated protein. Furthermore, this mutation has been detected in a family member with mild clinical signs including only migraine. Additionally, a second previously identified recurrent muta tion, C2272T, in exon 16 has been discovered in a patient with FHM.. 
10987655	109	113	EA-2	SpecificDisease	C535506
10987655	118	121	FHM	SpecificDisease	D020325
10987655	274	296	episodic ataxia type 2	SpecificDisease	C535506
10987655	298	302	EA-2	SpecificDisease	C535506
10987655	305	333	familial hemiplegic migraine	SpecificDisease	D020325
10987655	335	338	FHM	SpecificDisease	D020325
10987655	344	368	spinocerebellar ataxia 6	SpecificDisease	OMIM:183086
10987655	370	374	SCA6	SpecificDisease	OMIM:183086
10987655	398	402	EA-2	SpecificDisease	C535506
10987655	567	570	FHM	SpecificDisease	D020325
10987655	955	959	EA-2	SpecificDisease	C535506
10987655	1272	1280	migraine	SpecificDisease	D008881
10987655	1405	1408	FHM	SpecificDisease	D020325

10213492|t|Dominant negative effect of the APC1309 mutation: a possible explanation for genotype-phenotype correlations in familial adenomatous polyposis.
10213492|a|Inactivation of the adenomatous polyposis coli (APC) gene product initiates colorectal tumorigenesis. Patients with familial APC (FAP) carry germ-line mutations in the APC gene and develop multiple colorectal adenomas and subsequent carcinomas early in life. The severity of the disease correlates with the position of the inherited APC mutation (genotype-phenotype correlation). Together with the fact that both germ-line and sporadic APC mutations cluster in the central region of the APC gene, this points to a dominant negative effect of certain APC mutants. Loss of APC function was recently shown to result in enhanced beta-catenin-/Tcf-mediated transcription in colon epithelial cells. Here, we provide experimental evidence for a dominant negative effect of APC gene products associated with severe polyposis. Wild-type APC activity in beta-catenin-/Tcf-mediated transcription was strongly inhibited by a mutant APC that is truncated at codon 1309. In contrast, mutant APC gene products that are associated with attenuated polyposis (codon 386 or 1465) interfered only weakly with wild-type APC activity. These results suggest a molecular explanation for the genotype-phenotype correlation in FAP patients and support the idea that colorectal tumor growth might be, in part, driven by selection for a mutation in the mutation cluster region.. 
10213492	112	142	familial adenomatous polyposis	SpecificDisease	D011125
10213492	164	190	adenomatous polyposis coli	Modifier	D011125
10213492	192	195	APC	Modifier	D011125
10213492	260	272	familial APC	SpecificDisease	D011125
10213492	274	277	FAP	SpecificDisease	D011125
10213492	312	315	APC	Modifier	D011125
10213492	342	361	colorectal adenomas	SpecificDisease	D003123
10213492	377	387	carcinomas	DiseaseClass	D009369
10213492	477	480	APC	Modifier	D011125
10213492	580	583	APC	Modifier	D011125
10213492	631	634	APC	Modifier	D011125
10213492	694	697	APC	Modifier	D011125
10213492	715	718	APC	Modifier	D011125
10213492	910	913	APC	Modifier	D011125
10213492	951	960	polyposis	SpecificDisease	D044483
10213492	972	975	APC	Modifier	D011125
10213492	1064	1067	APC	Modifier	D011125
10213492	1121	1124	APC	Modifier	D011125
10213492	1164	1184	attenuated polyposis	SpecificDisease	C538265
10213492	1243	1246	APC	Modifier	D011125
10213492	1345	1348	FAP	Modifier	D011125
10213492	1384	1400	colorectal tumor	Modifier	D015179

1717985|t|Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism.
1717985|a|Piebaldism is an autosomal dominant genetic disorder characterized by cogenital patches of skin and hair from which melanocytes are completely absent. A similar disorder of mouse, dominant white spotting (W), results from mutations of the c-Kit protooncogene, which encodes and receptor for mast/stem cell growth factor. We identified a KIT gene mutation in a proband with classic autosomal dominant piebaldism. This mutation results in a Gly----Arg substitution at codon 664, within the tyrosine kinase domain. This substitution was not seen in any normal individuals and was completely linked to the piebald phenotype in the probands family. Piebaldism in this family thus appears to be the human homologue to dominant white spotting (W) of the mouse.. 
1717985	83	93	piebaldism	SpecificDisease	D016116
1717985	95	105	Piebaldism	SpecificDisease	D016116
1717985	112	147	autosomal dominant genetic disorder	DiseaseClass	D030342
1717985	495	505	piebaldism	SpecificDisease	D016116
1717985	697	704	piebald	Modifier	D016116
1717985	739	749	Piebaldism	SpecificDisease	D016116

8104633|t|An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy.
8104633|a|Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA; EC 3. 1. 6. 8). The 8 ARSA exons and adjacent intron boundaries from a patient with late-infantile metachromatic leukodystrophy were polymerase chain reaction (PCR) amplified in seven discrete reactions. Amplified ARSA exons were analysed for the presence of sequence alterations by single-strand conformation polymorphism analysis, followed by direct sequencing of PCR products. The patient was found to be homozygous for a C-- > T transition in exon IV that results in the substitution of a highly conserved threonine residue at amino acid 274 with a methionine (T274M). Analysis of a further 29 MLD patients revealed the presence of five additional homozygotes for T274M. All 6 T274M homozygotes (representing four families) were of Lebanese descent, and all were known to be the result of consanguineous marriages. The altered amino acid is rigidly conserved among 10 sulfatases from Escherichia coli to humans; therefore, it is most likely that the resultant mutant protein will have little or no enzyme activity. This is consistent with the very low ARSA activity measured in these patients and their uniformly severe clinical presentation 
8104633	60	103	late-infantile metachromatic leukodystrophy	SpecificDisease	D007966
8104633	105	133	Metachromatic leukodystrophy	SpecificDisease	D007966
8104633	135	138	MLD	SpecificDisease	D007966
8104633	146	192	autosomal recessive lysosomal storage disorder	DiseaseClass	D016464
8104633	205	234	deficiency of arylsulfatase A	SpecificDisease	D007966
8104633	326	369	late-infantile metachromatic leukodystrophy	SpecificDisease	D007966
8104633	840	843	MLD	Modifier	D007966

7717396|t|Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes.
7717396|a|Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expression of X-ALD and in their female relatives; these clinical expressions were cerebral childhood ALD, adrenomyeloneuropathy (AMN), and " Addison disease only " (ADO) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5 portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i. e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis 
7717396	26	55	X-linked adrenoleukodystrophy	SpecificDisease	D000326
7717396	143	163	peroxisomal disorder	DiseaseClass	D018901
7717396	165	194	X-linked adrenoleukodystrophy	SpecificDisease	D000326
7717396	196	201	X-ALD	SpecificDisease	D000326
7717396	446	451	X-ALD	SpecificDisease	D000326
7717396	534	537	ALD	SpecificDisease	D000326
7717396	539	560	adrenomyeloneuropathy	SpecificDisease	D000326
7717396	562	565	AMN	SpecificDisease	D000326
7717396	574	594	Addison disease only	Modifier	D000224
7717396	598	601	ADO	Modifier	D000224
7717396	689	692	ALD	SpecificDisease	D000326
7717396	731	736	X-ALD	Modifier	D000326
7717396	882	885	ALD	Modifier	D000326
7717396	966	969	AMN	SpecificDisease	D000326
7717396	1100	1103	ADO	Modifier	D000224
7717396	1349	1352	ALD	SpecificDisease	D000326
7717396	1357	1360	AMN	SpecificDisease	D000326
7717396	1475	1480	X-ALD	SpecificDisease	D000326
7717396	1527	1532	X-ALD	Modifier	D000326

8571951|t|Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias.
8571951|a|Atelosteogenesis type II (AO II) is a neonatally lethal chondrodysplasia whose clinical and histological characteristics resemble those of another chondrodysplasia, the much less severe diastrophic dysplasia (DTD). The similarity suggests a shared pathogenesis involving lesions in the same biochemical pathway and perhaps the same gene. DTD is caused by mutations in the recently identified diastrophic dysplasia sulfate-transporter gene (DTDST). Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro. Together with our recent observation that a third even more severe chondrodysplasia, achondrogenesis type IB, is also caused by mutations in DTDST, these results demonstrate a phenotypic series of three chondrodysplasias of increasing severity caused by lesions in a single sulfate-transporter gene. The severity of the phenotype appears to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein.. 
8571951	0	24	Atelosteogenesis type II	SpecificDisease	C535395
8571951	55	76	diastrophic dysplasia	Modifier	C536170
8571951	160	177	chondrodysplasias	DiseaseClass	D010009
8571951	179	203	Atelosteogenesis type II	SpecificDisease	C535395
8571951	205	210	AO II	SpecificDisease	C535395
8571951	235	251	chondrodysplasia	DiseaseClass	D010009
8571951	326	342	chondrodysplasia	DiseaseClass	D010009
8571951	365	386	diastrophic dysplasia	SpecificDisease	C536170
8571951	388	391	DTD	SpecificDisease	C536170
8571951	517	520	DTD	SpecificDisease	C536170
8571951	571	592	diastrophic dysplasia	Modifier	C536170
8571951	648	652	AOII	Modifier	C535395
8571951	892	908	chondrodysplasia	DiseaseClass	D010009
8571951	1028	1045	chondrodysplasias	DiseaseClass	D010009

10732816|t|Emerin, deficiency of which causes Emery-Dreifuss muscular dystrophy, is localized at the inner nuclear membrane.
10732816|a|X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscle disorder characterized by the clinical triad of progressive wasting of humero-peroneal muscles, early contractures of the elbows, Achilles tendons and postcervical muscles, and cardiac conduction block with a high risk of sudden death. The gene for EDMD on Xq28 encodes a novel protein named emerin that localizes at the nuclear membrane of skeletal, cardiac and smooth muscles and some other non-muscle tissues. To investigate a possible physiological role for emerin, we examined the ultrastructural localization of the protein in human skeletal muscle and HeLa cells, using ultrathin cryosections. We found that the immune-labeled colloidal gold particles were localized on the nucleoplasmic surface of the inner nuclear membrane, but not on the nuclear pore. Emerin stayed on the cytoplasmic surface of the nuclear lamina, even after detergent treatment that solubilizes membrane lipids and washes out membrane proteins. These results suggest that emerin anchors at the inner nuclear membrane through the hydrophobic stretch, and protrudes from the hydrophilic region to the nucleoplasm where it interacts with the nuclear lamina. We speculate that emerin contributes to maintain the nuclear structure and stability, as well as nuclear functions, particularly in muscle tissues that have severe stress with rigorous contraction-relaxation movements and calcium flux.. 
10732816	0	18	Emerin, deficiency	SpecificDisease	D020389
10732816	35	68	Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10732816	114	166	X-linked recessive Emery-Dreifuss muscular dystrophy	SpecificDisease	D020389
10732816	168	172	EDMD	SpecificDisease	D020389
10732816	180	205	inherited muscle disorder	DiseaseClass	D009135+D030342
10732816	257	291	wasting of humero-peroneal muscles	SpecificDisease	D019282
10732816	299	368	contractures of the elbows, Achilles tendons and postcervical muscles	CompositeMention	D003286
10732816	374	398	cardiac conduction block	SpecificDisease	D006327
10732816	419	431	sudden death	SpecificDisease	D003645
10732816	446	450	EDMD	SpecificDisease	D020389

10447258|t|Identification of a common PEX1 mutation in Zellweger syndrome.
10447258|a|The Zellweger spectrum of disease, encompassing Zellweger syndrome and the progressively milder phenotypes of neonatal adrenoleukodystrophy and infantile Refsum disease, is due to a failure to form functional peroxisomes. Cell fusion complementation studies demonstrated that these diseases are genetically heterogeneous, with two-thirds of all patients lying within a single complementation group, CG1. Molecular genetic and cell biology studies have shown that PEX1 is deficient in many CG1 patients. However, previous studies have focused on mildly affected patients and there is still no report of two mutant PEX1 alleles in any Zellweger syndrome patient. Furthermore, mutations in the PMP70 gene have also been identified in two Zellweger syndrome patients from CG1, raising the possibility that CG1 patients may represent a mixture of PEX1-deficient and PMP70-deficient individuals. To address the molecular basis of disease in Zellweger syndrome patients from CG1, we examined all 24 PEX1 exons in four patients, including both patients that have mutations in PMP70. PEX1 mutations were detected in all four patients, including a 1-bp insertion (c. 2097insT) in exon 13 that was present in three of the four patients. Subsequent studies demonstrated that this mutation is present in one-half of all CG1 patients and correlates with the Zellweger syndrome phenotype. As this mutation leads to a loss of protein function its frequency makes it the most common cause of Zellweger syndrome, helping to explain the high percentage of patients that belong to CG1. 
10447258	44	62	Zellweger syndrome	SpecificDisease	D015211
10447258	68	97	Zellweger spectrum of disease	DiseaseClass	D015211
10447258	112	130	Zellweger syndrome	SpecificDisease	D015211
10447258	174	203	neonatal adrenoleukodystrophy	SpecificDisease	OMIM:202370
10447258	208	232	infantile Refsum disease	SpecificDisease	D052919
10447258	697	715	Zellweger syndrome	Modifier	D015211
10447258	799	817	Zellweger syndrome	Modifier	D015211
10447258	999	1017	Zellweger syndrome	Modifier	D015211
10447258	1408	1426	Zellweger syndrome	Modifier	D015211
10447258	1539	1557	Zellweger syndrome	SpecificDisease	D015211

10861282|t|Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis.
10861282|a|Ankylosing spondylitis (AS) is a common and highly familial rheumatic disorder. The sibling recurrence risk ratio for the disease is 63 and heritability assessed in twins > 90%. Although MHC genes, including HLA-B27, contribute only 20-50% of the genetic risk for the disease, no non-MHC gene has yet been convincingly demonstrated to influence either susceptibility to the disease or its phenotypic expression. Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13.1. We performed a linkage study of chromosome 22 in 200 families with AS affected sibling-pairs. Association of alleles of the CYP2D6 gene was examined by both case-control and within-family means. For case-control studies, 617 unrelated individuals with AS (361 probands from sibling-pair and parent-case trio families and 256 unrelated non-familial sporadic cases) and 402 healthy ethnically matched controls were employed. For within-family association studies, 361 families including 161 parent-case trios and 200 affected sibling-pair families were employed. Homozygosity for poor metabolizer alleles was found to be associated with AS. Heterozygosity for the most frequent poor metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. We postulate that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS. 
10861282	60	82	ankylosing spondylitis	SpecificDisease	D013167
10861282	84	106	Ankylosing spondylitis	SpecificDisease	D013167
10861282	108	110	AS	SpecificDisease	D013167
10861282	144	162	rheumatic disorder	DiseaseClass	D012216
10861282	594	596	AS	SpecificDisease	D013167
10861282	780	782	AS	SpecificDisease	D013167
10861282	965	967	AS	SpecificDisease	D013167
10861282	1348	1350	AS	SpecificDisease	D013167
10861282	1476	1478	AS	SpecificDisease	D013167
10861282	1542	1544	AS	SpecificDisease	D013167
10861282	1617	1619	AS	SpecificDisease	D013167
10861282	1738	1740	AS	SpecificDisease	D013167

10746568|t|Molecular analysis of the genotype-phenotype relationship in factor X deficiency.
10746568|a|Factor X deficiency is a rare haemorrhagic condition, normally inherited as an autosomal recessive trait, in which a variable clinical presentation correlates poorly with laboratory phenotype. The factor X (F10) genes of 14 unrelated individuals with factor X deficiency (12 familial and two sporadic cases) were sequenced yielding a total of 13 novel mutations. Family studies were performed in order to distinguish the contributions of individual mutant F10 alleles to the clinical and laboratory phenotypes. Missense mutations were studied by means of molecular modelling, whereas single basepair substitutions in splice sites and the 5 flanking region were examined by in vitro splicing assay and luciferase reporter gene assay respectively. The deletion allele of a novel hexanucleotide insertion/deletion polymorphism in the F10 gene promoter region was shown by reporter gene assay, to reduce promoter activity by approximately 20%. One family manifesting an autosomal dominant pattern of inheritance possessed three clinically affected members who were heterozygous for a splice-site mutation that was predicted to lead to the production of a truncated protein product. A model which accounts for the dominant negative effect of this lesion is presented. Variation in the antigen level of heterozygous relatives of probands was found to be significantly higher between families than within families, consistent with the view that the nature of the F10 lesion (s) segregating in a given family is a prime determinant of the laboratory phenotype. By contrast, no such relationship could be discerned between laboratory phenotype and polymorphism genotype.. 
10746568	61	80	factor X deficiency	SpecificDisease	D005171
10746568	82	101	Factor X deficiency	SpecificDisease	D005171
10746568	112	134	haemorrhagic condition	DiseaseClass	D006474
10746568	333	352	factor X deficiency	SpecificDisease	D005171

10888879|t|Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy.
10888879|a|The gene Prph2 encodes a photoreceptor-specific membrane glycoprotein, peripherin-2 (also known as peripherin/rds), which is inserted into the rims of photoreceptor outer segment discs in a complex with rom-1 (ref. 2). The complex is necessary for the stabilization of the discs, which are renewed constantly throughout life, and which contain the visual pigments necessary for photon capture. Mutations in Prph2 have been shown to result in a variety of photoreceptor dystrophies, including autosomal dominant retinitis pigmentosa and macular dystrophy. A common feature of these diseases is the loss of photoreceptor function, also seen in the retinal degeneration slow (rds or Prph2 Rd2/Rd2) mouse, which is homozygous for a null mutation in Prph2. It is characterized by a complete failure to develop photoreceptor discs and outer segments, downregulation of rhodopsin and apoptotic loss of photoreceptor cells. The electroretinograms (ERGs) of Prph2Rd2/Rd2 mice have greatly diminished a-wave and b-wave amplitudes, which decline to virtually undetectable concentrations by two months. Subretinal injection of recombinant adeno-associated virus (AAV) encoding a Prph2 transgene results in stable generation of outer segment structures and formation of new stacks of discs containing both perpherin-2 and rhodopsin, which in many cases are morphologically similar to normal outer segments. Moreover, the re-establishment of the structural integrity of the photoreceptor layer also results in electrophysiological correction. These studies demonstrate for the first time that a complex ultrastructural cell defect can be corrected both morphologically and functionally by in vivo gene transfer.. 
10888879	60	80	retinal degeneration	Modifier	D012162
10888879	563	588	photoreceptor dystrophies	DiseaseClass	D058499
10888879	600	639	autosomal dominant retinitis pigmentosa	SpecificDisease	D012174
10888879	644	661	macular dystrophy	SpecificDisease	D008268
10888879	754	774	retinal degeneration	Modifier	D012162

2563633|t|Phenylalanine hydroxylase gene haplotypes in Polynesians: evolutionary origins and absence of alleles associated with severe phenylketonuria.
2563633|a|A total of 630 haplotypes for the phenylalanine hydroxylase (PAH) gene locus were established in five groups of Polynesians comprising Samoans, Tongans, Cook Islanders, Maori, and Niueans. Considerable genetic continuity was demonstrated between these widely dispersed populations, since three common haplotypes (4, 1, and 7) constituted over 95% of alleles. A control group of individuals from Southeast Asia shared the same major haplotypes, 4, 1, and 7, with Polynesians. These data provide further support for the theories of genetic homogeneity and of Asian affinities of the Polynesian precursor populations. The absence of severe phenylketonuria (PKU) in both Polynesians and Southeast Asians is consistent with the lack of PAH haplotypes 2 and 3, on which the severe PKU mutants have arisen among Caucasians.. 
2563633	125	140	phenylketonuria	SpecificDisease	D010661
2563633	779	794	phenylketonuria	SpecificDisease	D010661
2563633	796	799	PKU	SpecificDisease	D010661
2563633	917	920	PKU	Modifier	D010661

10557309|t|cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene.
10557309|a|Alveolar rhabdomyosarcoma is an aggressive pediatric cancer of striated muscle characterized in 60% of cases by a t (2; 13) (q35; q14). This results in the fusion of PAX3, a developmental transcription factor required for limb myogenesis, with FKHR, a member of the forkhead family of transcription factors. The resultant PAX3-FKHR gene possesses transforming properties; however, the effects of this chimeric oncogene on gene expression are largely unknown. To investigate the actions of these transcription factors, both Pax3 and PAX3-FKHR were introduced into NIH 3T3 cells, and the resultant gene expression changes were analyzed with a murine cDNA microarray containing 2, 225 elements. We found that PAX3-FKHR but not PAX3 activated a myogenic transcription program including the induction of transcription factors MyoD, Myogenin, Six1, and Slug as well as a battery of genes involved in several aspects of muscle function. Notable among this group were the growth factor gene Igf2 and its binding protein Igfbp5. Relevance of this model was suggested by verification that three of these genes (IGFBP5, HSIX1, and Slug) were also expressed in alveolar rhabdomyosarcoma cell lines. This study utilizes cDNA microarrays to elucidate the pattern of gene expression induced by an oncogenic transcription factor and demonstrates the profound myogenic properties of PAX3-FKHR in NIH 3T3 cells.. 
10557309	105	130	Alveolar rhabdomyosarcoma	SpecificDisease	D018232
10557309	148	183	pediatric cancer of striated muscle	SpecificDisease	D019042
10557309	1254	1279	alveolar rhabdomyosarcoma	Modifier	D018232

3032521|t|Re-evaluation of the sublocalization of esterase D and its relation to the retinoblastoma locus by in situ hybridization.
3032521|a|In situ hybridization of a cDNA probe for the esterase D gene (ESD) was carried out on human chromosomes. The probe hybridized most strongly to 13q14. 2 and 13q14. 3. This observation raises doubts concerning the most recently published assignment of ESD to 13q14. 1. A deletion in an individual with retinoblastoma was reported to separate the closely linked ESD and retinoblastoma (RB1) loci, placing ESD proximal to RB1. Quantitative in situ hybridization studies of this deletion do not confirm this interpretation. Rather, they suggest that ESD is missing from the deleted chromosome 13 and duplicated on the normal homolog. From these findings, we conclude that the deletion in this individual cannot be used to determine the orientation nor the sublocalization of ESD and RB1 within the 13q14 region. 
3032521	75	89	retinoblastoma	Modifier	D012175
3032521	423	437	retinoblastoma	SpecificDisease	D012175
3032521	490	504	retinoblastoma	Modifier	D012175

10612394|t|The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder.
10612394|a|We show that hypomorphic mutations in hMRE11, but not in ATM, are present in certain individuals with an ataxia-telangiectasia-like disorder (ATLD). The cellular features resulting from these hMRE11 mutations are similar to those seen in A-T as well as NBS and include hypersensitivity to ionizing radiation, radioresistant DNA synthesis, and abrogation of ATM-dependent events, such as the activation of Jun kinase following exposure to gamma irradiation. Although the mutant hMre11 proteins retain some ability to interact with hRad50 and Nbs1, formation of ionizing radiation-induced hMre11 and Nbs1 foci was absent in hMRE11 mutant cells. These data demonstrate that ATM and the hMre11/hRad50/Nbs1 protein complex act in the same DNA damage response pathway and link hMre11 to the complex pathology of A-T.. 
10612394	81	116	ataxia-telangiectasia-like disorder	SpecificDisease	OMIM:604391
10612394	223	258	ataxia-telangiectasia-like disorder	SpecificDisease	OMIM:604391
10612394	260	264	ATLD	SpecificDisease	OMIM:604391
10612394	356	359	A-T	SpecificDisease	D001260
10612394	371	374	NBS	SpecificDisease	D049932
10612394	387	425	hypersensitivity to ionizing radiation	SpecificDisease	D004194
10612394	924	927	A-T	SpecificDisease	D001260

2450401|t|Duchenne muscular dystrophy gene expression in normal and diseased human muscle.
2450401|a|A probe for the 5 end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD. Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion. In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers.. 
2450401	0	27	Duchenne muscular dystrophy	Modifier	D020388
2450401	110	137	Duchenne muscular dystrophy	Modifier	D020388
2450401	139	142	DMD	Modifier	D020388
2450401	268	271	DMD	SpecificDisease	D020388
2450401	408	411	DMD	Modifier	D020388

6086495|t|Localisation of the Becker muscular dystrophy gene on the short arm of the X chromosome by linkage to cloned DNA sequences.
6086495|a|A linkage study in 30 Becker muscular dystrophy (BMD) kindreds using three cloned DNA sequences from the X chromosome which demonstrate restriction fragment length polymorphisms (RFLPs), suggests that the BMD gene is located on the short arm of the X chromosome, in the p21 region. The genes for Becker and Duchenne dystrophies must therefore be closely linked, if not allelic, and any future DNA probes found to be of practical use in one disorder should be equally applicable to the other. The linkage analysis also provides data on the frequency of recombination along the short arm of the X chromosome, and across the centromeric region.. 
6086495	20	45	Becker muscular dystrophy	Modifier	C537666
6086495	146	171	Becker muscular dystrophy	SpecificDisease	C537666
6086495	173	176	BMD	SpecificDisease	C537666
6086495	329	332	BMD	Modifier	C537666
6086495	420	451	Becker and Duchenne dystrophies	CompositeMention	D020388|C537666

10830915|t|Age of the intronic GAA triplet repeat expansion mutation in Friedreich ataxia.
10830915|a|Friedreich ataxia (FRDA), the most frequently inherited ataxia, is due in the vast majority of cases to a large expansion of an intronic GAA repeat. Using linkage disequilibrium analysis based on haplotype data of seven polymorphic markers close to the frataxin gene, the age of FRDA founding mutational event (s) is estimated to be at least 682 +/-203 generations (95% confidence interval  564-801 g), a dating which is consistent with little or no negative selection and provides further evidence for an ancient spread of a pre-mutation (at-risk alleles) in western Europe.. 
10830915	61	78	Friedreich ataxia	SpecificDisease	D005621
10830915	80	97	Friedreich ataxia	SpecificDisease	D005621
10830915	99	103	FRDA	SpecificDisease	D005621
10830915	126	142	inherited ataxia	DiseaseClass	D013132
10830915	359	363	FRDA	Modifier	D005621

10556298|t|The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region.
10556298|a|Prader-Willi syndrome (PWS) is a complex neurogenetic disorder. The phenotype is likely to be a contiguous gene syndrome involving genes which are paternally expressed only, located in the human 15q11-q13 region. Four mouse models of PWS have been reported but these do not definitively allow the delineation of the critical region and the associated genes involved in the aetiology of PWS. Moreover, targeted mutagenesis of mouse homologues of the human candidate PWS genes does not appear to result in any of the features of PWS. Therefore, the isolation of new genes in this region remains crucial for a better understanding of the molecular basis of PWS. In this manuscript, we report the characterization of MAGEL2 and its mouse homologue Magel2. These are located in the human 15q11-q13 and mouse 7C regions, in close proximity to NDN/Ndn. By northern blot analysis we did not detect any expression of MAGEL2/Magel2 but by RT-PCR analysis, specific expression was detected in fetal and adult brain and in placenta. Both genes are intronless with tandem direct repeat sequences contained within a CpG island in the 5-untranscribed region. The transcripts encode putative proteins that are homologous to the MAGE proteins and NDN. Moreover, MAGEL2/Magel2 are expressed only from the paternal allele in brain, suggesting a potential role in the aetiology of PWS and its mouse model, respectively.. 
10556298	89	101	Prader-Willi	Modifier	D011218
10556298	110	131	Prader-Willi syndrome	SpecificDisease	D011218
10556298	133	136	PWS	SpecificDisease	D011218
10556298	151	172	neurogenetic disorder	DiseaseClass	D020271
10556298	206	230	contiguous gene syndrome	DiseaseClass	D025063
10556298	344	347	PWS	SpecificDisease	D011218
10556298	496	499	PWS	SpecificDisease	D011218
10556298	575	578	PWS	Modifier	D011218
10556298	637	640	PWS	SpecificDisease	D011218
10556298	764	767	PWS	SpecificDisease	D011218
10556298	1471	1474	PWS	SpecificDisease	D011218

1361100|t|Multiple origins for phenylketonuria in Europe.
1361100|a|Phenylketonuria (PKU), a disorder of amino acid metabolism prevalent among Caucasians and other ethnic groups, is caused primarily by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). PKU is a highly heterogeneous disorder, with more than 60 molecular lesions identified in the PAH gene. The haplotype associations, relative frequencies, and distributions of five prevalent PAH mutations (R158Q, R261Q, IVS10nt546, R408W, and IVS12n1) were established in a comprehensive European sample population and subsequently were examined to determine the potential roles of several genetic mechanisms in explaining the present distribution of the major PKU alleles. Each of these five mutations was strongly associated with only one of the more than 70 chromosomal haplotypes defined by eight RFLPs in or near the PAH gene. These findings suggest that each of these mutations arose through a single founding event that occurred within time periods ranging from several hundred to several thousand years ago. From the significant differences observed in the relative frequencies and distributions of these five alleles throughout Europe, four of these putative founding events could be localized to specific ethnic subgroups. Together, these data suggest that there were multiple, geographically and ethnically distinct origins for PKU within the European population.. 
1361100	21	36	phenylketonuria	SpecificDisease	D010661
1361100	48	63	Phenylketonuria	SpecificDisease	D010661
1361100	65	68	PKU	SpecificDisease	D010661
1361100	73	106	disorder of amino acid metabolism	DiseaseClass	D000592
1361100	184	242	deficiency of the hepatic enzyme phenylalanine hydroxylase	SpecificDisease	OMIM:261600
1361100	250	253	PKU	SpecificDisease	D010661
1361100	710	713	PKU	Modifier	D010661
1361100	1388	1391	PKU	SpecificDisease	D010661

10724160|t|Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein.
10724160|a|The Rho-family GTPase, Cdc42, can regulate the actin cytoskeleton through activation of Wiskott-Aldrich syndrome protein (WASP) family members. Activation relieves an autoinhibitory contact between the GTPase-binding domain and the carboxy-terminal region of WASP proteins. Here we report the autoinhibited structure of the GTPase-binding domain of WASP, which can be induced by the C-terminal region or by organic co-solvents. In the autoinhibited complex, intramolecular interactions with the GTPase-binding domain occlude residues of the C terminus that regulate the Arp2/3 actin-nucleating complex. Binding of Cdc42 to the GTPase-binding domain causes a dramatic conformational change, resulting in disruption of the hydrophobic core and release of the C terminus, enabling its interaction with the actin regulatory machinery. These data show that intrinsically unstructured peptides such as the GTPase-binding domain of WASP can be induced into distinct structural and functional states depending on context.. 
10724160	48	72	Wiskott-Aldrich syndrome	Modifier	D014923
10724160	170	194	Wiskott-Aldrich syndrome	Modifier	D014923

1733838|t|Localisation of the gene for Norrie disease to between DXS7 and DXS426 on Xp.
1733838|a|A highly informative microsatellite marker, DXS426, which maps proximal to DXS7 in the interval Xp11. 4-Xp11 4-Xp11. 23, has been used to refine further the localisation of the gene for Norrie disease (NDP). The results from a multiply informative crossover localize the NDP gene proximal to DXS7. In conjunction with information from 2 NDP patients who have a deletion for DXS7 but not for DSX426, our data indicate that the NDP gene lies between DXS7 and DXS426 on proximal Xp.
1733838	29	43	Norrie disease	SpecificDisease	C537849
1733838	264	278	Norrie disease	SpecificDisease	C537849
1733838	280	283	NDP	SpecificDisease	C537849
1733838	349	352	NDP	Modifier	C537849
1733838	415	418	NDP	Modifier	C537849
1733838	504	507	NDP	Modifier	C537849

7479827|t|Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood.
7479827|a|beta-Oxidation of long-chain fatty acids provides the major source of energy in the heart. Defects in enzymes of the beta-oxidation pathway cause sudden, unexplained death in childhood, acute hepatic encephalopathy or liver failure, skeletal myopathy, and cardiomyopathy. Very-long-chain acyl-CoA dehydrogenase [VLCAD; very-long-chain-acyl-CoA  (acceptor) 2, 3-oxidoreductase, EC 1. 3 3. 99 99. 13] catalyzes the first step in beta-oxidation. We have isolated the human VLCAD cDNA and gene and determined the complete nucleotide sequences. Polymerase chain reaction amplification of VLCAD mRNA and genomic exons defined the molecular defects in two patients with VLCAD deficiency who presented with unexplained cardiac arrest and cardiomyopathy. In one, a homozygous mutation in the consensus dinucleotide of the donor splice site (g + 1-- > a) was associated with universal skipping of the prior exon (exon 11). The second patient was a compound heterozygote, with a missense mutation, C1837-- > T, changing the arginine at residue 613 to tryptophan on one allele and a single base deletion at the intron-exon 6 boundary as the second mutation. This initial delineation of human mutations in VLCAD suggests that VLCAD deficiency reduces myocardial fatty acid beta-oxidation and energy production and is associated with cardiomyopathy and sudden death in childhood. 
7479827	39	88	very-long-chain acyl-CoA dehydrogenase deficiency	SpecificDisease	C536353
7479827	97	111	cardiomyopathy	SpecificDisease	D009202
7479827	116	128	sudden death	SpecificDisease	D003645
7479827	289	314	sudden, unexplained death	SpecificDisease	D003645
7479827	335	357	hepatic encephalopathy	SpecificDisease	D006501
7479827	361	374	liver failure	SpecificDisease	D017093
7479827	376	393	skeletal myopathy	SpecificDisease	D009135
7479827	399	413	cardiomyopathy	SpecificDisease	D009202
7479827	806	822	VLCAD deficiency	SpecificDisease	C536353
7479827	854	868	cardiac arrest	SpecificDisease	D006323
7479827	873	887	cardiomyopathy	SpecificDisease	D009202
7479827	1356	1372	VLCAD deficiency	SpecificDisease	C536353
7479827	1463	1477	cardiomyopathy	SpecificDisease	D009202
7479827	1482	1494	sudden death	SpecificDisease	D003645

1577476|t|An error in dystrophin mRNA processing in golden retriever muscular dystrophy, an animal homologue of Duchenne muscular dystrophy.
1577476|a|Golden retriever muscular dystrophy (GRMD) is a spontaneous, X-linked, progressively fatal disease of dogs and is also a homologue of Duchenne muscular dystrophy (DMD). Two-thirds of DMD patients carry detectable deletions in their dystrophin gene. The defect underlying the remaining one-third of DMD patients is undetermined. Analysis of the canine dystrophin gene in normal and GRMD dogs has failed to demonstrate any detectable loss of exons. Here, we have demonstrated a RNA processing error in GRMD that results from a single base change in the 3 consensus splice site of intron 6. The seventh exon is then skipped, which predicts a termination of the dystrophin reading frame within its N-terminal domain in exon 8. This is the first example of dystrophin deficiency caused by a splice-site mutation.. 
1577476	42	77	golden retriever muscular dystrophy	SpecificDisease	D009136
1577476	102	129	Duchenne muscular dystrophy	SpecificDisease	D020388
1577476	131	166	Golden retriever muscular dystrophy	SpecificDisease	D009136
1577476	168	172	GRMD	SpecificDisease	D009136
1577476	265	292	Duchenne muscular dystrophy	SpecificDisease	D020388
1577476	294	297	DMD	SpecificDisease	D020388
1577476	314	317	DMD	Modifier	D020388
1577476	429	432	DMD	Modifier	D020388
1577476	512	516	GRMD	Modifier	D009136
1577476	631	635	GRMD	SpecificDisease	D009136
1577476	883	904	dystrophin deficiency	SpecificDisease	OMIM:310200

1981994|t|Serum amyloid A and P protein genes in familial Mediterranean fever.
1981994|a|Two recent studies have suggested the involvement of serum amyloid A (SAA) and P (APCS) genes in familial Mediterranean fever (MEF). To test the role of SAA and APCS in MEF and MEF-amyloidosis, we studied 17 informative families (15 Armenians, 2 non-Ashkenazi Jews) and 8 MEF patients with amyloidosis using a candidate gene approach. No evidence for any MEF-associated polymorphism was found in any of the 41 Armenian and Jewish MEF patients tested. Our family studies allowed us to rule out tight linkage between SAA and MEF (lod score = -2. 16, theta less than or equal to 0. 06). For APCS we found that the allele frequency in the MEF-amyloidosis patients was similar to that in 18 unrelated MEF patients without amyloidosis and their 33 healthy parents. 
1981994	39	67	familial Mediterranean fever	SpecificDisease	D010505
1981994	166	194	familial Mediterranean fever	SpecificDisease	D010505
1981994	196	199	MEF	SpecificDisease	D010505
1981994	238	241	MEF	SpecificDisease	D010505
1981994	246	261	MEF-amyloidosis	SpecificDisease	D000686|D010505
1981994	341	344	MEF	Modifier	D010505
1981994	359	370	amyloidosis	DiseaseClass	D000686
1981994	424	427	MEF	Modifier	D010505
1981994	499	502	MEF	Modifier	D010505
1981994	592	595	MEF	SpecificDisease	D010505
1981994	704	719	MEF-amyloidosis	Modifier	D000686|D010505
1981994	765	768	MEF	Modifier	D010505
1981994	786	797	amyloidosis	DiseaseClass	D000686

1201235|t|Glucose-6-phosphate dehydrogenase variants from Italian subjects associated with severe neonatal jaundice.
1201235|a|Screening for the G6PD deficiency was carried out at the Maternity Division of the Galliera Hospital in Genoa, Italy. Two groups of subjects with hyperbilirubinaemia of non-immunological origin were examined  (a) 302 newborn babies of Sardinian extraction (on cord blood) and (b) 201 newborn babies of south Italian ancestry (on peripheral blood). Among 503 subjects, 43 showed an enzyme deficiency; in 39 the defect was of the Mediterranean type. In one case, previously described, the enzyme was of the A- type. In the remaining cases three different variants were identified. In the present work these three cases, each with severe neonatal jaundice, are reported. Their parents originated from Calabria, from Sardinia and from Sicily. The abnormal enzymes are respectively designated as GdDcbrousse-like, GdGallura and GdAgrigento.. 
1201235	81	105	severe neonatal jaundice	SpecificDisease	D007567
1201235	125	140	G6PD deficiency	SpecificDisease	D005955
1201235	253	272	hyperbilirubinaemia	DiseaseClass	D006932
1201235	735	759	severe neonatal jaundice	SpecificDisease	D007567

1351034|t|Loss of normal allele of the APC gene in an adrenocortical carcinoma from a patient with familial adenomatous polyposis.
1351034|a|Endocrine neoplasms have been reported occasionally in patients with familial adenomatous polyposis (FAP). An adrenocorotical carcinoma was studied in a patient with a family history of FAP. Loss of heterozygosity (LOH) in the region close to the adenomatous polyposis coli (APC) gene was detected in this carcinoma, and evidence was obtained that there was a loss of the normal allele of the APC gene. This is the first demonstration of LOH at the APC locus in adrenocortical tumors. The present results and our previous data on LOH in a recurring desmoid tumor suggest that the heterozygous mutant/wild-type condition of the APC gene may give rise to benign tumors, and that functional loss of this gene leads to development of tumors not only in the colon but also in other various parts of the body in FAP patients.. 
1351034	29	32	APC	Modifier	D011125
1351034	44	68	adrenocortical carcinoma	SpecificDisease	D018268
1351034	89	119	familial adenomatous polyposis	SpecificDisease	D011125
1351034	121	140	Endocrine neoplasms	DiseaseClass	D004701
1351034	190	220	familial adenomatous polyposis	SpecificDisease	D011125
1351034	222	225	FAP	SpecificDisease	D011125
1351034	231	256	adrenocorotical carcinoma	SpecificDisease	D018268
1351034	307	310	FAP	SpecificDisease	D011125
1351034	368	394	adenomatous polyposis coli	Modifier	D011125
1351034	396	399	APC	Modifier	D011125
1351034	427	436	carcinoma	DiseaseClass	D002277
1351034	514	517	APC	Modifier	D011125
1351034	570	573	APC	Modifier	D011125
1351034	583	604	adrenocortical tumors	SpecificDisease	D018268
1351034	670	683	desmoid tumor	SpecificDisease	C535944
1351034	748	751	APC	Modifier	D011125
1351034	774	787	benign tumors	DiseaseClass	D009369
1351034	851	857	tumors	DiseaseClass	D009369
1351034	927	930	FAP	Modifier	D011125

7191069|t|Heterozygous C2-deficiency and myasthenia gravis.
7191069|a|Complement deficiency states in myasthenia gravis (MG) have not been reported previously. We describe a 19-year-old woman with typical MG and heterozygous C2 deficiency, along with HLA typing of the patient and her immediate family.. 
7191069	13	26	C2-deficiency	SpecificDisease	OMIM:217000
7191069	31	48	myasthenia gravis	SpecificDisease	D009157
7191069	50	71	Complement deficiency	Modifier	D007153
7191069	82	99	myasthenia gravis	SpecificDisease	D009157
7191069	101	103	MG	SpecificDisease	D009157
7191069	185	187	MG	SpecificDisease	D009157
7191069	205	218	C2 deficiency	SpecificDisease	OMIM:217000

10472529|t|Large heterozygous deletion masquerading as homozygous missense mutation: a pitfall in diagnostic mutation analysis.
10472529|a|The clinical use of molecular analyses in recessive disorders relies on the exact characterization of both mutant alleles in the affected patient. This can be problematic when only part of the gene is examined or when relevant DNA alterations are not recognized by standard methods. We present a child in whom phenylketonuria was apparently caused by homozygosity for the mutation E390G in exon 11 of the phenylalanine hydroxylase (PAH) gene. However, the clinical severity of the disease was not quite as mild as expected, the mutation was not identified in the father despite confirmed paternity, and the paternal allele showed a highly unusual pattern of polymorphic markers in the PAH gene. Presence of a large deletion involving exons 9, 10 and 11 of the phenylalanine hydroxylase gene was confirmed by long-range PCR. Diagnostic DNA analyses should include a comprehensive examination of the whole relevant gene in the patient and confirmation of carrier status in both parents.. 
10472529	159	178	recessive disorders	DiseaseClass	D030342
10472529	427	442	phenylketonuria	SpecificDisease	D010661

2912069|t|Two point mutations are responsible for G6PD polymorphism in Sardinia.
2912069|a|The human X-linked gene encoding glucose 6-phosphate dehydrogenase (G6PD) is highly polymorphic; more than 300 G6PD variants have been identified. G6PD deficiency in different geographical areas appears to have arisen through independent mutational events, but within the same population it may also be heterogeneous. One example is the island of Sardinia, where careful clinical and biochemical studies have identified four different G6PD variants. We cloned and sequenced the four G6PD variants from Sardinia and found that only two mutations are responsible for G6PD deficiency in this area  one mutation is the cause of the G6PD Seattle-like phenotype, a milder form of G6PD deficiency; the other mutation is responsible for all forms of very severe G6PD deficiency in Sardinia and, possibly, in the Mediterranean.. 
2912069	218	233	G6PD deficiency	SpecificDisease	D005955
2912069	636	651	G6PD deficiency	SpecificDisease	D005955
2912069	699	726	G6PD Seattle-like phenotype	SpecificDisease	D005955
2912069	745	760	G6PD deficiency	SpecificDisease	D005955
2912069	825	840	G6PD deficiency	SpecificDisease	D005955

6902670|t|Familial discoid lupus erythematosus associated with heterozygote C2 deficiency.
6902670|a|Two siblings with chronic discoid lupus erythematosus and several family members were found with heterozygous C2 deficiency. An association with histocompatibility markers HLA-B18 and HLA-Dw2 was demonstrated, and the slow allotype of factor B was present. Linkage studies in this family suggested a close linkage between the C2 deficiency gene and genes coding for B18, Dw2, and BfS antigens. One HLA-ACB/DBf recombinant was observed showing closer linkage between HLA-D and Bf than between HLA-B and Bf.. 
6902670	0	36	Familial discoid lupus erythematosus	SpecificDisease	D008179
6902670	66	79	C2 deficiency	SpecificDisease	OMIM:217000
6902670	99	134	chronic discoid lupus erythematosus	SpecificDisease	D008179
6902670	191	204	C2 deficiency	SpecificDisease	OMIM:217000
6902670	407	420	C2 deficiency	Modifier	OMIM:217000

7545954|t|A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
7545954|a|A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.. 
7545954	27	52	breast and ovarian cancer	Modifier	D061325
7545954	165	190	breast and ovarian cancer	CompositeMention	D061325
7545954	846	871	breast and ovarian cancer	Modifier	D061325
7545954	944	957	breast cancer	Modifier	D001943

8198128|t|Recombinations in individuals homozygous by descent localize the Friedreich ataxia locus in a cloned 450-kb interval.
8198128|a|The locus for Friedreich ataxia (FRDA), a severe neurodegenerative disease, is tightly linked to markers D9S5 and D9S15, and analysis of rare recombination events has suggested the order cen-FRDA-D9S5-D9S15-qter. We report here the construction of a YAC contig extending 800 kb centromeric to D9S5 and the isolation of five new microsatellite markers from this region. In order to map these markers with respect to the FRDA locus, all within a 1-cM confidence interval, we sought to increase the genetic information of available FRDA families by considering homozygosity by descent and association with founder haplotypes in isolated populations. This approach allowed us to identify one phase-known recombination and one probable historic recombination on haplotypes from Reunion Island patients, both of which place three of the five markers proximal to FRDA. This represents the first identification of close FRDA flanking markers on the centromeric side. The two other markers allowed us to narrow the breakpoint of a previously identified distal recombination that is > 180 kb from D9S5 (26P). Taken together, the results place the FRDA locus in a 450-kb interval, which is small enough for direct search of candidate genes. A detailed rare cutter restriction map and a cosmid contig covering this interval were constructed and should facilitate the search of genes in this region.. 
8198128	65	82	Friedreich ataxia	SpecificDisease	D005621
8198128	132	149	Friedreich ataxia	SpecificDisease	D005621
8198128	151	155	FRDA	SpecificDisease	D005621
8198128	167	192	neurodegenerative disease	DiseaseClass	D019636
8198128	537	541	FRDA	Modifier	D005621
8198128	647	651	FRDA	Modifier	D005621
8198128	974	978	FRDA	SpecificDisease	D005621
8198128	1030	1034	FRDA	Modifier	D005621
8198128	1255	1259	FRDA	Modifier	D005621

2220826|t|Further mapping of an ataxia-telangiectasia locus to the chromosome 11q23 region.
2220826|a|We recently mapped the gene for ataxia-telangiectasia group A (ATA) to chromosome 11q22-23 by linkage analysis, using the genetic markers THY1 and pYNB3. 12 (D11S144). The most likely order was cent-AT-S144-THY1. The present paper describes further mapping of the AT locus by means of a panel of 10 markers that span approximately 60 cM in the 11q22-23 region centered around S144 and THY1. Location scores indicate that three contiguous subsegments within the [S144-THY1] segment, as well as three contiguous segments telomeric to THY1, are each unlikely to contain the AT locus, while the more centromeric [STMY-S144] segment is most likely to contain the AT locus. These data, together with recent refinements in the linkage and physical maps of 11q22-23, place the AT locus at 11q23. 
2220826	22	43	ataxia-telangiectasia	Modifier	D001260
2220826	114	135	ataxia-telangiectasia	Modifier	D001260
2220826	346	348	AT	Modifier	D001260
2220826	653	655	AT	Modifier	D001260
2220826	740	742	AT	Modifier	D001260
2220826	851	853	AT	Modifier	D001260

1311721|t|Proliferation-related expression of p19/nm23 nucleoside diphosphate kinase.
1311721|a|High level expression of the nm23-H1 gene, which encodes for a nucleoside diphosphate kinase, has been found to correlate with diminished metastasis in some tumors but not in others. We have previously identified the protein product of the nm23-H1 gene in two-dimensional electrophoretic gels and have designated it p19/nm23. In neuroblastoma, higher levels of p19/nm23, which are associated with amplification of the N-myc oncogene, large tumor mass, and metastasis, were observed in advanced stage tumors compared with limited stage disease. Because of the variable expression of nm23-H1 in different tumors, we have investigated the relationship between amounts of the protein and cell proliferation. The levels of p19/nm23 were compared between resting and mitotically stimulated normal human PBLs and in leukemia cells. The amount of p19/nm23 increased in normal lymphocytes in response to mitotic stimulation and paralleled the increase in DNA synthesis. In leukemia cells obtained from patients with different subtypes of acute leukemia, p19/nm23 levels were also increased relative to resting normal lymphocytes. Treatment of mitotically stimulated lymphocytes with cyclosporin, which inhibits proliferation, blocked the increase in p19/nm23; treatment of the leukemia cell line HL-60 with dimethylsulfoxide, which induces terminal differentiation, resulted in diminished levels of p19/nm23. Our data therefore provide evidence that nm23-H1 expression is related to cell proliferative activity.. 
1311721	233	239	tumors	DiseaseClass	D009369
1311721	405	418	neuroblastoma	SpecificDisease	D009447
1311721	516	521	tumor	Modifier	D009369
1311721	576	582	tumors	DiseaseClass	D009369
1311721	679	685	tumors	DiseaseClass	D009369
1311721	885	893	leukemia	Modifier	D007938
1311721	1040	1048	leukemia	Modifier	D007938
1311721	1105	1119	acute leukemia	SpecificDisease	D007938
1311721	1344	1352	leukemia	Modifier	D007938

116187|t|Carrier detection of pyruvate carboxylase deficiency in fibroblasts and lymphocytes.
116187|a|Pyruvate carboxylase (E. C. 6. 4. 1. 1) activity was determined in the circulating peripheral lymphocytes and cultured skin fibroblasts from the family of a patient with hepatic, cerebral, renal cortical, leukocyte, and fibroblast pyruvate carboxylase deficiency (PC Portland deficiency). Lymphocyte activities were  mother, 33--39%; father, 11--29%; brother, 82--103%; and sister, 38--48% of the lowest normal. Fibroblasts from the patients mother and father had 42 and 34%, respectively, of the activity of the lowest normal. These data demonstrate that the disease is inherited in an autosomal recessive manner and that lymphocytes and fibroblasts can be used to detect carriers. Neither pyruvate carboxylase nor mitochondrial PEPCK activity in lymphocytes was increased by a 21-hr fast. 
116187	21	52	pyruvate carboxylase deficiency	SpecificDisease	D015324
116187	316	347	pyruvate carboxylase deficiency	SpecificDisease	D015324
116187	349	371	PC Portland deficiency	SpecificDisease	D015324

2852474|t|Complex glycerol kinase deficiency: molecular-genetic, cytogenetic, and clinical studies of five Japanese patients.
2852474|a|Five male Japanese patients with complex glycerol kinase deficiency (CGKD) and their relatives were studied clinically, cytogenetically, and molecular-genetically. All patients had muscular dystrophy or muscle weakness, mental retardation, congenital adrenal hypoplasia, and glycerol kinase deficiency. High-resolution GTG-banded chromosomes showed a microdeletion in the Xp21 region in all four patients examined and in all five mothers. Southern hybridizations, after digestions by restriction endonucleases, with various cloned DNAs (D2, 99-6, B24, C7, L1-4, cDMD13-14, J66-HI, P20, J-Bir, ERT87-30, ERT87-15, ERT87-8, ERT87-1, XJ-1. 1, 754, cx5. 7, and OTC-1) that are located around Xp21 also showed a deletion in the genome of all patients and mothers. Although the deletion differed in size among patients, a segment commonly absent was located between the genomic sequences corresponding to L1-4 and cDMD13-14. This finding indicated that the gene coding for glycerol kinase (GK) is located within this segment. A comparison of the clinical manifestations of the present five patients and reported CGKD or Duchenne muscular dystrophy (DMD) patients with DNA deletion suggests the existence of a certain gene responsible for gonadotropin deficiency (GTD). The result of the present study and results of previous studies suggest that genes for ornithine transcarbamylase (OTC), DMD, and GK and putative genes responsible for congenital adrenal hypoplasia (AHC) and GTD are arranged from telomere to centromere as pter--GTD--AHC--GK--DMD--OTC--cen 
2852474	0	34	Complex glycerol kinase deficiency	SpecificDisease	C538138
2852474	149	183	complex glycerol kinase deficiency	SpecificDisease	C538138
2852474	185	189	CGKD	SpecificDisease	C538138
2852474	297	315	muscular dystrophy	DiseaseClass	D009136
2852474	319	334	muscle weakness	DiseaseClass	D018908
2852474	336	354	mental retardation	DiseaseClass	D008607
2852474	356	385	congenital adrenal hypoplasia	SpecificDisease	D000312
2852474	391	417	glycerol kinase deficiency	DiseaseClass	C538138
2852474	1222	1226	CGKD	Modifier	C538138
2852474	1230	1257	Duchenne muscular dystrophy	Modifier	D020388
2852474	1259	1262	DMD	Modifier	D020388
2852474	1348	1371	gonadotropin deficiency	SpecificDisease	C535764
2852474	1373	1376	GTD	SpecificDisease	C535764
2852474	1500	1503	DMD	SpecificDisease	D020388
2852474	1547	1576	congenital adrenal hypoplasia	SpecificDisease	D000312
2852474	1578	1581	AHC	SpecificDisease	D000312
2852474	1587	1590	GTD	SpecificDisease	C535764

7726234|t|Duchenne muscular dystrophy and myotonic dystrophy in the same patient.
7726234|a|We report on the first patient identified with myotonic dystrophy and Duchenne muscular dystrophy (DMD). The family of the propositus had a strong history of myotonic dystrophy, and there was an intrafamilial pathological expansion of the responsible CTG repeat between the mildly affected mother (160 repeats; normal 27 repeats) and her more severely affected son (650 repeats), and his sister (650 repeats). The propositus was an isolated case of Duchenne muscular dystrophy with marked dystrophin deficiency in muscle biopsy. The patient was still ambulatory post age 16. Myotonic dystrophy could interfere to some extent with the progression of Duchenne dystrophy. However, other interpretations are possible. Twelve percent of dystrophin revertant fibers as observed by immunohistochemistry could be sufficient to ameliorate typical DMD clinical severity, or the patient may present a somatic mosaic. The pathophysiological interactions of these two unlinked disorders are discussed at the clinical and histopathological levels.. 
7726234	0	27	Duchenne muscular dystrophy	SpecificDisease	D020388
7726234	32	50	myotonic dystrophy	SpecificDisease	D009223
7726234	119	137	myotonic dystrophy	SpecificDisease	D009223
7726234	142	169	Duchenne muscular dystrophy	SpecificDisease	D020388
7726234	171	174	DMD	SpecificDisease	D020388
7726234	230	248	myotonic dystrophy	SpecificDisease	D009223
7726234	521	548	Duchenne muscular dystrophy	SpecificDisease	D020388
7726234	561	582	dystrophin deficiency	SpecificDisease	OMIM:310200
7726234	647	665	Myotonic dystrophy	SpecificDisease	D009223
7726234	721	739	Duchenne dystrophy	SpecificDisease	D020388
7726234	910	913	DMD	Modifier	D020388

8500791|t|Autosomal recessive transmission of hemophilia A due to a von Willebrand factor mutation.
8500791|a|The differential diagnosis of the genetic bleeding disorders, hemophilia A and von Willebrand disease, is occasionally confounded by the close molecular relationship of coagulation factor VIII and von Willebrand factor (vWF). This report describes the autosomal inheritance of a hemophilia A phenotype due to a mutation of vWF that results in defective factor VIII binding. The proband was a female patient with low levels of factor VIII activity. Polymerase chain reaction (PCR) amplification and DNA sequencing were employed to examine exons encoding the putative factor VIII binding domain of vWF. The patient was found to be homozygous for a single point mutation causing a Thr-- > Met substitution at amino acid position 28 in the mature vWF subunit. The phenotypic expression of the mutation was determined to be recessive because heterozygous family members were clinically unaffected. Recombinant vWF containing the observed amino acid substitution was expressed in COS-1 cells. The mutant vWF was processed and secreted normally, and was functionally equivalent to wild-type vWF in its ability to bind to platelets. However, the mutant failed to bind factor VIII, demonstrating that the mutation was functionally related to the observed hemophilia phenotype. The family we describe demonstrates the recessive inheritance of a recently recognized class of genetic bleeding disorders, we call " autosomal hemophilia. " We conclude that vWF mutation may be an under recognized cause of hemophilia, especially in cases where the inheritance pattern is not consistent with X-linked transmission. 
8500791	36	48	hemophilia A	SpecificDisease	D006467
8500791	58	72	von Willebrand	Modifier	D014842
8500791	124	150	genetic bleeding disorders	DiseaseClass	D025861
8500791	152	164	hemophilia A	SpecificDisease	D006467
8500791	169	191	von Willebrand disease	SpecificDisease	D014842
8500791	287	301	von Willebrand	Modifier	D014842
8500791	369	381	hemophilia A	Modifier	D006467
8500791	1336	1346	hemophilia	Modifier	D006467|D002836
8500791	1502	1512	hemophilia	SpecificDisease	D006467|D002836
8500791	1582	1592	hemophilia	SpecificDisease	D006467|D002836

10737980|t|Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously described.
10737980|a|X-linked Adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. It mainly involves the nervous system white matter, adrenal cortex and testes. Several distinct clinical phenotypes are known. The principal biochemical abnormality is the accumulation of saturated very-long-chain fatty acids (VLCFAs  > C22  0, mainly C26  0), which is due to impaired capacity for beta-oxidation in peroxisomes. Diagnosis is usually based on the VLCFA levels in plasma or cultured skin fibroblasts in both patients and carriers. In 0. 1% of affected males, however, the plasma C26  0 level is borderline normal, and 15% of obligate female carriers have normal results. Effective mutation detection in these families is therefore fundamental to unambiguously determine the genetic status of each individual at risk. Of particular concern are female members of kindreds segregating X-ALD mutations, because normal VLCFA levels do not guarantee lack of carrier status. We describe a fast method for detection of X-ALD mutations. The method is based on SSCP analysis of nested PCR fragments followed by sequence-determination reactions. Using this methodology we have found X-ALD mutations in 30 kindreds, including 15 not previously reported. 
10737980	20	49	X-linked adrenoleukodystrophy	Modifier	D000326
10737980	100	129	X-linked Adrenoleukodystrophy	SpecificDisease	D000326
10737980	131	136	X-ALD	SpecificDisease	D000326
10737980	159	178	peroxisomal disease	DiseaseClass	D018901
10737980	978	983	X-ALD	Modifier	D000326
10737980	1107	1112	X-ALD	Modifier	D000326
10737980	1268	1273	X-ALD	Modifier	D000326

7894491|t|Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.
7894491|a|We analysed 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene, using single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA. A total of eight putative disease-causing alterations were identified  four of these are frameshifts and two are nonsense mutations. In addition, we found two missense mutations, one of which changes the final cysteine of the BRCA1 zinc finger motif to glycine. These data are consistent with a tumour suppressor model, and support the notion that this candidate gene is in fact BRCA1. The heterogeneity of mutations, coupled with the large size of the gene, indicates that clinical application of BRCA1 mutation testing will be technically challenging.. 
7894491	57	82	breast and ovarian cancer	CompositeMention	D061325
7894491	133	161	breast and/or ovarian cancer	CompositeMention	D061325
7894491	622	628	tumour	Modifier	D009369

2355960|t|Screening for carriers of Tay-Sachs disease among Ashkenazi Jews. A comparison of DNA-based and enzyme-based tests.
2355960|a|BACKGROUND AND METHODS. The prevention of Tay-Sachs disease (GM2 gangliosidosis, type 1) depends on the identification of carriers of the gene for this autosomal recessive disorder. We compared the enzyme-based test widely used in screening for Tay-Sachs disease with a test based on analysis of DNA. We developed methods to detect the three mutations in the HEXA gene that occur with high frequency among Ashkenazi Jews  two mutations cause infantile Tay-Sachs disease, and the third causes the adult-onset form of the disease. DNA segments containing these mutation sites were amplified with the polymerase chain reaction and analyzed for the presence of the mutations. RESULTS. Among 62 Ashkenazi obligate carriers of Tay-Sachs disease, the three specific mutations accounted for all but one of the mutant alleles (98 percent). In 216 Ashkenazi carriers identified by the enzyme test, DNA analysis showed that 177 (82 percent) had one of the identified mutations. Of the 177, 79 percent had the exon 11 insertion mutation, 18 percent had the intron 12 splice-junction mutation, and 3 percent had the less severe exon 7 mutation associated with adult-onset disease. The results of the enzyme tests in the 39 subjects (18 percent) who were defined as carriers but in whom DNA analysis did not identify a mutant allele were probably false positive (although there remains some possibility of unidentified mutations). In addition, of 152 persons defined as noncarriers by the enzyme-based test, 1 was identified as a carrier by DNA analysis (i. e e., a false negative enzyme-test result). CONCLUSIONS. The increased specificity and predictive value of the DNA-based test make it a useful adjunct to the diagnostic tests currently used to screen for carriers of Tay-Sachs disease. 
2355960	26	43	Tay-Sachs disease	SpecificDisease	D013661
2355960	158	175	Tay-Sachs disease	SpecificDisease	D013661
2355960	177	203	GM2 gangliosidosis, type 1	SpecificDisease	D013661
2355960	268	296	autosomal recessive disorder	DiseaseClass	D030342
2355960	361	378	Tay-Sachs disease	SpecificDisease	D013661
2355960	568	585	Tay-Sachs disease	SpecificDisease	D013661
2355960	837	854	Tay-Sachs disease	SpecificDisease	D013661
2355960	1876	1893	Tay-Sachs disease	SpecificDisease	D013661

8002973|t|Adrenoleukodystrophy gene encodes an 80 kDa membrane protein.
8002973|a|An antibody against the synthetic C-terminal peptides deduced from the cDNA of the gene responsible for X-linked adrenoleukodystrophy (ALD) was produced to characterize the product of the ALD gene. The antibody reacted with the 80 kDa band protein in control fibroblasts, while no bands were detected in the fibroblasts from a patient with ALD (# 163), in which mRNA of the ALD gene was undetectable based on Northern blot analysis. The 293T cells transfected with the full-coding cDNA inserted in the expression vector produced a new 80 kDa protein, as detected by Western blot. In an immunocytological study, the staining was in a punctate pattern, in the normal fibroblasts. However, there was no punctate staining in the # 163 cells. These data thus indicate that the ALD gene encodes an 80 kDa membrane protein.. 
8002973	0	20	Adrenoleukodystrophy	Modifier	D000326
8002973	166	195	X-linked adrenoleukodystrophy	SpecificDisease	D000326
8002973	197	200	ALD	SpecificDisease	D000326
8002973	250	253	ALD	Modifier	D000326
8002973	402	405	ALD	SpecificDisease	D000326
8002973	436	439	ALD	Modifier	D000326
8002973	834	837	ALD	Modifier	D000326

2568588|t|Preferential germline mutation of the paternal allele in retinoblastoma.
2568588|a|The event triggering malignant proliferation in 70% of retinoblastoma tumours is loss of heterozygosity for chromosome 13q14, whereby the normal retinoblastoma gene (RB1) allele is lost and an already mutated RB1 allele remains in the tumour. The first allele suffers a mutational event--deletion, duplication or point mutation (manuscript in preparation) --either in the germ line (all bilateral patients) or in a somatic retinal cell (most unilateral patients). Most bilateral patients have no family history of retinoblastoma and are presumed to have new germline mutations which arose in the egg, sperm or early embryo. We have determined the parental origin of the retained allele in nine retinoblastoma tumours from eight unrelated non-familial cases by using RB1-linked genetic markers. Six tumours retained the paternal allele and three retained the maternal allele. Of the three unilateral tumours, only one retained the paternal RB1 allele. Thus, there is no evidence that the paternal RB1 allele is preferentially retained in retinoblastoma, as has been suggested to be the case in osteosarcoma. By contrast, tumours from four of the five bilateral patients retained the paternal RB1 allele. This suggests either that new germline RB1 mutations arise more frequently during spermatogenesis than during oogenesis, or that imprinting in the early embryo affects chromosomal susceptibility to mutation.. 
2568588	57	71	retinoblastoma	SpecificDisease	D012175
2568588	128	150	retinoblastoma tumours	SpecificDisease	D012175
2568588	218	232	retinoblastoma	Modifier	D012175
2568588	308	314	tumour	DiseaseClass	D009369
2568588	587	601	retinoblastoma	SpecificDisease	D012175
2568588	767	789	retinoblastoma tumours	SpecificDisease	D012175
2568588	871	878	tumours	DiseaseClass	D009369
2568588	961	979	unilateral tumours	DiseaseClass	D009369
2568588	1110	1124	retinoblastoma	SpecificDisease	D012175
2568588	1166	1178	osteosarcoma	SpecificDisease	D012516
2568588	1193	1200	tumours	DiseaseClass	D009369

10817650|t|Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.
10817650|a|Mutations at the ataxia-telangiectasia (A-T) locus on chromosome band 11q22 cause a distinctive autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer, ischemic heart disease, and early mortality. PCR amplification from genomic DNA and automated sequencing of the entire coding region (66 exons) and splice junctions detected 77 mutations (85%) in 90 A-T chromosomes. Heteroduplex analysis detected another 42 mutations at the A-T locus. Out of a total of 71 unique mutations, 50 were found only in a single family, and 51 had not been reported previously. Most (58/71, 82%) mutations were frameshift and nonsense mutations that are predicted to cause truncation of the A-T protein; the less common mutation types were missense (9/71, 13%), splicing (3/71, 4%) and one in-frame deletion, 2546 3 (1/71, 1%). The mean survival and height distribution of 134 A-T patients correlated significantly with the specific mutations present in the patients. Patients homozygous for a single truncating mutation, typically near the N-terminal end of the gene, or heterozygous for the in-frame deletion 2546 3, were shorter and had significantly shorter survival than those heterozygous for a splice site or missense mutation, or heterozygous for two truncating mutations. Alterations of the length or amino acid composition of the A-T gene product affect the A-T clinical phenotype in different ways. Mutation analysis at the A-T locus may help estimate the prognosis of A-T patients.. 
10817650	17	38	ataxia-telangiectasia	Modifier	D001260
10817650	72	75	A-T	Modifier	D001260
10817650	103	124	ataxia-telangiectasia	Modifier	D001260
10817650	126	129	A-T	Modifier	D001260
10817650	182	210	autosomal recessive syndrome	DiseaseClass	D030342
10817650	258	264	cancer	DiseaseClass	D009369
10817650	266	288	ischemic heart disease	SpecificDisease	D017202
10817650	465	468	A-T	Modifier	D001260
10817650	541	544	A-T	Modifier	D001260
10817650	784	787	A-T	Modifier	D001260
10817650	970	973	A-T	Modifier	D001260
10817650	1433	1436	A-T	Modifier	D001260
10817650	1461	1464	A-T	Modifier	D001260
10817650	1528	1531	A-T	Modifier	D001260
10817650	1573	1576	A-T	Modifier	D001260

7815415|t|Anticipation resulting in elimination of the myotonic dystrophy gene: a follow up study of one extended family.
7815415|a|We have re-examined an extended myotonic dystrophy (DM) family, previously described in 1955, in order to study the long term effects of anticipation in DM and in particular the implications for families affected by this disease. This follow up study provides data on 35 gene carriers and 46 asymptomatic at risk family members in five generations. Clinical anticipation, defined as the cascade of mild, adult, childhood, or congenital disease in subsequent generations, appeared to be a relentless process, occurring in all affected branches of the family. The cascade was found to proceed asynchronously in the different branches, mainly because of an unequal number of generations with mild disease. The transition from the mild to the adult type was associated with transmission through a male parent. Stable transmission of the asymptomatic/mild phenotype showed a female transmission bias. We further examined the extent and causes of gene loss in this pedigree. Gene loss in the patient group was complete, owing to infertility of the male patients with adult onset disease and the fact that mentally retarded patients did not procreate. Out of the 46 at risk subjects in the two youngest generations, only one was found to have a full mutation. This is the only subject who may transmit the gene to the sixth generation. No protomutation carriers were found in the fourth and fifth generations. Therefore it is highly probable that the DM gene will be eliminated from this pedigree within one generation. The high population frequency of DM can at present not be explained by the contribution of asymptomatic cases in the younger generations of known families, but is probably caused by the events in the ancestral generations.. 
7815415	45	63	myotonic dystrophy	Modifier	D009223
7815415	144	162	myotonic dystrophy	Modifier	D009223
7815415	164	166	DM	Modifier	D009223
7815415	265	267	DM	SpecificDisease	D009223
7815415	537	555	congenital disease	DiseaseClass	D030342
7815415	1135	1146	infertility	DiseaseClass	D007246
7815415	1211	1228	mentally retarded	DiseaseClass	D008607
7815415	1556	1558	DM	Modifier	D009223
7815415	1658	1660	DM	SpecificDisease	D009223

10571943|t|Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome.
10571943|a|We report new mutations in exon 9 of the WT1 gene that did not alter the ratio of +/- KTS splice isoforms in two unrelated patients with Frasier syndrome (FS). The mutation of intron 9 inducing defective alternative splicing was reported to be responsible for this syndrome. The mutations found in our cases occurred in the same exon of the WT1 gene as detected in Denys-Drash syndrome (DDS) and could not be explained by the previously proposed mechanism. The results suggest that the two syndromes originate from the same WT1 gene abnormality. From a molecular biological point of view, we concluded that the two diseases were not separable, and that FS should be included as an atypical form of DDS.. 
10571943	100	116	Frasier syndrome	SpecificDisease	D052159
10571943	255	271	Frasier syndrome	SpecificDisease	D052159
10571943	273	275	FS	SpecificDisease	D052159
10571943	483	503	Denys-Drash syndrome	SpecificDisease	D030321
10571943	505	508	DDS	SpecificDisease	D030321
10571943	642	662	WT1 gene abnormality	SpecificDisease	D009396
10571943	771	773	FS	SpecificDisease	D052159
10571943	816	819	DDS	SpecificDisease	D030321

10500204|t|Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia.
10500204|a|Friedreich ataxia (FRDA), the most common of the inherited ataxias, is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs. FRDA is caused by a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 in 97% of patients. The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria and is severely reduced in FRDA patients. Frataxin function is still unknown but the knockout of the yeast frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration and loss of mtDNA associated with elevated intramitochondrial iron. Here we report in vivo evidence of impaired mitochondrial respiration in skeletal muscle of FRDA patients. Using phosphorus magnetic resonance spectroscopy we demonstrated a maximum rate of muscle mitochondrial ATP production (V (max)) below the normal range in all 12 FRDA patients and a strong negative correlation between mitochondrial V (max) and the number of GAA repeats in the smaller allele. Our results show that FRDA is a nuclear-encoded mitochondrial disorder affecting oxidative phosphorylation and give a rationale for treatments aimed to improve mitochondrial function in this condition.. 
10500204	65	82	Friedreich ataxia	SpecificDisease	D005621
10500204	84	101	Friedreich ataxia	SpecificDisease	D005621
10500204	103	107	FRDA	SpecificDisease	D005621
10500204	133	150	inherited ataxias	DiseaseClass	D013132
10500204	158	199	autosomal recessive degenerative disorder	DiseaseClass	D019636
10500204	259	291	progressive gait and limb ataxia	CompositeMention	D020234|D001259
10500204	293	324	absence of deep tendon reflexes	DiseaseClass	D012021
10500204	326	352	extensor plantar responses	DiseaseClass	D001405
10500204	358	394	loss of position and vibration sense	CompositeMention	D053421
10500204	415	419	FRDA	SpecificDisease	D005621
10500204	484	488	FRDA	Modifier	D005621
10500204	537	541	FRDA	Modifier	D005621
10500204	660	664	FRDA	Modifier	D005621
10500204	983	987	FRDA	Modifier	D005621
10500204	1160	1164	FRDA	Modifier	D005621
10500204	1313	1317	FRDA	SpecificDisease	D005621
10500204	1339	1361	mitochondrial disorder	DiseaseClass	D028361

2912886|t|Chronic nonspherocytic hemolytic anemia (CNSHA) and glucose 6 phosphate dehydrogenase (G6PD) deficiency in a patient with familial amyloidotic polyneuropathy (FAP). Molecular study of a new variant (G6PD Clinic) with markedly acidic pH optimum.
2912886|a|A new glucose-6-phosphate dehydrogenase (G6PD) variant with severe erythrocytic G6PD deficiency and a unique pH optimum is described in a young patient with chronic nonspherocytic hemolytic anemia (CNSHA) and familial amyloidotic polyneuropathy (FAP). Chronic hemolysis was present in the absence of infections, oxidant drugs or ingestion of faba beans. Residual enzyme activity was about 2. 6% and 63% of normal activity in erythrocytes and leucocytes, respectively. A molecular study using standard methods showed G6PD in the patient to have normal electrophoretic mobility (at pH 7. 0, 8. 0 and 8. 8), normal apparent affinity for substrates (Km, G6P and NADP) and a slightly abnormal utilization of substrate analogues (decreased deamino-NADP and increased 2-deoxyglucose-6-phosphate utilization). Heat stability was found to be markedly decreased (8% of residual activity after 20 min of incubation at 46 degrees C) and a particular characteristic of this enzyme was a biphasic pH curve with a greatly increased activity at low pH. Although molecular characteristics of this variant closely resemble those of G6PD Bangkok and G6PD Duarte, it can be distinguished from these and all other previously reported variants by virtue of its unusual pH curve. Therefore the present variant has been designated G6PD Clinic to distinguish it from other G6PD variants previously described 
2912886	0	39	Chronic nonspherocytic hemolytic anemia	SpecificDisease	D000746
2912886	41	46	CNSHA	SpecificDisease	D000746
2912886	52	103	glucose 6 phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
2912886	122	157	familial amyloidotic polyneuropathy	SpecificDisease	D028227
2912886	159	162	FAP	SpecificDisease	D028227
2912886	312	340	erythrocytic G6PD deficiency	SpecificDisease	D005955
2912886	402	441	chronic nonspherocytic hemolytic anemia	SpecificDisease	D000746
2912886	443	448	CNSHA	SpecificDisease	D000746
2912886	454	489	familial amyloidotic polyneuropathy	SpecificDisease	D028227
2912886	491	494	FAP	SpecificDisease	D028227
2912886	497	514	Chronic hemolysis	SpecificDisease	D006461

3422216|t|Regional localization of polymorphic DNA loci on the proximal long arm of the X chromosome using deletions associated with choroideremia.
3422216|a|In two unrelated families, males have been identified who suffer from choroideremia and at the same time have an interstitial deletion on the proximal long arm of the X chromosome. By high-resolution banding we have characterized the deletion chromosomes as del (X) (q21. 1-q21 1-q21. 33) and del (X) (q21. 2-q21 2-q21. 31) respectively. By Southern blot analysis we have mapped ten different polymorphic DNA loci relative to the position of the deletion and the choroideremia locus TCD. One probe, p31, was shown to cover one of the breakpoints of the smallest deletion. The following order of the loci was suggested by deletion mapping  cen-DXS106-DXS72-TCD- (DXYS1/DXYS23/DXYS5) - DXYS2- (DXYS12/DXS3) - (DXS17/DXS101) - Xqter.
3422216	123	136	choroideremia	SpecificDisease	D015794
3422216	208	221	choroideremia	SpecificDisease	D015794
3422216	601	614	choroideremia	Modifier	D015794

2016095|t|A de novo unbalanced reciprocal translocation identified as paternal in origin in the Prader-Willi syndrome.
2016095|a|Interstitial cytogenetic deletions involving the paternally derived chromosome 15q11-13 have been described in patients with the Prader-Willi syndrome (PWS). We report a child with PWS and a de novo unbalanced karyotype -45, XY, -9, -15, + der (9) t (9; 15) (q34; q13). Molecular studies with the DNA probe pML34 confirmed that only a single Prader Willi critical region (PWCR  15q11. 2-q12) copy was present. Hybridisation of patient and parental DNA with the multi-allelic probe CMW1, which maps to pter-15q13, showed that the chromosome involved in the translocation was paternal in origin. This is the first example of a paternally-derived PWCR allele loss caused by an unbalanced translocation that has arisen de novo. 
2016095	86	107	Prader-Willi syndrome	SpecificDisease	D011218
2016095	238	259	Prader-Willi syndrome	SpecificDisease	D011218
2016095	261	264	PWS	SpecificDisease	D011218
2016095	290	293	PWS	SpecificDisease	D011218
2016095	451	463	Prader Willi	Modifier	D011218

10807385|t|Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.
10807385|a|CONTEXT  Most hereditary ovarian cancers are associated with germline mutations in BRCA1 or BRCA2. Attempts to define the clinical significance of BRCA mutation status in ovarian cancer have produced conflicting results, especially regarding survival. OBJECTIVE  To determine whether hereditary ovarian cancers have distinct clinical and pathological features compared with sporadic (nonhereditary) ovarian cancers. DESIGN AND SETTING  Retrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at our institution, which is a comprehensive cancer center as designated by the National Cancer Institute, over a 12-year period (December 1986 to August 1998). PATIENTS  The study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group. From the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2. The remaining 101 cases from the same series not associated with a BRCA mutation and 2 additional groups (Gynecologic Oncology Group protocols 52 and 111) with ovarian cancer from clinical trials (for the survival analysis) were included for comparison. MAIN OUTCOME MEASURES  Age at diagnosis, surgical stage, histologic cell type and grade, and surgical outcome; and response to chemotherapy and survival for advanced-stage (II and IV) cases. RESULTS  Hereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1- vs BRCA2-linked patients (54 vs 62 years; P =. 04). Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases. The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (P <. 001). Those with hereditary cancers had improved survival compared with the nonhereditary group (P =. 004). For stage III cancers, BRCA mutation status was an independent prognostic variable (P =. 03). CONCLUSIONS  Although BRCA-associated hereditary ovarian cancers in this population have surgical and pathological characteristics similar to those of sporadic cancers, advanced-stage hereditary cancer patients survive longer than nonhereditary cancer patients. Age penetrance is greater for BRCA1-linked than for BRCA2-linked cancers in this population.
10807385	30	69	BRCA-linked and sporadic ovarian cancer	CompositeMention	OMIM:604370|OMIM:612555|OMIM:613399|D010051
10807385	85	111	hereditary ovarian cancers	SpecificDisease	D061325
10807385	242	256	ovarian cancer	SpecificDisease	D010051
10807385	355	381	hereditary ovarian cancers	SpecificDisease	D061325
10807385	445	485	sporadic (nonhereditary) ovarian cancers	SpecificDisease	D010051
10807385	565	580	ovarian cancers	SpecificDisease	D010051
10807385	648	654	cancer	Modifier	D009369
10807385	692	698	Cancer	Modifier	D009369
10807385	1223	1237	ovarian cancer	SpecificDisease	D010051
10807385	1517	1535	Hereditary cancers	DiseaseClass	D009369
10807385	2069	2087	hereditary cancers	DiseaseClass	D009369
10807385	2164	2181	stage III cancers	DiseaseClass	D009369
10807385	2276	2318	BRCA-associated hereditary ovarian cancers	SpecificDisease	OMIM:604370|OMIM:612555|OMIM:613399
10807385	2405	2421	sporadic cancers	DiseaseClass	D009369
10807385	2423	2455	advanced-stage hereditary cancer	Modifier	D009386
10807385	2485	2505	nonhereditary cancer	Modifier	D009369
10807385	2546	2588	BRCA1-linked than for BRCA2-linked cancers	CompositeMention	OMIM:604370|OMIM:612555

1302008|t|Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.
1302008|a|Denys-Drash syndrome is a rare human developmental disorder affecting the urogenital system and leading to renal failure, intersex disorders and Wilms tumour. In this report, four individuals with this syndrome are described carrying germline point mutations in the Wilms tumour suppressor gene, WT1. Three of these mutations were in the zinc finger domains of WT1. The fourth occurred within intron 9, preventing splicing at one of the alternatively chosen splice donor sites of exon 9 when assayed in vitro. These results provide genetic evidence for distinct functional roles of the WT1 isoforms in urogenital development.. 
1302008	46	59	Wilms' tumour	Modifier	D009396
1302008	105	125	Denys-Drash syndrome	SpecificDisease	D030321
1302008	142	164	developmental disorder	DiseaseClass	D002658
1302008	212	225	renal failure	DiseaseClass	D051437
1302008	227	245	intersex disorders	DiseaseClass	D012734
1302008	250	262	Wilms tumour	SpecificDisease	D009396
1302008	371	383	Wilms tumour	Modifier	D009396

3014348|t|Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy.
3014348|a|Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder for which the biochemical defect is as yet unknown. Recently, two cloned segments of human X-chromosome DNA have been described which detect structural alterations within or near the genetic locus responsible for the disorder. Both of these cloned segments were described as tightly linked to the locus and were capable of detecting deletions in the DNA of boys affected with DMD. In an attempt to determine more precisely the occurrence of these deletions within a large population of DMD patients and the accuracy of one of the segments, DXS164 (pERT87), in determining the inheritance of the DMD X chromosome, the subclones 1, 8 and 15 were made available to many investigators throughout the world. Here we describe the combined results of more than 20 research laboratories with respect to the occurrence of deletions at the DXS164 locus in DNA samples isolated from patients with DMD and Becker muscular dystrophy (BMD). The results indicate that the DXS164 locus apparently recombines with DMD 5% of the time, but is probably located between independent sites of mutation which yield DMD. The breakpoints of some deletions are delineated within the DXS164 locus, and it is evident that the deletions at the DMD locus are frequent and extremely large.. 
3014348	48	86	Becker and Duchenne muscular dystrophy	CompositeMention	D020388|C537666
3014348	88	115	Duchenne muscular dystrophy	SpecificDisease	D020388
3014348	117	120	DMD	SpecificDisease	D020388
3014348	128	163	X-linked recessive genetic disorder	DiseaseClass	D040181
3014348	540	543	DMD	SpecificDisease	D020388
3014348	650	653	DMD	Modifier	D020388
3014348	759	762	DMD	Modifier	D020388
3014348	1050	1053	DMD	SpecificDisease	D020388
3014348	1058	1083	Becker muscular dystrophy	SpecificDisease	C537666
3014348	1085	1088	BMD	SpecificDisease	C537666
3014348	1161	1164	DMD	SpecificDisease	D020388
3014348	1255	1258	DMD	SpecificDisease	D020388
3014348	1378	1381	DMD	Modifier	D020388

7802009|t|Additional case of female monozygotic twins discordant for the clinical manifestations of Duchenne muscular dystrophy due to opposite X-chromosome inactivation.
7802009|a|A pair of female monozygotic (MZ) twins, heterozygous carriers for a deletion in the DMD gene and discordant for the clinical manifestations of Duchenne muscular dystrophy, were analyzed by molecular studies, in situ hybridization, and methylation pattern of X chromosomes to search for opposite X inactivation as an explanation of their clinical discordance. Results in lymphocytes and skin fibroblast cell lines suggest a partial mirror inactivation with the normal X chromosome preferentially active in the unaffected twin, and the maternal deleted X chromosome preferentially active in the affected twin. A review shows that MZ female twins discordant for X-linked diseases are not uncommon. Twinning and X inactivation may be interrelated and could explain the female twins discordant for X-linked traits.. 
7802009	90	117	Duchenne muscular dystrophy	SpecificDisease	D020388
7802009	246	249	DMD	Modifier	D020388
7802009	305	332	Duchenne muscular dystrophy	SpecificDisease	D020388
7802009	821	838	X-linked diseases	DiseaseClass	D040181

1127526|t|Analbuminemia in a neonate.
1127526|a|A small-for-gestational-age infant, found to have analbuminemia in the neonatal period, is reported and the twelve cases recorded in the world literature are reviewed. Patients lacking this serum protein are essentially asymptomatic, apart from minimal ankle edema and ease of fatigue. Apparent compensatory mechanisms which come into play when serum albumin is low include prolonged half-life of albumin and transferrin, an increase in serum globulins, beta lipoprotein, and glycoproteins, arterial hypotension with reduced capillary hydrostatic pressure, and the ability to respond with rapid sodium and chloride diuresis in response to small volume changes. Examination of plasma amino acids, an investigation not previously reported, revealed an extremely low plasma tryptophan level, a finding which may be important in view of the role of tryptophan in albumin synthesis.. 
1127526	0	13	Analbuminemia	SpecificDisease	OMIM:103600
1127526	78	91	analbuminemia	SpecificDisease	OMIM:103600
1127526	281	292	ankle edema	DiseaseClass	D016512
1127526	297	312	ease of fatigue	DiseaseClass	D005221
1127526	519	539	arterial hypotension	DiseaseClass	D007022

7857677|t|Homozygous presence of the crossover (fusion gene) mutation identified in a type II Gaucher disease fetus: is this analogous to the Gaucher knock-out mouse model?
7857677|a|Gaucher disease (GD) is an inherited deficiency of beta-glucocerebrosidase (EC 3. 1. 2. 45, gene symbol GBA). In type I GD, the CNS is not involved (nonneuronopathic), whereas in type II GD (acute neuronopathic) CNS involvement is early and rapidly progressive, while in type III GD (subacute neuronopathic) CNS involvement occurs later and is slowly progressive. The T6433C (L444P) substitution is prevalent in type GD II. It may occur alone as a single base-pair mutation but often is found as part of a complex allele containing additional GBA nucleotide substitutions, G6468C (A456P) and G6482C (V460V), without (recNciI) or with (recTL) G5957C (D409H). This complex allele is presumed to have formed by recombination (crossover, fusion) of the structural gene with the pseudogene, which contains the mutated sequences. Two complex alleles have never been demonstrated to coexist in any individual. We devised a selective PCR method for the specific amplification of the normal and/or fusion gene. Using this procedure we demonstrated the fusion gene in homozygous form for the first time, in a Macedonian/Ashkenazi Jewish GD type II fetus. Both parents were carriers of the recombination. This was confirmed by direct sequence analysis. A previous conceptus in this family was stillborn at 36 weeks, with features of severe type II GD. Neonates showing a severe clinical phenotype, analogous to the early neonatal lethal disease occurring in mice homozygous for a null allele produced by targeted disruption of GBA, have been described elsewhere, but the specific mutations in these cases have not yet been characterized. (ABSTRACT TRUNCATED AT 250 WORDS) 
7857677	76	99	type II Gaucher disease	Modifier	D005776
7857677	163	178	Gaucher disease	SpecificDisease	D005776
7857677	180	182	GD	SpecificDisease	D005776
7857677	200	237	deficiency of beta-glucocerebrosidase	SpecificDisease	D005776
7857677	276	285	type I GD	SpecificDisease	D005776
7857677	342	352	type II GD	SpecificDisease	D005776
7857677	434	445	type III GD	SpecificDisease	D005776
7857677	575	585	type GD II	SpecificDisease	D005776
7857677	1290	1300	GD type II	Modifier	D005776
7857677	1445	1454	stillborn	DiseaseClass	D005313
7857677	1492	1502	type II GD	SpecificDisease	D005776

10403837|t|Decrease in GTP cyclohydrolase I gene expression caused by inactivation of one allele in hereditary progressive dystonia with marked diurnal fluctuation.
10403837|a|Hereditary progressive dystonia with marked diurnal fluctuation (HPD; dopa-responsive dystonia, DRD) have been recently found to be caused by a genetic defect in the GTP cyclohydrolase I (GCH1) gene. In this study, we quantified the mRNA level of GCH1 in phytohemagglutinin (PHA) -stimulated mononuclear blood cells from one Japanese family that do not have a mutation in the coding region or splice junctions of the gene. The results showed that the amounts of the GCH1 mRNA were decreased to about 40% of the normal level in both patients and carriers. In addition, we found that the GCH1 mRNA was transcribed from only one allele, indicating that the other allele was in an inactive state. These results suggest that some novel mutations should exist on one of the alleles in some unknown region of the GCH1 gene, and may decrease the GCH1 mRNA causing the HPD/DRD symptoms.. 
10403837	89	120	hereditary progressive dystonia	SpecificDisease	D020821
10403837	154	185	Hereditary progressive dystonia	SpecificDisease	D020821
10403837	219	222	HPD	SpecificDisease	D020821
10403837	224	248	dopa-responsive dystonia	SpecificDisease	C538007
10403837	250	253	DRD	SpecificDisease	C538007
10403837	298	312	genetic defect	DiseaseClass	D030342
10403837	1014	1017	HPD	Modifier	D020821
10403837	1018	1021	DRD	Modifier	C538007

10447259|t|Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes.
10447259|a|Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency characterized by thrombocytopenia, eczema, and recurrent infections, and caused by mutations in the WAS protein (WASP) gene. WASP contains several functional domains through which it interacts with proteins involved in intracellular signaling and regulation of the actin cytoskeleton. In this report, 17 WASP gene mutations were identified, 12 of which are novel. DNA of affected males and obligate carriers was PCR amplified and analyzed by SSCA, heteroduplex analysis, and direct sequencing. The effects of the mutations at the mRNA and protein level were ascertained by RT-PCR and Western blot analyses. All missense mutations were located in exons 1-4. Most of the nonsense, frameshift and splice site mutations were found in exons 6-11. Mutations that alter splice sites led to the synthesis of several types of mRNAs, a fraction of which represented the normally spliced product. The presence of normally spliced transcripts was correlated with a milder phenotype. When one such case was studied by Western blotting, reduced amounts of normal-size WASP were present. In other cases as well, a correlation was found between the amount of normal or mutant WASP present and the phenotypes of the affected individuals. No protein was detected in two individuals with severe WAS. Reduced levels of a normal-size WASP with a missense mutation were seen in two individuals with XLT. It is concluded that mutation analysis at the DNA level is not sufficient for predicting clinical course. Studies at the transcript and protein level are needed for a better assessment.. 
10447259	23	47	Wiskott-Aldrich syndrome	Modifier	D014923
10447259	139	163	Wiskott-Aldrich syndrome	SpecificDisease	D014923
10447259	165	168	WAS	SpecificDisease	D014923
10447259	176	211	X-linked recessive immunodeficiency	DiseaseClass	D053632
10447259	229	245	thrombocytopenia	DiseaseClass	D013921
10447259	247	253	eczema	DiseaseClass	D004485
10447259	312	315	WAS	Modifier	D014923
10447259	1488	1491	WAS	SpecificDisease	D014923
10447259	1589	1592	XLT	SpecificDisease	OMIM:313900

511159|t|Incidence and characteristics of glucose-6-phosphate dehydrogenase variants in Japan.
511159|a|A total of 3000 men living in Yamaguchi were screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency using Beutlers spot test and three types of starch gel electrophoresis. These electrophoresis used a phosphate buffer system at pH 7. 0, a TRIS-EDTA-borate buffer system at pH 8. 6, and a TRIS-hydrochloride buffer system at pH 8.. Fifteen G6PD-deficient variants were found at the rate of 0. 5% and classified into four groups. As new variants, G6PD Konan, Kamiube, and Kiwa were identified. These three variants had a mild to moderate G6PD deficiency and were not associated with any clinical signs. G6PD Konan had fast electrophoretic mobility as compared with normal levels, G6PD Kiwa had slightly elevated electrophoretic mobility, and G6PD Kamiube had normal electrophoretic mobility. These three variants had normal levels of Km G6P, Km NADP, and Ki NADPH, normal utilizations of both 2-deoxy-G6P and deamino-NAPD, normal heat stability, and a normal pH curve. The other variant was G6PD Ube, which we had previously found in Yamaguchi (Nakashima et al., 1977). One boy with G6PD Ube was Korean 
511159	144	195	glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
511159	435	449	G6PD-deficient	Modifier	D005955
511159	632	647	G6PD deficiency	SpecificDisease	D005955

8266996|t|Difference in methylation patterns within the D15S9 region of chromosome 15q11-13 in first cousins with Angelman syndrome and Prader-Willi syndrome.
8266996|a|Abnormalities of chromosome region 15q11-13 are associated with Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Differences between the methylation patterns of the region of chromosome 15q11-13 which hybridizes to the highly conserved DNA, DN34, in normal individuals and in patients with AS and PWS have been described. We report on a family in which first cousins are affected by AS and PWS as a result of a familial paracentric inversion of 15q11-q13. The results of the studies on this family demonstrate the differences in the methylation patterns in the 2 conditions and the phenomenon of genomic imprinting, whereby genetic information is expressed differently dependent on the parent of origin.. 
8266996	104	121	Angelman syndrome	SpecificDisease	D017204
8266996	126	147	Prader-Willi syndrome	SpecificDisease	D011218
8266996	213	230	Angelman syndrome	SpecificDisease	D017204
8266996	232	234	AS	SpecificDisease	D017204
8266996	240	261	Prader-Willi syndrome	SpecificDisease	D011218
8266996	263	266	PWS	SpecificDisease	D011218
8266996	446	448	AS	SpecificDisease	D017204
8266996	453	456	PWS	SpecificDisease	D011218
8266996	539	541	AS	SpecificDisease	D017204
8266996	546	549	PWS	SpecificDisease	D011218

1307245|t|Mutations in the candidate gene for Norrie disease.
1307245|a|Recently, we and others have isolated a candidate gene for X linked Norrie disease (ND) which was found to be deleted or disrupted in several patients. As a prerequisite for the identification of point mutations in the ND gene we have established the exon-intron structure of this gene. In 17 unrelated patients and 15 controls, PCR products derived from the promoter region, exons 1 and 2 as well as the coding part of exon 3 were analysed with the single strand conformation polymorphism (SSCP) technique. In 12 patients altered PCR fragments were detected which were studied in detail by direct sequencing. Eleven different mutations were found, and all but one are likely to give rise to significant structural changes in the predicted protein. These findings, and the absence of functionally relevant base changes in healthy controls, emphasize the causal role of this candidate gene in Norrie disease and pave the way for reliable diagnosis and carrier detection.. 
1307245	36	50	Norrie disease	SpecificDisease	C537849
1307245	111	134	X linked Norrie disease	SpecificDisease	C537849
1307245	136	138	ND	SpecificDisease	C537849
1307245	271	273	ND	Modifier	C537849
1307245	944	958	Norrie disease	SpecificDisease	C537849

7874117|t|A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia.
7874117|a|Kniest dysplasia is a moderately severe chondrodysplasia phenotype that results from mutations in the gene for type II collagen, COL2A1. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss. Recently, deletions of all or part of exon 12 have been identified in individuals with Kniest dysplasia, suggesting that mutations within this region of the protein may primarily result in the Kniest dysplasia phenotype. We used SSCP to analyze an amplified genomic DNA fragment containing exon 12 from seven individuals with Kniest dysplasia. An abnormality was identified in one patient. DNA sequence analysis demonstrated that the patient was heterozygous for a G to A transition that implied substitution of glycine103 of the triple helical domain by aspartate. The mutation was not observed in DNA from either of the clinically unaffected parents of the proband. Protein microsequencing demonstrated expression of the abnormal allele in cartilage. These data demonstrate that point mutations which result in single amino acid substitutions can produce Kniest dysplasia and further support the hypothesis that alteration of a domain, which includes the region encoded by exon 12, in the type II collagen protein leads to this disorder.. 
7874117	87	103	Kniest dysplasia	SpecificDisease	C537207
7874117	105	121	Kniest dysplasia	SpecificDisease	C537207
7874117	145	161	chondrodysplasia	Modifier	D010009
7874117	284	311	short trunk and extremities	SpecificDisease	D006130
7874117	313	332	mid-face hypoplasia	DiseaseClass	D019767
7874117	334	346	cleft palate	SpecificDisease	D002972
7874117	348	354	myopia	DiseaseClass	D009216
7874117	356	374	retinal detachment	SpecificDisease	D012163
7874117	380	392	hearing loss	DiseaseClass	D034381
7874117	481	497	Kniest dysplasia	SpecificDisease	C537207
7874117	587	603	Kniest dysplasia	Modifier	C537207
7874117	720	736	Kniest dysplasia	SpecificDisease	C537207
7874117	1251	1267	Kniest dysplasia	SpecificDisease	C537207

10434119|t|Linkage analysis of 5 novel van der Woude syndrome kindreds to 1q32-q41 markers further supports locus homogeneity of the disease trait.
10434119|a|van der Woude syndrome (vWS, MIM 119300) is a rare autosomal dominant clefting condition with cardinal features of mucous cysts (lower-lip pits) and clefts to the lip and/or palate. The vWS gene has been assigned to a locus in 1q32-q41 by linkage analysis and physical mapping. We have investigated 5 novel vWS families through probands attended for cleft lip and/or palate repair at the Department of Maxillofacial Surgery of Hopital Trousseau, Paris, in order to tentatively refine the genetic map of the vWS region in 1q32-q41 and possibly identify unlinked pedigrees. Linkage analysis was carried out to 6 microsatellite markers (D1S249, D1S425, D1S491, D1S205, D1S414, D1S425), yielding a maximum cumulative LOD score of Z = 3. 27 at theta = 0. 00 for D1S245. The innermost four markers were found to be tightly linked to one another, with no evidence for recombination. Our results support linkage of vWS within a region of tightly linked markers and do not favour locus heterogeneity of the disease trait.
10434119	28	50	van der Woude syndrome	Modifier	C536528
10434119	137	159	van der Woude syndrome	SpecificDisease	C536528
10434119	161	164	vWS	SpecificDisease	C536528
10434119	188	225	autosomal dominant clefting condition	DiseaseClass	C536528
10434119	252	264	mucous cysts	SpecificDisease	D009078
10434119	266	280	lower-lip pits	SpecificDisease	C536528
10434119	286	317	clefts to the lip and/or palate	CompositeMention	D002971|D002972
10434119	323	326	vWS	Modifier	C536528
10434119	444	447	vWS	Modifier	C536528
10434119	487	510	cleft lip and/or palate	Modifier	D002971|D002972
10434119	644	647	vWS	Modifier	C536528
10434119	1044	1047	vWS	SpecificDisease	C536528

3578281|t|Hypopigmentation in the Prader-Willi syndrome.
3578281|a|Cutaneous and ocular pigmentation were evaluated in 29 individuals with the Prader-Willi syndrome (PWS). Criteria for hypopigmentation included the presence of type I or II skin, the lightest skin type in the family by history, and iris translucency on globe transillumination. On the basis of these criteria, 48% of the PWS individuals were hypopigmented. The presence of hypopigmentation correlated with a small interstitial deletion on the proximal long arm of chromosome 15; however, this deletion was also found in individuals who did not meet the full criteria for hypopigmentation. Hairbulb tyrosinase activity and glutathione content, as well as urine cysteinyldopa excretion, were low in PWS individuals with and without hypopigmentation and did not separate these two groups. We conclude that hypopigmentation is found in a significant proportion of individuals with PWS and that the hypopigmentation may be associated with a deletion of the long arm of chromosome 15. The mechanism for the hypopigmentation is unknown.. 
3578281	0	16	Hypopigmentation	DiseaseClass	D017496
3578281	24	45	Prader-Willi syndrome	SpecificDisease	D011218
3578281	47	80	Cutaneous and ocular pigmentation	CompositeMention	D010859
3578281	123	144	Prader-Willi syndrome	SpecificDisease	D011218
3578281	146	149	PWS	SpecificDisease	D011218
3578281	165	181	hypopigmentation	DiseaseClass	D017496
3578281	368	371	PWS	Modifier	D011218
3578281	389	402	hypopigmented	Modifier	D017496
3578281	420	436	hypopigmentation	DiseaseClass	D017496
3578281	618	634	hypopigmentation	DiseaseClass	D017496
3578281	744	747	PWS	Modifier	D011218
3578281	777	793	hypopigmentation	DiseaseClass	D017496
3578281	850	866	hypopigmentation	DiseaseClass	D017496
3578281	924	927	PWS	SpecificDisease	D011218
3578281	941	957	hypopigmentation	DiseaseClass	D017496
3578281	1048	1064	hypopigmentation	DiseaseClass	D017496

495634|t|Deficiency of the fifth component of complement in human subjects. Clinical, genetic and immunologic studies in a large kindred.
495634|a|The discovery of a large kindred with a heritable deficiency of the fifth component of complement (C5) has permitted the accumulation of new clinical, genetic and immunologic data concerning the role of C5 in human subjects. The proband, who has had nine episodes of disseminated gonococcal infection, has a hemolytic C5 level of approximately 0. 5 per cent of normal. No C5 protein was detectable, but low levels of functional C5 activity could be found using a sensitive bactericidal assay. The probands twin as well as another sister also had extremely low levels of hemolytic C5 (approximately 0. 5 per cent normal), but both these subjects have been healthy. Hemolytic complement and bacteriolytic activity could be restored by the addition of purified C5. No chemotactic activity for polymorphonuclear leukocytes could be generated in the C5-deficient serums upon activation of either the classic or alternative pathways, again demonstrating the importance of C5 in human subjects for the production of chemotactic factors. The chemotactic responsiveness of the patients polymorphonuclear leukocytes and monocytes to preformed chemotactic factors was not depressed. Twenty-two of 32 other family members from three generations had depressed whole hemolytic complement levels. In 19 of 30 family members, levels of hemolytic C5 ranged from 13 to 64 per cent of normal. No linkage for C5 deficiency and the A or B loci of the major histocompatibility complex could be found. These data suggest an autosomal codominant mode of inheritance of C5 deficiency. Deficiency of C5 is compatible with good health, but it can be associated with repeated disseminated gonococcal infection 
495634	0	47	Deficiency of the fifth component of complement	SpecificDisease	OMIM:609536
495634	179	226	deficiency of the fifth component of complement	SpecificDisease	OMIM:609536
495634	409	429	gonococcal infection	SpecificDisease	D006069
495634	974	986	C5-deficient	Modifier	OMIM:609536
495634	1518	1531	C5 deficiency	SpecificDisease	OMIM:609536
495634	1674	1687	C5 deficiency	SpecificDisease	OMIM:609536
495634	1689	1705	Deficiency of C5	SpecificDisease	OMIM:609536
495634	1790	1810	gonococcal infection	SpecificDisease	D006069

8533762|t|A new glucose-6-phosphate dehydrogenase variant, G6PD Orissa (44 Ala-->Gly), is the major polymorphic variant in tribal populations in India.
8533762|a|Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is usually found at high frequencies in areas of the world where malaria has been endemic. The frequency and genetic basis of G6PD deficiency have been studied in Africa, around the Mediterranean, and in the Far East, but little such information is available about the situation in India. To determine the extent of heterogeneity of G6PD, we have studied several different Indian populations by screening for G6PD deficiency, followed by molecular analysis of deficient alleles. The frequency of G6PD deficiency varies between 3% and 15% in different tribal and urban groups. Remarkably, a previously unreported deficient variant, G6PD Orissa (44 Ala-- > Gly), is responsible for most of the G6PD deficiency in tribal Indian populations but is not found in urban populations, where most of the G6PD deficiency is due to the G6PD Mediterranean (188 Ser-- > Phe) variant. The KmNADP of G6PD Orissa is fivefold higher than that of the normal enzyme. This may be due to the fact that the alanine residue that is replaced by glycine is part of a putative coenzyme-binding site.. 
8533762	142	189	Deficiency of glucose-6-phosphate dehydrogenase	SpecificDisease	D005955
8533762	262	269	malaria	SpecificDisease	D008288
8533762	323	338	G6PD deficiency	SpecificDisease	D005955
8533762	606	621	G6PD deficiency	SpecificDisease	D005955
8533762	693	708	G6PD deficiency	SpecificDisease	D005955
8533762	889	904	G6PD deficiency	SpecificDisease	D005955
8533762	991	1006	G6PD deficiency	SpecificDisease	D005955

1655284|t|Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.
1655284|a|Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms tumor (nephroblastoma). To investigate its possible role, we have analyzed the coding exons of the Wilms tumor suppressor gene (WT1) for germline mutations. In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found. Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II). These mutations directly affect DNA sequence recognition. In two families analyzed, the mutations were shown to arise de novo. Wilms tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele. Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development.. 
1655284	26	38	Wilms' tumor	Modifier	D009396
1655284	110	130	Denys-Drash syndrome	SpecificDisease	D030321
1655284	132	152	Denys-Drash syndrome	SpecificDisease	D030321
1655284	195	217	urogenital aberrations	DiseaseClass	D014564
1655284	228	241	renal failure	SpecificDisease	D051437
1655284	243	264	pseudohermaphroditism	SpecificDisease	D012734
1655284	270	281	Wilms tumor	SpecificDisease	D009396
1655284	283	297	nephroblastoma	SpecificDisease	D009396
1655284	375	386	Wilms tumor	Modifier	D009396
1655284	461	481	Denys-Drash syndrome	SpecificDisease	D030321
1655284	807	819	Wilms tumors	SpecificDisease	D009396
1655284	875	880	tumor	DiseaseClass	D009369
1655284	1004	1024	Denys-Drash syndrome	SpecificDisease	D030321

10366443|t|Molecular basis of feline beta-glucuronidase deficiency: an animal model of mucopolysaccharidosis VII.
10366443|a|A family of domestic cats was found that exhibited clinical and biochemical abnormalities consistent with mucopolysaccharidosis VII, an autosomal recessive lysosomal storage disorder caused by beta-glucuronidase deficiency. beta-Glucuronidase activity was undetectable in affected cat fibroblasts and restored by retroviral gene transfer of rat beta-glucuronidase cDNA. beta-Glucuronidase mRNA was normal in affected cat testis by Northern blot analysis. Normal feline beta-glucuronidase cDNA was cloned and characterized, and amplified from affected cat fibroblasts by reverse transcription coupled polymerase chain reaction. There was a G-to-A transition in the affected cat cDNA that predicted an E351K substitution, destroyed a BssSI site, and eliminated GUSB enzymatic activity in expression studies. Multiple species comparison and the crystal structure of human beta-glucuronidase indicated that E351 is a highly conserved residue most likely essential in maintenance of the enzymes conformation. BssSI digestion of polymerase chain reaction products amplified from genomic DNA indicated that affected cats were homozygous and cats with half-normal beta-glucuronidase activity were heterozygous for the missense mutation. Carriers identified in this manner produced affected kittens in prospective breedings, and a feline MPS VII breeding colony has been established.. 
10366443	26	55	beta-glucuronidase deficiency	SpecificDisease	D016538
10366443	76	101	mucopolysaccharidosis VII	SpecificDisease	D016538
10366443	209	234	mucopolysaccharidosis VII	SpecificDisease	D016538
10366443	239	285	autosomal recessive lysosomal storage disorder	DiseaseClass	D016464
10366443	296	325	beta-glucuronidase deficiency	SpecificDisease	D016538
10366443	1432	1439	MPS VII	Modifier	D016538

10581027|t|Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis.
10581027|a|Papillon-Lefevre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1. 2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers. 
10581027	61	80	periodontal disease	SpecificDisease	D010510
10581027	85	107	palmoplantar keratosis	DiseaseClass	D007645
10581027	109	134	Papillon-Lefevre syndrome	SpecificDisease	D010214
10581027	139	163	keratosis palmoplantaris	DiseaseClass	D007645
10581027	169	185	periodontopathia	SpecificDisease	D010510
10581027	187	190	PLS	SpecificDisease	D010214
10581027	211	239	autosomal recessive disorder	DiseaseClass	D030342
10581027	301	314	periodontitis	SpecificDisease	D010518
10581027	420	430	tooth loss	SpecificDisease	D016388
10581027	432	454	Palmoplantar keratosis	DiseaseClass	D007645
10581027	507	521	hyperkeratosis	SpecificDisease	D017488
10581027	580	589	Keratosis	SpecificDisease	D007642
10581027	646	649	PLS	Modifier	D010214
10581027	672	685	periodontitis	SpecificDisease	D010518
10581027	690	704	hyperkeratosis	SpecificDisease	D017488
10581027	730	752	palmoplantar keratosis	DiseaseClass	D007645
10581027	756	769	periodontitis	SpecificDisease	D010518
10581027	799	812	periodontitis	SpecificDisease	D010518
10581027	1386	1389	PLS	Modifier	D010214

8563759|t|Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities.
8563759|a|The breast and ovarian cancer susceptibility gene, BRCA1, has been cloned and shown to encode a zinc-finger protein of unknown function. Mutations in BRCA1 account for at least 80% of families with both breast and ovarian cancer, as well as some non-familial sporadic ovarian cancers. The loss of wild-type BRCA1 in tumours of individuals carrying one nonfunctional BRCA1 allele suggests that BRCA1 encodes a tumour suppressor that may inhibit the proliferation of mammary epithelial cells. To examine the role of BRCA1 in normal tissue growth and differentiation, and to generate a potential model for the cancer susceptibility associated with loss of BRCA1 function, we have created a mouse line carrying a mutation in one Brca1 allele. Analysis of mice homozygous for the mutant allele indicate that Brca1 is critical for normal development, as these mice died in utero between 10 and 13 days of gestation (E10-E13). Abnormalities in Brca1-deficient embryos were most evident in the neural tube, with 40% of the embryos presenting with varying degrees of spina bifida and anencephaly. In addition, the neuroepithelium in Brca1-deficient embryos appeared disorganized, with signs of both rapid proliferation and excessive cell death.. 
8563759	0	16	Brca1 deficiency	SpecificDisease	OMIM:604370
8563759	34	53	embryonic lethality	DiseaseClass	D020964
8563759	71	100	neuroepithelial abnormalities	DiseaseClass	D018302
8563759	106	131	breast and ovarian cancer	Modifier	D061325
8563759	305	330	breast and ovarian cancer	CompositeMention	D061325
8563759	370	385	ovarian cancers	SpecificDisease	D010051
8563759	418	425	tumours	DiseaseClass	D009369
8563759	511	517	tumour	Modifier	D009369
8563759	709	715	cancer	Modifier	D009369
8563759	1039	1054	Brca1-deficient	Modifier	OMIM:604370
8563759	1160	1172	spina bifida	SpecificDisease	D016135
8563759	1177	1188	anencephaly	SpecificDisease	D000757
8563759	1226	1241	Brca1-deficient	Modifier	OMIM:604370

8301658|t|X linked recessive thrombocytopenia.
8301658|a|A Saudi Arab boy presented in early childhood with thrombocytopenia, morphologically large and normal sized platelets, increased mean platelet volume, and a hypermegakaryocytic bone marrow. There was no clinical and laboratory evidence of any significant immunological abnormalities. Similar findings in two other brothers suggested strongly that they were all suffering from an X linked recessive thrombocytopenic disorder. Results of DNA analysis with the probe M27 beta are consistent with X linkage and indicate also that the locus of the relevant gene lies close to or is identical to the locus of the gene for the Wiskott-Aldrich syndrome (WAS). Because of various features which include the presence of large and normal sized platelets (rather than small platelets) and freedom from significant immune deficiencies, it is likely that the X linked recessive thrombocytopenia in this family is an isolated entity quite distinct from the classical WAS phenotype. However, a modified expression of the WAS gene producing a mild phenotypic variant cannot be excluded entirely.. 
8301658	0	35	X linked recessive thrombocytopenia	SpecificDisease	OMIM:313900
8301658	88	104	thrombocytopenia	SpecificDisease	D013921
8301658	292	319	immunological abnormalities	DiseaseClass	D007154
8301658	416	460	X linked recessive thrombocytopenic disorder	SpecificDisease	OMIM:313900
8301658	657	681	Wiskott-Aldrich syndrome	SpecificDisease	D014923
8301658	683	686	WAS	SpecificDisease	D014923
8301658	839	858	immune deficiencies	DiseaseClass	D007154
8301658	882	917	X linked recessive thrombocytopenia	SpecificDisease	OMIM:313900
8301658	989	992	WAS	Modifier	D014923
8301658	1042	1045	WAS	Modifier	D014923

7315872|t|Genetics of cerebrotendinous xanthomatosis (CTX): an autosomal recessive trait with high gene frequency in Sephardim of Moroccan origin.
7315872|a|We described 6 patients (from 3 families) affected with cerebrotendinous xanthomatosis (CTX). All are Sephardic Jews of Moroccan extraction. In view of the small number of CTX patients diagnosed in the world (a total of 50 including our 6 patients), we are probably dealing with an ethnic subgroup with a high CTX gene frequency, which we have estimated to be 1/108. Since there are differences in expression in this disease, we recommend cholestanol study in cases of undiagnosed cataract or tendinous xanthomas in childhood or early adolescence. The diagnosis in CTX is important not only for genetic counseling, but also in veiw of possible treatment.. 
7315872	12	42	cerebrotendinous xanthomatosis	SpecificDisease	D019294
7315872	44	47	CTX	SpecificDisease	D019294
7315872	193	223	cerebrotendinous xanthomatosis	SpecificDisease	D019294
7315872	225	228	CTX	SpecificDisease	D019294
7315872	309	312	CTX	Modifier	D019294
7315872	618	626	cataract	SpecificDisease	D002386
7315872	630	649	tendinous xanthomas	SpecificDisease	D014973
7315872	702	705	CTX	SpecificDisease	D019294

8408659|t|A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins.
8408659|a|Plasma HDL are a negative risk factor for atherosclerosis. Cholesteryl ester transfer protein (CETP; 476 amino acids) transfers cholesteryl ester from HDL to other lipoproteins. Subjects with homozygous CETP deficiency caused by a gene splicing defect have markedly elevated HDL; however, heterozygotes have only mild increases in HDL. We describe two probands with a CETP missense mutation (442 D  G). Although heterozygous, they have threefold increases in HDL concentration and markedly decreased plasma CETP mass and activity, suggesting that the mutation has dominant effects on CETP and HDL in vivo. Cellular expression of mutant cDNA results in secretion of only 30% of wild type CETP activity. Moreover, coexpression of wild type and mutant cDNAs leads to inhibition of wild type secretion and activity. The dominant effects of the CETP missense mutation during cellular expression probably explains why the probands have markedly increased HDL in the heterozygous state, and suggests that the active molecular species of CETP may be multimeric.. 
8408659	177	192	atherosclerosis	SpecificDisease	D050197
8408659	338	353	CETP deficiency	SpecificDisease	OMIM:143470

2571579|t|Huntington disease: no evidence for locus heterogeneity.
2571579|a|A total of 63 families with Huntington disease (HD) were examined for linkage between HD and G8 (D4S10). The families included 57 Caucasian, four Black American, and two Japanese. The combined maximum lod score was 87. 69 at theta = 0. 04 (99% confidence interval 0. 018-0. 071). The maximum frequency of recombination was 0. 03 in males and 0. 05 in females. Fifty-seven families gave positive lod scores; five small families gave mildly negative lod scores. The maximum likelihood estimate of alpha, the proportion of linked loci, was 1. 0 with a lower 99% confidence interval of 0. 88. These data suggest that there is only one HD locus, although a second rare locus cannot be ruled out. 
2571579	0	18	Huntington disease	SpecificDisease	D006816
2571579	85	103	Huntington disease	SpecificDisease	D006816
2571579	105	107	HD	SpecificDisease	D006816
2571579	143	145	HD	SpecificDisease	D006816
2571579	688	690	HD	Modifier	D006816

3258663|t|Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand disease.
3258663|a|Severe von Willebrand disease is characterized by undetectable or trace quantities of von Willebrand factor in plasma and tissue stores. We have studied the genomic DNA of 10 affected individuals from six families with this disorder using probes from the 5 and 3 ends of the vWF cDNA and with a probe extending from the 5 end into the central region. Southern blots of restriction endonuclease digests and gene dosage analysis measurements carried out with quantitative slot blots of undigested genomic DNA separated these patients into three groups. The first group consisted of a family with complete homozygous deletions of the vWF gene in the four probands. Gene dosage analysis was consistent with heterozygous deletions in both of the asymptomatic parents and four asymptomatic siblings of this kindred (P less than 0. 01). The second group was comprised of a family in which there was a complete heterozygous deletion of the vWF gene in the proband and one asymptomatic parent, suggesting that a different type of genetic abnormality was inherited from the other parent. Thus, the patient appeared to be doubly heterozygous for interacting genetic abnormalities affecting vWF expression. In the third group, no gene deletions could be detected. Alloantibodies developed only in the kindred with homozygous deletions. These techniques should prove useful in identifying carriers of severe von Willebrand disease and also in defining patients predictably at risk of developing alloantibodies to vWF. 
3258663	45	59	von Willebrand	Modifier	D014842
3258663	100	129	severe von Willebrand disease	SpecificDisease	D056729
3258663	131	160	Severe von Willebrand disease	SpecificDisease	D056729
3258663	217	231	von Willebrand	Modifier	D014842
3258663	1152	1171	genetic abnormality	DiseaseClass	D030342
3258663	1278	1299	genetic abnormalities	DiseaseClass	D030342
3258663	1519	1548	severe von Willebrand disease	SpecificDisease	D056729

7795591|t|Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma.
7795591|a|Germline mutations in the RB1 gene confer hereditary predisposition to retinoblastoma. We have performed a mutation survey of the RB1 gene in 232 patients with hereditary or non hereditary retinoblastoma. We systematically explored all 27 exons and flanking sequences as well as the promotor. All types of point mutations are represented and are found unequally distributed along the RB1 gene sequence. In the population we studied, exons 3, 8, 18 and 19 are preferentially altered. The range of frequency of detection of germline mutations is about 20%, indicating that other mechanisms of inactivation of RB1 should be involved. The spectrum of mutations presented here should help to improve the clinical management of retinoblastoma and to understand the molecular mechanisms leading to tumorigenesis.. 
7795591	77	121	hereditary and non hereditary retinoblastoma	CompositeMention	D012175
7795591	194	208	retinoblastoma	SpecificDisease	D012175
7795591	283	326	hereditary or non hereditary retinoblastoma	CompositeMention	D012175
7795591	845	859	retinoblastoma	SpecificDisease	D012175

2773936|t|Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein.
2773936|a|The nosology of the inborn errors of myelin metabolism has been stymied by the lack of molecular genetic analysis. Historically, Pelizaeus-Merzbacher disease has encompassed a host of neurologic disorders that present with a deficit of myelin, the membrane elaborated by glial cells that encircles and successively enwraps axons. We describe here a Pelizaeus-Merzbacher pedigree of the classical type, with X-linked inheritance, a typical clinical progression, and a pathologic loss of myelinating cells and myelin in the central nervous system. To discriminate variants of Pelizaeus-Merzbacher disease, a set of oligonucleotide primers was constructed to polymerase-chain-reaction (PCR) amplify and sequence the gene encoding proteolipid protein (PLP), a structural protein that comprises half of the protein of the myelin sheath. The PLP gene in one of two affected males and the carrier mother of this family exhibited a single base difference in the more than 2 kb of the PLP gene sequenced, a C----T transition that would create a serine substitution for proline at the carboxy end of the protein. Our results delineate the clinical features of Pelizaeus-Merzbacher disease, define the possible molecular pathology of this dysmyelinating disorder, and address the molecular classification of inborn errors of myelin metabolism. Patients with the classical form (type I) and the more severely affected, connatal variant of Pelizaeus-Merzbacher disease (type II) would be predicted to display mutation at the PLP locus. The other variants (types III-VI), which have sometimes been categorized as Pelizaeus-Merzbacher disease, may represent mutations in genes encoding other structural myelin proteins or proteins critical to myelination.. 
2773936	0	28	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
2773936	33	82	X-linked neurologic disorder of myelin metabolism	DiseaseClass	D020279
2773936	167	201	inborn errors of myelin metabolism	DiseaseClass	D020279
2773936	276	304	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
2773936	331	351	neurologic disorders	DiseaseClass	D009422
2773936	372	389	deficit of myelin	DiseaseClass	D003711
2773936	496	516	Pelizaeus-Merzbacher	Modifier	OMIM:312080
2773936	721	749	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
2773936	1297	1325	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
2773936	1375	1398	dysmyelinating disorder	DiseaseClass	D003711
2773936	1444	1478	inborn errors of myelin metabolism	DiseaseClass	D020279
2773936	1574	1612	Pelizaeus-Merzbacher disease (type II)	SpecificDisease	OMIM:312080
2773936	1746	1774	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080

7874163|t|CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.
7874163|a|We have identified a novel gene containing CAG repeats and mapped it to chromosome 14q32. 1, the genetic locus for Machado-Joseph disease (MJD). In normal individuals the gene contains between 13 and 36 CAG repeats, whereas most of the clinically diagnosed patients and all of the affected members of a family with the clinical and pathological diagnosis of MJD show expansion of the repeat-number (from 68-79). Southern blot analyses and genomic cloning demonstrates the existence of related genes. These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD. 
7874163	35	57	Machado-Joseph disease	SpecificDisease	D017827
7874163	196	218	Machado-Joseph disease	SpecificDisease	D017827
7874163	220	223	MJD	SpecificDisease	D017827
7874163	439	442	MJD	SpecificDisease	D017827
7874163	698	701	MJD	SpecificDisease	D017827

3659917|t|Conservation of the Duchenne muscular dystrophy gene in mice and humans.
3659917|a|A portion of the Duchenne muscular dystrophy (DMD) gene transcript from human fetal skeletal muscle and mouse adult heart was sequenced, representing approximately 25 percent of the total, 14-kb DMD transcript. The nucleic acid and predicted amino acid sequences from the two species are nearly 90 percent homologous. The amino acid sequence that is predicted from this portion of the DMD gene indicates that the protein product might serve a structural role in muscle, but the abundance and tissue distribution of the messenger RNA suggests that the DMD protein is not nebulin.. 
3659917	20	47	Duchenne muscular dystrophy	Modifier	D020388
3659917	90	117	Duchenne muscular dystrophy	Modifier	D020388
3659917	119	122	DMD	Modifier	D020388
3659917	268	271	DMD	Modifier	D020388
3659917	458	461	DMD	Modifier	D020388
3659917	624	627	DMD	Modifier	D020388

2303408|t|Deficiency of the murine fifth complement component (C5). A 2-base pair gene deletion in a 5'-exon.
2303408|a|To ascertain the molecular mechanism that causes murine C5 deficiency, genomic and cDNA libraries were constructed from mouse liver DNA and mRNA employing the congenic strains B10. D2/nSnJ and B10. D2/oSnJ that are sufficient and deficient for C5, respectively. Genomic fragments were isolated which correspond to PvuII and HindIII restriction fragment length polymorphisms associated with C5 deficiency. Sequence analyses demonstrated that each of these polymorphisms resulted from single base pair substitutions and that neither substitution would probably cause or contribute to the C5 deficiency. Sequence analyses of C5 sufficient and deficient cDNAs revealed a 2 base-pair deletion in the deficient cDNAs. The " TA " deletion was located near the 5 end of the cDNA. This deletion shifts the reading frame of the C5 mRNA so that the termination codon UGA is present 4 base pairs downstream from the deletion. Genomic DNA was amplified and sequenced corresponding to the area surrounding the 2-base pair deletion. Six C5-deficient strains, A/HeJ, AKR/J, DBA/2J, NZB/B1NJ, SWR/J, and B10. D2/oSnJ, and four C5-sufficient strains, Balb/CJ, C57Bl/6J, DBA/1J, and B10. D2/nSnJ, were analyzed. The sequencing data revealed that the 2 base pairs were deleted from the C5 gene of each deficient mouse tested but not from the C5 gene of any sufficient mouse. These data demonstrate that  1) there is an identical 2-base pair deletion in an exon of the C5 gene in several different C5-deficient mouse strains; 2) the mRNA transcribed from the C5D gene retains this deletion; and 3) this mutation should result in C5 protein deficiency.
2303408	0	56	Deficiency of the murine fifth complement component (C5)	SpecificDisease	OMIM:609536
2303408	156	169	C5 deficiency	SpecificDisease	OMIM:609536
2303408	330	346	deficient for C5	SpecificDisease	OMIM:609536
2303408	490	503	C5 deficiency	SpecificDisease	OMIM:609536
2303408	686	699	C5 deficiency	SpecificDisease	OMIM:609536
2303408	1122	1134	C5-deficient	Modifier	OMIM:609536
2303408	1577	1589	C5-deficient	Modifier	OMIM:609536
2303408	1708	1729	C5 protein deficiency	SpecificDisease	OMIM:609536

2241452|t|Recurrent meningitis in a patient with congenital deficiency of the C9 component of complement. First case of C9 deficiency in Europe.
2241452|a|We describe the first cases, to our knowledge, of C9 deficiency in Europe that were detected in a Swiss family, of which two members--one with a complete deficiency and the other with approximately half-normal C9 levels--experienced bacterial meningitis. The index patient, a 56-year-old white man with a history of purulent meningitis at the age of 23 years, presented with an acute meningococcal meningitis. No impairment of cellular immunity or immunoglobulin deficiency could be found. Complement assays showed a complete deficiency of the C9 component, while the other individual component levels were normal and the hemolytic activity (measured using the CH50 assay) was only slightly reduced. A family study revealed complete C9 deficiency in the patients healthy brother and half-normal C9 concentrations in his sister, his son (who also had experienced an episode of bacterial meningitis), and his niece, consistent with an inherited C9 deficiency. This first case of recurrent meningitis in a white patient with complete C9 deficiency suggests that this complement defect may also be a risk factor for bacterial, especially neisserial, infections.. 
2241452	10	20	meningitis	SpecificDisease	D008581
2241452	39	94	congenital deficiency of the C9 component of complement	SpecificDisease	OMIM:613825
2241452	110	123	C9 deficiency	SpecificDisease	OMIM:613825
2241452	185	198	C9 deficiency	SpecificDisease	OMIM:613825
2241452	368	388	bacterial meningitis	SpecificDisease	D016920
2241452	451	470	purulent meningitis	SpecificDisease	D008586
2241452	513	543	acute meningococcal meningitis	SpecificDisease	D008585
2241452	548	579	impairment of cellular immunity	DiseaseClass	D007153
2241452	583	608	immunoglobulin deficiency	SpecificDisease	D004406
2241452	652	691	complete deficiency of the C9 component	SpecificDisease	OMIM:613825
2241452	859	881	complete C9 deficiency	SpecificDisease	OMIM:613825
2241452	1011	1031	bacterial meningitis	SpecificDisease	D016920
2241452	1078	1091	C9 deficiency	SpecificDisease	OMIM:613825
2241452	1112	1132	recurrent meningitis	SpecificDisease	D008581+D012008
2241452	1157	1179	complete C9 deficiency	SpecificDisease	OMIM:613825
2241452	1199	1216	complement defect	DiseaseClass	D007153
2241452	1247	1291	bacterial, especially neisserial, infections	DiseaseClass	D016870

6387532|t|Bone marrow transplant in adrenoleukodystrophy.
6387532|a|An allogeneic bone marrow transplant (BMT) from a normal HLA identical sibling donor was performed in a 13-year-old boy with rapidly progressive adrenoleukodystrophy (ALD). Engraftment and complete hematologic recovery occurred within 4 weeks, but neurologic deterioration continued. The patient died of an adenovirus infection 141 days after BMT. ALD is characterized by abnormally high plasma levels of very long chain fatty acids (VLCFA) as a result of impaired capacity to degrade them. Ten days after BMT, the white blood cell VLCFA levels and enzyme activity became normal; after 3 months, there was progressive reduction of plasma VLCFA to levels only slightly above normal.. 
6387532	26	46	adrenoleukodystrophy	SpecificDisease	D000326
6387532	193	213	adrenoleukodystrophy	SpecificDisease	D000326
6387532	215	218	ALD	SpecificDisease	D000326
6387532	296	320	neurologic deterioration	DiseaseClass	D019636
6387532	355	375	adenovirus infection	SpecificDisease	D000257
6387532	396	399	ALD	SpecificDisease	D000326

7458742|t|Increased incidence of cataracts in male subjects deficient in glucose-6-phosphate dehydrogenase.
7458742|a|Glucose-6-phosphate dehydrogenase (G6PD) deficiency in RBCs was found significantly more frequently in 210 male cataractous patients than in 672 control subjects of Sardinian origin. The frequency of the deficiency was increasingly higher in presenile cataracts. In the G6PD-deficient group, the incidence of cortical and total cataracts was also increased. It is suggested that decrease of the G6PD activity in the lens, which accompanies its deficiency in the erythrocyte, might play a role in the cataracto-genesis of these patients. Moreover, G6PD deficiency should be added to other conditions, such as the galactosemic states and riboflavin deficiency, where cataracts represent a sensitive indicator of metabolic abnormalities of the RBC.. 
7458742	23	32	cataracts	SpecificDisease	D002386
7458742	50	96	deficient in glucose-6-phosphate dehydrogenase	SpecificDisease	D005955
7458742	98	149	Glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
7458742	210	221	cataractous	Modifier	D002386
7458742	350	359	cataracts	SpecificDisease	D002386
7458742	368	382	G6PD-deficient	Modifier	D005955
7458742	407	435	cortical and total cataracts	CompositeMention	D002386
7458742	645	660	G6PD deficiency	SpecificDisease	D005955
7458742	710	722	galactosemic	Modifier	OMIM:230400
7458742	734	755	riboflavin deficiency	SpecificDisease	D012257
7458742	763	772	cataracts	SpecificDisease	D002386
7458742	808	831	metabolic abnormalities	DiseaseClass	D008659

2894613|t|Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma.
2894613|a|Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas. Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type. We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. 4). Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself. An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative tumour suppressor which can be associated with both the inherited and sporadic forms of the cancer. Sporadic renal cell carcinomas have previously been associated with the loss of regions on chromosome 3p (refs 5, 6). Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same tumour suppressor gene on this chromosome.. 
2894613	0	25	Von Hippel-Lindau disease	SpecificDisease	D006623
2894613	77	97	renal cell carcinoma	SpecificDisease	D002292
2894613	99	124	Von Hippel-Lindau disease	SpecificDisease	D006623
2894613	126	129	VHL	SpecificDisease	D006623
2894613	137	164	autosomal dominant disorder	DiseaseClass	D030342
2894613	215	221	cancer	DiseaseClass	D009369
2894613	233	250	hemangioblastomas	SpecificDisease	D018325
2894613	282	300	phaeochromocytomas	SpecificDisease	D010673
2894613	302	325	pancreatic malignancies	SpecificDisease	OMIM:260350
2894613	331	352	renal cell carcinomas	SpecificDisease	D002292
2894613	354	375	Renal cell carcinomas	SpecificDisease	D002292
2894613	457	489	bilateral and multifocal tumours	CompositeMention	D009369
2894613	569	575	tumour	Modifier	D009369
2894613	606	609	VHL	Modifier	D006623
2894613	750	753	VHL	Modifier	D006623
2894613	804	807	VHL	Modifier	D006623
2894613	917	923	tumour	Modifier	D009369
2894613	972	978	tumour	Modifier	D009369
2894613	1028	1070	inherited and sporadic forms of the cancer	CompositeMention	D009369
2894613	1072	1102	Sporadic renal cell carcinomas	SpecificDisease	D002292
2894613	1241	1261	renal cell carcinoma	SpecificDisease	D002292
2894613	1334	1340	tumour	Modifier	D009369

2895982|t|Tightly linked flanking markers for the Lowe oculocerebrorenal syndrome, with application to carrier assessment.
2895982|a|The Lowe oculocerebrorenal syndrome (OCRL) is characterized by congenital cataract, mental retardation, and defective renal tubular function. A map assignment of OCRL to Xq24-q26 has been made previously by linkage analysis with DXS42 at Xq24-q26 (theta = 0, z = 5. 09) and with DXS10 at Xq26 (theta = 0, z = 6. 45). Two additional families were studied and three additional polymorphisms were identified at DXS42 by using a 35-kb sequence isolated with the probe detecting the original polymorphism at DXS42. With additional OCRL families made informative for DXS42, theta remained 0 with z = 6. 63; and for DXS10 theta = 0. 03 and z = 7. 07. Evidence for placing OCRL at Xq25 also comes from a female with Lowe syndrome and an X; 3 translocation. We have used the Xq25 breakpoint in this patient to determine the position of OCRL relative to the two linked markers. Each derivative chromosome was isolated away from its normal counterpart in somatic cell hybrids. DXS42 was mapped to the derivative chromosome X containing Xpterq25, and DXS10 was mapped to the derivative chromosome 3 containing Xq25-qter. The markers DXS10 and DXS42 therefore show tight linkage with OCRL in six families and flank the Xq25 breakpoint in a female patient with an X; 3 translocation. Linkage analysis with flanking markers was used to assess OCRL carrier status in women at risk. Results, when compared with carrier determination by ophthalmologic examination, indicated that the slit-lamp exam can be a sensitive and specific method of carrier determination in many cases 
2895982	40	71	Lowe oculocerebrorenal syndrome	SpecificDisease	D009800
2895982	117	148	Lowe oculocerebrorenal syndrome	SpecificDisease	D009800
2895982	150	154	OCRL	SpecificDisease	D009800
2895982	187	195	cataract	SpecificDisease	D002386
2895982	197	215	mental retardation	DiseaseClass	D008607
2895982	221	253	defective renal tubular function	DiseaseClass	D015499
2895982	275	279	OCRL	SpecificDisease	D009800
2895982	639	643	OCRL	Modifier	D009800
2895982	821	834	Lowe syndrome	SpecificDisease	D009800
2895982	1284	1288	OCRL	SpecificDisease	D009800
2895982	1441	1445	OCRL	Modifier	D009800

10716718|t|Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice.
10716718|a|Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia-telangiectasia (A-T), which is caused by mutations in the ATM gene. Through gene targeting, we have generated a line of Atm mutant mice, Atm (y/y) mice. In contrast to other Atm mutant mice, Atm (y/y) mice show a lower incidence of thymic lymphoma and survive beyond a few months of age. Atm (y/y) mice exhibit deficits in motor learning indicative of cerebellar dysfunction. Even though we found no gross cerebellar degeneration in older Atm (y/y) animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages. These findings establish that some neuropathological abnormalities seen in A-T patients also are present in Atm mutant mice. In addition, we report a previously unrecognized effect of Atm deficiency on development or maintenance of CD4 (+) 8 (+) thymocytes. We discuss these findings in the context of the hypothesis that abnormal development of Purkinje cells and lymphocytes contributes to the pathogenesis of A-T.. 
10716718	75	95	Motor incoordination	DiseaseClass	D002524
10716718	97	116	immune deficiencies	DiseaseClass	D007154
10716718	143	149	cancer	DiseaseClass	D009369
10716718	189	207	hereditary disease	DiseaseClass	D030342
10716718	208	229	ataxia-telangiectasia	SpecificDisease	D001260
10716718	231	234	A-T	SpecificDisease	D001260
10716718	447	462	thymic lymphoma	SpecificDisease	D013953
10716718	567	589	cerebellar dysfunction	DiseaseClass	D002526
10716718	621	644	cerebellar degeneration	DiseaseClass	D013132
10716718	803	834	neuropathological abnormalities	DiseaseClass	D009422
10716718	843	846	A-T	Modifier	D001260
10716718	952	966	Atm deficiency	SpecificDisease	OMIM:208900
10716718	1180	1183	A-T	SpecificDisease	D001260

1303173|t|Both mutations in G6PD A- are necessary to produce the G6PD deficient phenotype.
1303173|a|The high prevalence of glucose 6-phosphate dehydrogenase (G6PD) deficiency in African populations is due almost entirely to the enzyme variant A-, which differs from the wild-type G6PD B by two amino acid replacements, 68 Val-- > Met and 126 Asn-- > Asp. The non-deficient polymorphic variant G6PD A contains only the mutation 126 Asn-- > Asp. The frequencies of the G6PD A and of the G6PD A- genes in parts of Africa are both about 0. 2. The 68 Val-- > Met mutation has not been found in a B background. This could be because the 68 Val-- > Met mutation happened to arise in an A gene in the first instance, or because the 68 Val-- > Met mutation alone is not sufficient to cause G6PD deficiency. We have approached this question by producing G6PD B, A, A-, and G6PD 68 Val-- > Met in a bacterial expression system and analysing their biochemical properties. With each single mutation we found a slight decrease in both the specific activity and the yield of enzyme when compared to G6PD B. When both mutations were introduced together, there was a roughly additive effect on specific activity, but a much more drastic effect on enzyme yield (4% of normal). This synergistic effect was also demonstrated on thermal stability, especially at low NADP concentrations. Comparable results were produced when the replacement 119 Gln-- > Glu was studied instead of 126 Asn-- > Asp. We infer that the coexistence of the two mutations is responsible for enzyme deficiency in G6PD A- because they act synergistically in causing instability of the enzyme. 
1303173	55	69	G6PD deficient	Modifier	D005955
1303173	104	155	glucose 6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
1303173	762	777	G6PD deficiency	SpecificDisease	D005955
1303173	1527	1552	enzyme deficiency in G6PD	SpecificDisease	D005955

2253937|t|Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction.
2253937|a|We describe oligonucleotide primer sequences that can be used to amplify eight exons plus the muscle promoter of the dystrophin gene in a single multiplex polymerase chain reaction (PCR). When used in conjunction with an existing primer set, these two multiplex reactions detect about 98% of deletions in patients with Duchenne or Becker muscular dystrophy (DMD, BMD). Furthermore, these primers amplify most of the exons in the deletion prone " hot spot " region around exons 44 to 53, allowing determination of deletion endpoints and prediction of mutational effects on the translational reading frame. Thus, use of these PCR-based assays will allow deletion detection and prenatal diagnosis for most DMD/BMD patients in a fraction of the time required for Southern blot analysis.. 
2253937	20	23	DMD	Modifier	D020388
2253937	24	27	BMD	Modifier	C537666
2253937	392	429	Duchenne or Becker muscular dystrophy	CompositeMention	D020388|C537666
2253937	431	434	DMD	SpecificDisease	D020388
2253937	436	439	BMD	SpecificDisease	C537666
2253937	776	779	DMD	Modifier	D020388
2253937	780	783	BMD	Modifier	C537666

2591962|t|Recombination events that locate myotonic dystrophy distal to APOC2 on 19q.
2591962|a|We previously reported a recombination in an individual with myotonic dystrophy (DM) which placed the markers D19S19 and APOC2 on the same side of the DM locus. Haplotyping of this family with more recently characterized probes which are either tightly linked to DM or distal to the linkage group at q13. 2 shows that the DM locus is distal to APOC2. This is confirmed by other recombinants where DM segregates with distal probes. Additional marker to marker recombinations in unaffected individuals are reported and support the order and orientation of the DM linkage group as pter- (INSR, LDLR, S9) - (S19, BCL3, APOC2) - (CKMM, DM) - (S22, + + + PRKCG) -qter. The data presented here cannot determine whether DM is proximal or distal to CKMM. The consequences of this probe order for antenatal diagnosis and future research aiming to isolate the gene which is affected in DM are discussed. 
2591962	33	51	myotonic dystrophy	SpecificDisease	D009223
2591962	137	155	myotonic dystrophy	SpecificDisease	D009223
2591962	157	159	DM	SpecificDisease	D009223
2591962	227	229	DM	Modifier	D009223
2591962	339	341	DM	SpecificDisease	D009223
2591962	398	400	DM	Modifier	D009223
2591962	473	475	DM	SpecificDisease	D009223
2591962	634	636	DM	Modifier	D009223
2591962	788	790	DM	SpecificDisease	D009223
2591962	951	953	DM	SpecificDisease	D009223

10425038|t|New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCP strategy.
10425038|a|The gene for ataxia-telangiectasia, ATM, spans about 150 kb of genomic DNA. ATM mutations are found along the entire gene, with no evidence of a mutational hot spot. Using DNA as the starting material, we screened the ATM gene in 92 A-T patients, using an optimized single-strand conformation polymorphism (SSCP) technique that detected all previously known mutations in the polymerase chain reaction (PCR) segments being analyzed. To expedite screening, we sequentially loaded the SSCP gels with three different sets of PCR products that were pretested to avoid overlapping patterns. Many of the DNA changes we detected were intragenic polymorphisms. Of an expected 177 unknown mutations, we detected approximately 70%, mostly protein truncating mutations (that would have been detectable by protein truncation testing if RNA starting material had been available). Mutations have now been defined for every exon of the ATM gene. Herein, we present 35 new mutations and 34 new intragenic polymorphisms or rare variants within the ATM gene. This is the most comprehensive compilation of ATM polymorphisms assembled to date. Defining polymorphic sites as well as mutations in the ATM gene will be of great importance in designing automated methods for detecting mutations.. 
10425038	112	133	ataxia-telangiectasia	SpecificDisease	D001260
10425038	332	335	A-T	Modifier	D001260

10417280|t|Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints.
10417280|a|Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At a de novo frequency of approximately. 67-1/10, 000 births, these deletions represent a common structural chromosome change in the human genome. To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster. Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions. Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints. The END-repeat units are derived from large genomic duplications of a novel gene (HERC2), many copies of which are transcriptionally active in germline tissues. One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event. We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process. 
10417280	27	62	Prader-Willi and Angelman syndromes	CompositeMention	D011218|D017204
10417280	157	178	Prader-Willi syndrome	SpecificDisease	D011218
10417280	180	183	PWS	SpecificDisease	D011218
10417280	189	206	Angelman syndrome	SpecificDisease	D017204
10417280	208	210	AS	SpecificDisease	D017204
10417280	225	250	neurobehavioral disorders	DiseaseClass	D019954
10417280	1159	1162	PWS	Modifier	D011218
10417280	1163	1165	AS	Modifier	D017204

8530105|t|A 4-megabase YAC contig that spans the Langer-Giedion syndrome region on human chromosome 8q24.1: use in refining the location of the trichorhinophalangeal syndrome and multiple exostoses genes (TRPS1 and EXT1).
8530105|a|We have constructed a physical map covering over 4 Mb of human chromosome 8q24. 1 and used this map to refine the locations of the genes responsible for Langer-Giedion syndrome. The map is composed of overlapping YAC clones that were identified and ordered in relation to sequence tagged sites mapped to the Langer-Giedion chromosomal region on somatic cell hybrids. The minimal region of overlap of Langer-Giedion syndrome deletions, previously identified by analysis of 15 patients, was placed on the map by analysis of 2 patients whose deletions define the endpoints. The chromosome 8 breakpoint of a balanced t (8; 9) (q24. 11; q33. 3) translocation from a patient with trichorhinophalangeal syndrome (TRPS I) was found to be located just within the proximal end of the minimal deletion region. A deletion of 8q24. 11-q24. 3 in a patient with multiple exostoses was found to overlap the distal end of the LGS deletion region, indicating that the EXT1 gene is distal to the TRPS1 gene and supporting the hypothesis that Langer-Giedion syndrome is due to loss of functional copies of both the TRPS1 and the EXT1 genes 
8530105	39	62	Langer-Giedion syndrome	Modifier	D015826
8530105	134	164	trichorhinophalangeal syndrome	SpecificDisease	OMIM:190350
8530105	365	388	Langer-Giedion syndrome	SpecificDisease	D015826
8530105	612	635	Langer-Giedion syndrome	Modifier	D015826
8530105	886	916	trichorhinophalangeal syndrome	SpecificDisease	OMIM:190350
8530105	918	922	TRPS	SpecificDisease	OMIM:190350
8530105	1121	1124	LGS	Modifier	D015826
8530105	1235	1258	Langer-Giedion syndrome	SpecificDisease	D015826

8401501|t|Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA.
8401501|a|A susceptibility gene for hereditary breast-ovarian cancer, BRCA1, has been assigned by linkage analysis to chromosome 17q21. Candidate genes in this region include EDH17B2, which encodes estradiol 17 beta-hydroxysteroid dehydrogenase II (17 beta-HSD II), and RARA, the gene for retinoic acid receptor alpha. We have typed 22 breast and breast-ovarian cancer families with eight polymorphisms from the chromosome 17q12-21 region, including two in the EDH17B2 gene. Genetic recombination with the breast cancer trait excludes RARA from further consideration as a candidate gene for BRCA1. Both BRCA1 and EDH17B2 map to a 6 cM interval (between THRA1 and D17S579) and no recombination was observed between the two genes. However, direct sequencing of overlapping PCR products containing the entire EDH17B2 gene in four unrelated affected women did not uncover any sequence variation, other than previously described polymorphisms. Mutations in the EDH17B2 gene, therefore do not appear to be responsible for the hereditary breast-ovarian cancer syndrome. Single meiotic crossovers in affected women suggest that BRCA1 is flanked by the loci RARA and D17S78.. 
8401501	23	53	breast-ovarian cancer syndrome	DiseaseClass	D061325
8401501	171	203	hereditary breast-ovarian cancer	DiseaseClass	D061325
8401501	471	503	breast and breast-ovarian cancer	Modifier	D001943|D061325
8401501	641	654	breast cancer	Modifier	D001943
8401501	1155	1196	hereditary breast-ovarian cancer syndrome	DiseaseClass	D061325

313733|t|Hereditary C2 deficiency associated with common variable immunodeficiency.
313733|a|Homozygous C2 deficiency in a 19-year-old boy was associated with variable immunodeficiency manifested by marked hypoimmunoglobulinemia and impaired antibody responses, normal circulating B lymphocytes, and subnormal T-cell functions. Neither antilymphocytic autoantibodies nor chromosomal abnormalities were found. Serum immunoglobulin levels were within normal limits in his parents and brother who were heterozygous for C2 deficiency. The patients lymphocytes were homozygous at the HLA-D locus but expressed an antigen different from DW2.. 
313733	0	24	Hereditary C2 deficiency	SpecificDisease	OMIM:217000
313733	57	73	immunodeficiency	DiseaseClass	D007153
313733	86	99	C2 deficiency	SpecificDisease	OMIM:217000
313733	150	166	immunodeficiency	DiseaseClass	D007153
313733	188	210	hypoimmunoglobulinemia	DiseaseClass	D007153
313733	353	378	chromosomal abnormalities	DiseaseClass	D002869
313733	498	511	C2 deficiency	SpecificDisease	OMIM:217000

3012567|t|Isolation of molecular probes associated with the chromosome 15 instability in the Prader-Willi syndrome.
3012567|a|Flow cytometry and recombinant DNA techniques have been used to obtain reagents for a molecular analysis of the Prader-Willi syndrome (PWS). HindIII total-digest libraries were prepared in lambda phage Charon 21A from flow-sorted inverted duplicated no. 15 human chromosomes and propagated on recombination-proficient (LE392) and recBC-, sbcB- (DB1257) bacteria. Twelve distinct chromosome 15-specific probes have been isolated. Eight localized to the region 15q11----13. Four of these eight sublocalized to band 15q11. 2 and are shown to be deleted in DNA of one of two patients examined with the PWS. Heteroduplex analysis of two of these clones, which grew on DB1257 but not on LE392, revealed stem-loop structures in the inserts, indicative of inverted, repeated DNA elements. Such DNA repeats might account for some of the cloning instability of DNA segments from proximal 15q. Analysis of the genetic and physical instability associated with the repeated sequences we have isolated from band 15q11. 2 may elucidate the molecular basis for the instability of this chromosomal region in patients with the PWS or other diseases associated with chromosomal abnormalities in the proximal long arm of human chromosome 15 
3012567	83	104	Prader-Willi syndrome	SpecificDisease	D011218
3012567	218	239	Prader-Willi syndrome	SpecificDisease	D011218
3012567	241	244	PWS	SpecificDisease	D011218
3012567	704	707	PWS	SpecificDisease	D011218
3012567	1215	1218	PWS	SpecificDisease	D011218
3012567	1253	1278	chromosomal abnormalities	DiseaseClass	D002869

7543316|t|Myotonic dystrophy: evidence for a possible dominant-negative RNA mutation.
7543316|a|The trinucleotide expansion mutation causing myotonic dystrophy is in the 3 untranslated region of a protein kinase gene. The molecular mechanisms by which the expanded repeat causes the clinically variable and multisystemic disease, myotonic dystrophy, are not understood. It has been particularly difficult to rationalize the dominant inheritance with the fact that the expansion mutation lies outside of the protein-encoding gene elements, and should not be translated into protein. Here we use muscle biopsies from classical adult-onset myotonic dystrophy patients to study the accumulation of transcripts from both the normal and expanded DM kinase genes in patient muscle, and compare the results to normal and myopathic controls. We found relatively small decreases of DM kinase RNA in the total RNA pool from muscle; however, these reductions were not disease specific. Analysis of poly (A) + RNA showed dramatic decreases of both the mutant and normal DM kinase RNAs, and these changes were disease-specific. Our findings are consistent with a novel molecular pathogenetic mechanism for myotonic dystrophy  both the normal and expanded DM kinase genes are transcribed in patient muscle, but the abnormal expansion-containing RNA has a dominant effect on RNA metabolism by preventing the accumulation of poly (A) + RNA. The ability of the expansion mutation to alter accumulation of poly (A) + RNA in trans suggests that myotonic dystrophy may be the first example of a dominant-negative mutation manifested at the RNA level.. 
7543316	0	18	Myotonic dystrophy	SpecificDisease	D009223
7543316	121	139	myotonic dystrophy	SpecificDisease	D009223
7543316	287	308	multisystemic disease	DiseaseClass	D004194
7543316	310	328	myotonic dystrophy	SpecificDisease	D009223
7543316	617	635	myotonic dystrophy	Modifier	D009223
7543316	720	722	DM	Modifier	D009223
7543316	793	802	myopathic	Modifier	D009135
7543316	852	854	DM	Modifier	D009223
7543316	1037	1039	DM	Modifier	D009223
7543316	1172	1190	myotonic dystrophy	SpecificDisease	D009223
7543316	1221	1223	DM	Modifier	D009223
7543316	1505	1523	myotonic dystrophy	SpecificDisease	D009223

8004674|t|Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein.
8004674|a|McLeod syndrome is an X-linked multisystem disorder characterized by abnormalities in the neuromuscular and hematopoietic systems. We have assembled a cosmid contig of 360 kb that encompasses the McLeod gene locus. A 50 kb deletion was detected by screening DNA from patients with radiolabeled whole cosmids, and two transcription units were identified within this deletion. The mRNA expression pattern of one of them, designated as XK, correlates closely to the McLeod phenotype. XK encodes a novel protein with structural characteristics of prokaryotic and eukaryotic membrane transport proteins. Nucleotide sequence analysis of XK from two unrelated McLeod patients has identified point mutations at conserved splice donor and acceptor sites. These findings provide direct evidence that XK is responsible for McLeod syndrome.. 
8004674	26	41	McLeod syndrome	SpecificDisease	OMIM:300842
8004674	91	106	McLeod syndrome	SpecificDisease	OMIM:300842
8004674	113	142	X-linked multisystem disorder	DiseaseClass	D040181
8004674	287	293	McLeod	Modifier	OMIM:300842
8004674	554	560	McLeod	Modifier	OMIM:300842
8004674	744	750	McLeod	Modifier	OMIM:300842
8004674	903	918	McLeod syndrome	SpecificDisease	OMIM:300842

10790204|t|Molecular basis of very long chain acyl-CoA dehydrogenase deficiency in three Israeli patients: identification of a complex mutant allele with P65L and K247Q mutations, the former being an exonic mutation causing exon 3 skipping.
10790204|a|Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a life-threatening disorder of mitochondrial fatty acid beta-oxidation. We identified four novel mutations in three unrelated patients. All patients had the severe childhood form of VLCAD deficiency with early onset and high mortality. Immunoblot analysis revealed that VLCAD protein was undetectable in patients 2 and 3, whereas normal-size VLCAD protein and an aberrant form of VLCAD (4kDa smaller) were detected in patient 1. As expected, null mutations were found in patients 2 and 3  patient 2 is homozygous for a frameshift mutation, del 4 bp at 798-801, and patient 3 is homozygous for a nonsense mutation 65C > A (S22X). Patient 1 was homozygous for a complex mutant allele containing two alterations, including a 194C > T transition (P65L) and 739A > C transversion (K247Q); in the case of P65L, the amino acid change does not reduce enzyme activity. However, the nucleotide change resulted in exon 3 skipping, whereas the latter K247Q mutation had a drastic effect on enzyme activity. We verified these events by in vivo splicing experiments and transient expression analysis of mutant cDNAs. The P65L mutation locates 11 bases upstream of a splice donor site of intron 3. This is an example of an exonic mutation which affects exon-splicing.. 
10790204	19	68	very long chain acyl-CoA dehydrogenase deficiency	SpecificDisease	C536353
10790204	230	287	Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency	SpecificDisease	C536353
10790204	473	489	VLCAD deficiency	SpecificDisease	C536353

10932179|t|Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity.
10932179|a|Huntington disease (HD) is caused by expansion of a glutamine repeat in the amino-terminal region of huntingtin. Despite its widespread expression, mutant huntingtin induces selective neuronal loss in striatal neurons. Here we report that, in mutant mice expressing HD repeats, the production and aggregation of N-terminal huntingtin fragments preferentially occur in HD-affected neurons and their processes and axonal terminals. N-terminal fragments of mutant huntingtin form aggregates and induce neuritic degeneration in cultured striatal neurons. N-terminal mutant huntingtin also binds to synaptic vesicles and inhibits their glutamate uptake in vitro. The specific processing and accumulation of toxic fragments of N-terminal huntingtin in HD-affected striatal neurons, especially in their neuronal processes and axonal terminals, may contribute to the selective neuropathology of HD.. 
10932179	117	135	Huntington disease	SpecificDisease	D006816
10932179	137	139	HD	SpecificDisease	D006816
10932179	383	385	HD	Modifier	D006816
10932179	485	487	HD	Modifier	D006816
10932179	616	637	neuritic degeneration	DiseaseClass	D009410
10932179	863	865	HD	Modifier	D006816
10932179	1004	1006	HD	SpecificDisease	D006816

8240110|t|Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene.
8240110|a|BACKGROUND AND OBJECTIVES  Mutations of the peripherin/RDS gene have been reported in autosomal dominant retinitis pigmentosa, pattern macular dystrophy, and retinitis punctata albescens. We report herein the occurrence of three separate phenotypes within a single family with a novel 3-base pair deletion of codon 153 or 154 of the peripherin/RDS gene. DESIGN  Case reports with clinical features, fluorescein angiography, kinetic perimetry, electrophysiological studies, and molecular genetics. SETTING  University medical centers. PATIENTS  A 75-year-old woman, her two daughters (aged 44 and 50 years), and her 49-year-old son were screened for peripherin/RDS mutations because of the presence of multiple phenotypes within the same family. RESULTS  The mother presented at age 63 years with a profoundly abnormal electroretinogram (ERG) and adult-onset retinitis pigmentosa that progressed dramatically over 12 years, with marked loss of peripheral visual field. One daughter developed pattern macular dystrophy at age 31 years. At age 44 years, her ERG was moderately abnormal but her clinical disease was limited to the macula. Another daughter presented at age 42 years with macular degeneration and over 10 years developed the clinical picture of fundus flavimaculatus. Her peripheral visual field was preserved but her ERG was moderately abnormal. The son had onset of macular degeneration at age 44 years. Pericentral scotomas were present and the ERG was markedly abnormal. Fluorescein angiography revealed punctate pigment epithelial transmission defects. CONCLUSIONS  A 3-base pair deletion of codon 153 or 154 of the peripherin/RDS gene can produce clinically disparate phenotypes even within the same family.. 
8240110	31	51	retinitis pigmentosa	SpecificDisease	D012174
8240110	53	70	pattern dystrophy	SpecificDisease	D008268
8240110	76	97	fundus flavimaculatus	SpecificDisease	C535804
8240110	267	306	autosomal dominant retinitis pigmentosa	SpecificDisease	D012174
8240110	316	333	macular dystrophy	SpecificDisease	D008268
8240110	339	367	retinitis punctata albescens	SpecificDisease	OMIM:136880
8240110	1039	1059	retinitis pigmentosa	SpecificDisease	D012174
8240110	1172	1197	pattern macular dystrophy	SpecificDisease	D008268
8240110	1364	1384	macular degeneration	SpecificDisease	D008268
8240110	1437	1458	fundus flavimaculatus	SpecificDisease	C535804
8240110	1560	1580	macular degeneration	SpecificDisease	D008268
8240110	1598	1618	Pericentral scotomas	SpecificDisease	D012607

10441571|t|Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies.
10441571|a|The PAX6 gene is involved in ocular morphogenesis, and PAX6 mutations have been detected in various types of ocular anomalies, including aniridia, Peters anomaly, corneal dystrophy, congenital cataract, and foveal hypoplasia. The gene encodes a transcriptional regulator that recognizes target genes through its paired-type DNA-binding domain. The paired domain is composed of two distinct DNA-binding subdomains, the N-terminal subdomain (NTS) and the C-terminal subdomain (CTS), which bind respective consensus DNA sequences. The human PAX6 gene produces two alternative splice isoforms that have the distinct structure of the paired domain. The insertion, into the NTS, of 14 additional amino acids encoded by exon 5a abolishes the DNA-binding activity of the NTS and unmasks the DNA-binding ability of the CTS. Thus, exon 5a appears to function as a molecular switch that specifies target genes. We ascertained a novel missense mutation in four pedigrees with Peters anomaly, congenital cataract, Axenfeldt anomaly, and/or foveal hypoplasia, which, to our knowledge, is the first mutation identified in the splice-variant region. A T-- > A transition at the 20th nucleotide position of exon 5a results in a Val-- > Asp (GTC-- > GAC) substitution at the 7th codon of the alternative splice region. Functional analyses demonstrated that the V54D mutation slightly increased NTS binding and decreased CTS transactivation activity to almost half.. 
10441571	71	84	eye anomalies	DiseaseClass	D005124
10441571	195	211	ocular anomalies	DiseaseClass	D005124
10441571	223	231	aniridia	SpecificDisease	D015783
10441571	233	247	Peters anomaly	SpecificDisease	C537884
10441571	249	266	corneal dystrophy	SpecificDisease	D003317
10441571	268	287	congenital cataract	SpecificDisease	D002386
10441571	293	310	foveal hypoplasia	SpecificDisease	OMIM:136520
10441571	1050	1064	Peters anomaly	SpecificDisease	C537884
10441571	1066	1085	congenital cataract	SpecificDisease	D002386
10441571	1087	1104	Axenfeldt anomaly	SpecificDisease	C535679
10441571	1113	1130	foveal hypoplasia	SpecificDisease	OMIM:136520

1673289|t|A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates.
1673289|a|Utilizing the CEPH reference panel and genotypic data for 53 markers, we have constructed a 20-locus multipoint genetic map of human chromosome 4. New RFLPs are reported for four loci. The map integrates a high-resolution genetic map of 4p16 into a continuous map extending to 4q31 and an unlinked cluster of three loci at 4q35. The 20 linked markers form a continuous linkage group of 152 cM in males and 202 cM in females. Likely genetic locations are provided for 25 polymorphic anonymous sequences and 28 gene-specific RFLPs. The map was constructed employing the LINKAGE and CRIMAP computational methodologies to build the multipoint map via a stepwise algorithm. A detailed 10-point map of the 4p16 region constructed from the CEPH panel provides evidence for heterogeneity in the linkage maps constructed from families segregating for Huntington disease (HD). It additionally provides evidence for position-specific recombination frequencies in the telomeric region of 4p.. 
1673289	977	995	Huntington disease	SpecificDisease	D006816
1673289	997	999	HD	SpecificDisease	D006816

8566965|t|The murine homolog of the human breast and ovarian cancer susceptibility gene Brca1 maps to mouse chromosome 11D.
8566965|a|The recently cloned human breast and ovarian cancer susceptibility gene, BRCA1, is located on human chromosome 17q21. We have isolated murine genomic clones containing Brca1 as a first step in generating a mouse model for the loss of BRCA1 function. A mouse genomic library was screened using probes corresponding to exon 11 of the human BRCA1 gene. Two overlapping mouse clones were identified that hybridized to human BRCA1 exons 9-12. Sequence analysis of 1. 4 kb of the region of these clones corresponding to part of human exon 11 revealed 72% nucleic acid identity but only 50% amino acid identity with the human gene. The longest of the mouse Brca1 genomic clones maps to chromosome 11D, as determined by two-color fluorescence in situ hybridization. The synteny to human chromosome 17 was confirmed by cohybridization with the mouse probe for the NF1-gene. This comparative study confirms that the relative location of the BRCA1 gene has been conserved between mice and humans. 
8566965	32	57	breast and ovarian cancer	Modifier	D061325
8566965	140	165	breast and ovarian cancer	Modifier	D061325

8101038|t|High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy.
8101038|a|We identified a patient suffering from late-infantile metachromatic leukodystrophy (MLD) who has a residual arylsulfatase A (ARSA) activity of about 10%. Fibroblasts of the patient show significant sulfatide degradation activity exceeding that of adult MLD patients. Analysis of the ARSA gene in this patient revealed heterozygosity for two new mutant alleles  in one allele, deletion of C 447 in exon 2 leads to a frameshift and to a premature stop codon at amino acid position 105; in the second allele, a G-- > A transition in exon 5 causes a Gly309-- > Ser substitution. Transient expression of the mutant Ser309-ARSA resulted in only 13% enzyme activity of that observed in cells expressing normal ARSA. The mutant ARSA is correctly targeted to the lysosomes but is unstable. These findings are in contrast to previous results showing that the late-infantile type of MLD is always associated with the complete absence of ARSA activity. The expression of the mutant ARSA protein may be influenced by particular features of oligodendrocytes, such that the level of mutant enzyme is lower in these cells than in others.. 
8101038	64	107	late-infantile metachromatic leukodystrophy	SpecificDisease	D007966
8101038	148	191	late-infantile metachromatic leukodystrophy	SpecificDisease	D007966
8101038	193	196	MLD	SpecificDisease	D007966
8101038	356	365	adult MLD	Modifier	D007966
8101038	958	984	late-infantile type of MLD	SpecificDisease	D007966

10802660|t|De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint switch.
10802660|a|Prader-Willi syndrome (PWS) is a neurogenetic disease characterized by infantile hypotonia, gonadal hypoplasia, obsessive behaviour and neonatal feeding difficulties followed by hyperphagia, leading to profound obesity. PWS is due to a lack of paternal genetic information at 15q11-q13 (ref. 2). Five imprinted, paternally expressed genes map to the PWS region, MKRN3 (ref. 3), NDN (ref. 4), NDNL1 (ref. 5), SNRPN (refs 6-8) and IPW (ref. 9), as well as two poorly characterized framents designated PAR-1 and PAR-5 (ref. 10). Imprinting of this region involves a bipartite imprinting centre (IC), which overlaps SNRPN (refs 10, 11). Deletion of the SNRPN promoter/exon 1 region (the PWS IC element) appears to impair the establishment of the paternal imprint in the male germ line and leads to PWS. Here we report a PWS family in which the father is mosaic for an IC deletion on his paternal chromosome. The deletion chromosome has acquired a maternal methylation imprint in his somatic cells. We have made identical findings in chimaeric mice generated from two independent embryonic stem (ES) cell lines harbouring a similar deletion. Our studies demonstrate that the PWS IC element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance.. 
10802660	116	137	Prader-Willi syndrome	SpecificDisease	D011218
10802660	139	142	PWS	SpecificDisease	D011218
10802660	149	169	neurogenetic disease	DiseaseClass	D020271
10802660	187	206	infantile hypotonia	SpecificDisease	D009123
10802660	208	226	gonadal hypoplasia	SpecificDisease	D006058
10802660	294	305	hyperphagia	SpecificDisease	D006963
10802660	327	334	obesity	SpecificDisease	D009765
10802660	336	339	PWS	SpecificDisease	D011218
10802660	466	469	PWS	Modifier	D011218
10802660	799	802	PWS	Modifier	D011218
10802660	910	913	PWS	SpecificDisease	D011218
10802660	932	935	PWS	Modifier	D011218
10802660	1286	1289	PWS	Modifier	D011218

1897530|t|Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyl transferase.
1897530|a|Galactosemia is an autosomal recessive disorder of human galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT). The molecular basis of this disorder is at present not well understood. We report here two missense mutations which result in low or undetectable enzymatic activity. First, we identified at nucleotide 591 a transition which substitutes glutamine 188 by arginine. The mutated glutamine is not only highly conserved in evolution (conserved also in Escherichia coli and Saccharomyces cerevisiae), but is also two amino acid residues downstream from the active site histidine-proline-histidine triad and results in about 10% of normal enzymatic activity. The arginine 188 mutation is the most common galactosemia mutation characterized to date. It accounts for one-fourth of the galactosemia alleles studied. Second, we report the substitution of arginine 333 by tryptophan, caused by a transition at nucleotide 1025. The area surrounding this missense mutation is the most highly conserved domain in the homologous enzymes from E. coli, yeast, and humans, and this mutation results in undetectable enzymatic activity, suggesting that this is a severe mutation. This second mutation appears to be rare, since it was found only in the patient we sequenced. Our data provide further evidence for the heterogeneity of galactosemia at the molecular level, heterogeneity which might be related to the variable clinical outcome observed in this disorder.. 
1897530	34	46	galactosemia	Modifier	D005693
1897530	158	170	Galactosemia	SpecificDisease	D005693
1897530	177	235	autosomal recessive disorder of human galactose metabolism	DiseaseClass	D005693
1897530	246	311	deficiency of the enzyme galactose-1-phosphate uridyl transferase	SpecificDisease	D005693
1897530	916	928	galactosemia	Modifier	D005693
1897530	995	1007	galactosemia	Modifier	D005693
1897530	1531	1543	galactosemia	SpecificDisease	D005693

10078732|t|Neurophysiologic follow-up of long-term dietary treatment in adult-onset adrenoleukodystrophy.
10078732|a|OBJECTIVE  To monitor the effects of dietary treatment in adult-onset adrenoleukodystrophy (ALD) by means of somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs). BACKGROUND  SEPs and MEPs have proved useful in revealing signs of progressively severe, central dying-back axonopathy in early stages of adult-onset ALD. METHODS  Eight patients with adult-onset ALD underwent clinical examination, brain and spine MRI, and SEP and MEP studies before and after 3 years of Lorenzos oil dietary therapy. RESULTS  Before treatment, brain MRI was normal in five patients. Three of these patients had pure spinal SEP abnormalities and in the remaining two patients SEPs showed signs of involvement of both the spinal and cerebral somatosensory tracts. After treatment, the three patients with pure spinal abnormalities showed clinical and neurophysiologic worsening, whereas the two patients with a more advanced stage of disease (exhibited by SEPs) showed substantially unchanged clinical and neurophysiologic features. The patients with abnormal brain MRI at the onset of treatment showed clinical and neurophysiologic worsening. CONCLUSIONS  Lorenzos oil therapy had no effect on patients with evidence of inflammatory brain lesions. Moreover, in patients without clear signs of inflammatory damage, this treatment does not modify significantly the natural course of the disease. However, because effective treatments should begin before the onset of severe neurologic symptoms, SEPs and MEPs should be considered to evaluate the effectiveness of other experimental treatments in the patient with a negative brain MRI.
10078732	73	93	adrenoleukodystrophy	SpecificDisease	D000326
10078732	165	185	adrenoleukodystrophy	SpecificDisease	D000326
10078732	187	190	ALD	SpecificDisease	D000326
10078732	376	397	dying-back axonopathy	SpecificDisease	D016472
10078732	429	432	ALD	SpecificDisease	D000326
10078732	475	478	ALD	SpecificDisease	D000326
10078732	713	737	spinal SEP abnormalities	DiseaseClass	D016472
10078732	905	925	spinal abnormalities	DiseaseClass	D016472
10078732	1316	1342	inflammatory brain lesions	DiseaseClass	D004660

10577908|t|The molecular basis of Sjogren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene.
10577908|a|Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH). To define the molecular defects causing SLS, we performed mutation analysis of the FALDH gene in probands from 63 kindreds with SLS. Among these patients, 49 different mutations-including 10 deletions, 2 insertions, 22 amino acid substitutions, 3 nonsense mutations, 9 splice-site defects, and 3 complex mutations-were found. All of the patients with SLS were found to carry mutations. Nineteen of the missense mutations resulted in a severe reduction of FALDH enzyme catalytic activity when expressed in mammalian cells, but one mutation (798G-- > C [K266N]) seemed to have a greater effect on mRNA stability. The splice-site mutations led to exon skipping or utilization of cryptic acceptor-splice sites. Thirty-seven mutations were private, and 12 mutations were seen in two or more probands of European or Middle Eastern descent. Four single-nucleotide polymorphisms (SNPs) were found in the FALDH gene. At least four of the common mutations (551C-- > T, 682C-- > T, 733G-- > A, and 798 + 1delG) were associated with multiple SNP haplotypes, suggesting that these mutations originated independently on more than one occasion or were ancient SLS genes that had undergone intragenic recombination. Our results demonstrate that SLS is caused by a strikingly heterogeneous group of mutations in the FALDH gene and provide a framework for understanding the genetic basis of SLS and the development of DNA-based diagnostic tests.. 
10577908	23	47	Sjogren-Larsson syndrome	SpecificDisease	D016111
10577908	109	133	Sjogren-Larsson syndrome	SpecificDisease	D016111
10577908	135	138	SLS	SpecificDisease	D016111
10577908	146	174	autosomal recessive disorder	DiseaseClass	D030342
10577908	192	202	ichthyosis	DiseaseClass	D007057
10577908	204	222	mental retardation	DiseaseClass	D008607
10577908	224	234	spasticity	DiseaseClass	D009128
10577908	240	290	deficient activity of fatty aldehyde dehydrogenase	SpecificDisease	D016111
10577908	340	343	SLS	SpecificDisease	D016111
10577908	428	431	SLS	SpecificDisease	D016111
10577908	651	654	SLS	SpecificDisease	D016111
10577908	1445	1448	SLS	Modifier	D016111
10577908	1529	1532	SLS	SpecificDisease	D016111
10577908	1673	1676	SLS	SpecificDisease	D016111

7055648|t|Severe-glucose-6-phosphate dehydrogenase (G6PD) deficiency associated with chronic hemolytic anemia, granulocyte dysfunction, and increased susceptibility to infections: description of a new molecular variant (G6PD Barcelona).
7055648|a|Molecular, kinetic, and functional studies were carried out on erythrocytes and leukocytes in a Spanish male with G6PD deficiency, congenital nonspherocytic hemolytic anemia (CNSHA), and increased susceptibility to infections. G6PD activity was absent in patients red cells and was about 2% of normal in leukocytes. Molecular studies using standard methods (WHO, 1967) showed G6PD in the patient to have a slightly fast electrophoretic mobility at pH 8. 0 with otherwise normal properties (heat stability at 46 degrees C, apparent affinity for substrates, optimum pH, and utilization of substrate analogues). Other tests showed the patients granulocytes to engulf latex particles normally, but to have impaired reduction of nitroblue tetrazolium and ferricytochrome-c as well as reduced iodination. Chemotaxis and random migration of the patients granulocytes were normal as were myeloperoxidase, leukocyte alkaline phosphatase (LAP), and ultrastructural features. The molecular characteristics of G6PD in the patient differed from those of all previously reported variants associated with CNSHA, so the present variant was provisionally called G6PD Barcelona to distinguish it from other G6PD variants previously described. Possible mechanisms for the severe deficiency of G6PD in erythrocytes and granulocytes was investigated by studies on the immunologic specific activity of the mutant enzyme. 
7055648	0	58	Severe-glucose-6-phosphate dehydrogenase (G6PD) deficiency	SpecificDisease	D005955
7055648	83	99	hemolytic anemia	SpecificDisease	D000743
7055648	101	124	granulocyte dysfunction	DiseaseClass	D007960
7055648	341	356	G6PD deficiency	SpecificDisease	D005955
7055648	358	400	congenital nonspherocytic hemolytic anemia	SpecificDisease	D000746
7055648	402	407	CNSHA	SpecificDisease	D000746
7055648	1317	1322	CNSHA	SpecificDisease	D000746
7055648	1487	1505	deficiency of G6PD	SpecificDisease	D005955

8162071|t|Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly.
8162071|a|Mutation or deletion of the PAX6 gene underlies many cases of aniridia. Three lines of evidence now converge to implicate PAX6 more widely in anterior segment malformations including Peters anomaly. First, a child with Peters anomaly is deleted for one copy of PAX6. Second, affected members of a family with dominantly inherited anterior segment malformations, including Peters anomaly are heterozygous for an R26G mutation in the PAX6 paired box. Third, a proportion of Sey/+ Smalleye mice, heterozygous for a nonsense mutation in murine Pax-6, have an ocular phenotype resembling Peters anomaly. We therefore propose that a variety of anterior segment anomalies may be associated with PAX6 mutations.. 
8162071	55	85	anterior segment malformations	DiseaseClass	C537775
8162071	96	111	Peters' anomaly	SpecificDisease	C537884
8162071	175	183	aniridia	SpecificDisease	D015783
8162071	255	285	anterior segment malformations	DiseaseClass	C537775
8162071	296	310	Peters anomaly	SpecificDisease	C537884
8162071	332	346	Peters anomaly	SpecificDisease	C537884
8162071	443	473	anterior segment malformations	DiseaseClass	C537775
8162071	485	499	Peters anomaly	SpecificDisease	C537884
8162071	696	710	Peters anomaly	SpecificDisease	C537884
8162071	751	777	anterior segment anomalies	DiseaseClass	C537775

10364525|t|In Swedish families with hereditary prostate cancer, linkage to the HPC1 locus on chromosome 1q24-25 is restricted to families with early-onset prostate cancer.
10364525|a|Prostate cancer clusters in some families, and an estimated 5% -10% of all cases are estimated to result from inheritance of prostate cancer-susceptibility genes. We previously reported evidence of linkage to the 1q24-25 region (HPC1) in 91 North American and Swedish families each with multiple cases of prostate cancer (Smith et al. 1996). In the present report we analyze 40 (12 original and 28 newly identified) Swedish families with hereditary prostate cancer (HPC) that, on the basis of 40 markers spanning a 25-cM interval within 1q24-25, have evidence of linkage. In the complete set of families, a maximum two-point LOD score of 1. 10 was observed at D1S413 (at a recombination fraction [theta] of. 1), with a maximum NPL (nonparametric linkage) Z score of 1. 64 at D1S202 (P =. 05). The evidence of linkage to this region originated almost exclusively from the subset of 12 early-onset (age < 65 years) families, which yielded a maximum LOD score of 2. 38 at D1S413 (straight theta = 0) and an NPL Z score of 1. 95 at D1S422 (P =. 03). Estimates from heterogeneity tests suggest that, within Sweden, as many as 50% of early-onset families had evidence of linkage to the HPC1 region. These results are consistent with the hypothesis of linkage to HPC1 in a subset of families with prostate cancer, particularly those with an early age at diagnosis. 
10364525	25	51	hereditary prostate cancer	SpecificDisease	C537243
10364525	144	159	prostate cancer	SpecificDisease	D011471
10364525	161	176	Prostate cancer	SpecificDisease	D011471
10364525	466	481	prostate cancer	SpecificDisease	D011471
10364525	599	625	hereditary prostate cancer	SpecificDisease	C537243
10364525	627	630	HPC	SpecificDisease	C537243
10364525	1451	1466	prostate cancer	SpecificDisease	D011471

2037285|t|Localisation of the myotonic dystrophy locus to 19q13.2-19q13.3 and its relationship to twelve polymorphic loci on 19q.
2037285|a|The order of fourteen polymorphic markers localised to the long arm of human chromosome 19 has been established by multipoint mapping in a set of 40 CEPH (Centre dEtude de Polymorphisme Humain, Paris) reference families. We report here the linkage relationship of the myotonic dystrophy (DM) locus to twelve of these markers as studied in 45 families with DM. The resulting genetic map is supported by the localisation of the DNA markers in a panel of somatic cell hybrids. Ten of the twelve markers have been shown to be proximal to the DM gene and two, PRKCG and D19S22, distal but at distances of approximately 25 cM and 15 cM, respectively. The closest proximal markers are APOC2 (apolipoprotein C-II) and CKM (creatine kinase, muscle) approximately 3 cM and 2 cM from the DM gene respectively, in the order APOC2-CKM-DM. The distance between APOC2, CKM and DM (of the order of 2 million base pairs) and their known orientation should permit directional chromosome walking and jumping. The data presented here should enable us to determine whether or not new markers are distal to APOC2/CKM and thus potentially flank the DM gene.. 
2037285	20	38	myotonic dystrophy	Modifier	D009223
2037285	388	406	myotonic dystrophy	Modifier	D009223
2037285	408	410	DM	Modifier	D009223
2037285	476	478	DM	SpecificDisease	D009223
2037285	658	660	DM	Modifier	D009223
2037285	897	899	DM	Modifier	D009223
2037285	982	984	DM	SpecificDisease	D009223
2037285	1246	1248	DM	Modifier	D009223

10712225|t|A recurrent expansion of a maternal allele with 36 CAG repeats causes Huntington disease in two sisters.
10712225|a|Large intergenerational repeat expansions of the CAG trinucleotide repeat in the HD gene have been well documented for the male germline. We describe a recurrent large expansion of a maternal allele with 36 CAG repeats (to 66 and 57 repeats, respectively, in two daughters) associated with onset of Huntington disease (HD) in the second and third decade in a family without history of HD. Our findings give evidence of a gonadal mosaicism in the unaffected mother. We hypothesize that large expansions also occur in the female germline and that a negative selection of oocytes with long repeats might explain the different instability behavior of the male and the female germlines.. 
10712225	70	88	Huntington disease	SpecificDisease	D006816
10712225	186	188	HD	Modifier	D006816
10712225	404	422	Huntington disease	SpecificDisease	D006816
10712225	424	426	HD	SpecificDisease	D006816
10712225	490	492	HD	SpecificDisease	D006816

10072428|t|Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer.
10072428|a|Inherited mutations in the E-cadherin gene (CDH1) were described recently in three Maori kindreds with familial gastric cancer. Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences. Each family contained  (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer. Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain. In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years. We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations. However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.
10072428	56	79	familial gastric cancer	SpecificDisease	D013274
10072428	84	101	colorectal cancer	SpecificDisease	D015179
10072428	206	229	familial gastric cancer	SpecificDisease	D013274
10072428	231	254	Familial gastric cancer	SpecificDisease	D013274
10072428	323	337	gastric cancer	Modifier	D013274
10072428	442	465	familial gastric cancer	Modifier	D013274
10072428	629	643	gastric cancer	SpecificDisease	D013274
10072428	740	754	gastric cancer	SpecificDisease	D013274
10072428	1027	1056	gastric and colorectal cancer	CompositeMention	D015179|D013274
10072428	1092	1106	gastric cancer	SpecificDisease	D013274
10072428	1142	1159	colorectal cancer	SpecificDisease	D015179
10072428	1242	1265	familial gastric cancer	SpecificDisease	D013274
10072428	1329	1344	gastric cancers	SpecificDisease	D013274
10072428	1465	1493	colorectal and other cancers	DiseaseClass	D015179|D009369
10072428	1584	1601	colorectal cancer	SpecificDisease	D015179
10072428	1684	1714	gastric and colorectal cancers	CompositeMention	D015179|D013274

3346017|t|Germinal mosaicism in Duchenne muscular dystrophy.
3346017|a|We have identified a Duchenne muscular dystrophy (DMD) pedigree where the disease is associated with a molecular deletion within the DMD locus. We have examined the meiotic segregation products of the common female ancestor using marker restriction fragment length polymorphisms (RFLPs) detected by probes that lie within this deletion. These studies show that this female has transmitted three distinct types of X chromosome to her offspring. This observation may be explained by postulating that the mutation arose as a postzygotic deletion within this common ancestor, who was consequently germinally mosaic.. 
3346017	22	49	Duchenne muscular dystrophy	SpecificDisease	D020388
3346017	72	99	Duchenne muscular dystrophy	Modifier	D020388
3346017	101	104	DMD	Modifier	D020388
3346017	184	187	DMD	Modifier	D020388

3347839|t|Expression of the murine Duchenne muscular dystrophy gene in muscle and brain.
3347839|a|Complementary DNA clones were isolated that represent the 5 terminal 2. 5 kilobases of the murine Duchenne muscular dystrophy (Dmd) messenger RNA (mRNA). Mouse Dmd mRNA was detectable in skeletal and cardiac muscle and at a level approximately 90 percent lower in brain. Dmd mRNA is also present, but at much lower than normal levels, in both the muscle and brain of three different strains of dystrophic mdx mice. The identification of Dmd mRNA in brain raises the possibility of a relation between human Duchenne muscular dystrophy (DMD) gene expression and the mental retardation found in some DMD males. These results also provide evidence that the mdx mutations are allelic variants of mouse Dmd gene mutations. 
3347839	25	52	Duchenne muscular dystrophy	Modifier	D020388
3347839	177	204	Duchenne muscular dystrophy	Modifier	D020388
3347839	473	483	dystrophic	Modifier	D020388
3347839	585	612	Duchenne muscular dystrophy	SpecificDisease	D020388
3347839	614	617	DMD	SpecificDisease	D020388
3347839	643	661	mental retardation	DiseaseClass	D008607
3347839	676	679	DMD	Modifier	D020388

7790377|t|Human peroxisomal targeting signal-1 receptor restores peroxisomal protein import in cells from patients with fatal peroxisomal disorders.
7790377|a|Two peroxisomal targeting signals, PTS1 and PTS2, are involved in the import of proteins into the peroxisome matrix. Human patients with fatal generalized peroxisomal deficiency disorders fall into at least nine genetic complementation groups. Cells from many of these patients are deficient in the import of PTS1-containing proteins, but the causes of the protein-import defect in these patients are unknown. We have cloned and sequenced the human cDNA homologue (PTS1R) of the Pichia pastoris PAS8 gene, the PTS1 receptor (McCollum, D., E. Monosov, and S. Subramani. 1993. J. Cell Biol. 121  761-774). The PTS1R mRNA is expressed in all human tissues examined. Antibodies to the human PTS1R recognize this protein in human, monkey, rat, and hamster cells. The protein is localized mainly in the cytosol but is also found to be associated with peroxisomes. Part of the peroxisomal PTS1R protein is tightly bound to the peroxisomal membrane. Antibodies to PTS1R inhibit peroxisomal protein-import of PTS1-containing proteins in a permeabilized CHO cell system. In vitro-translated PTS1R protein specifically binds a serine-lysine-leucine-peptide. A PAS8-PTS1R fusion protein complements the P. pastoris pas8 mutant. The PTS1R cDNA also complements the PTS1 protein-import defect in skin fibroblasts from patients--belonging to complementation group two--diagnosed as having neonatal adrenoleukodystrophy or Zellweger syndrome. The PTS1R gene has been localized to a chromosomal location where no other peroxisomal disorder genes are known to map. Our findings represent the only case in which the molecular basis of the protein-import deficiency in human peroxisomal disorders is understood. 
7790377	116	137	peroxisomal disorders	DiseaseClass	D018901
7790377	294	326	peroxisomal deficiency disorders	DiseaseClass	D018901
7790377	1391	1417	PTS1 protein-import defect	SpecificDisease	OMIM:202370|OMIM:214100
7790377	1513	1542	neonatal adrenoleukodystrophy	SpecificDisease	OMIM:202370
7790377	1546	1564	Zellweger syndrome	SpecificDisease	D015211
7790377	1641	1661	peroxisomal disorder	Modifier	D018901
7790377	1759	1784	protein-import deficiency	DiseaseClass	D008661
7790377	1794	1815	peroxisomal disorders	DiseaseClass	D018901

8012387|t|X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus.
8012387|a|Three forms of X-linked spastic paraplegia (SPG) have been defined. One locus (SPG 1) maps to Xq28 while two clinically distinct forms map to Xq22 (SPG2). A rare X-linked dysmyelinating disorder of the central nervous system, Pelizaeus-Merzbacher disease (PMD), has also been mapped to Xq21-q22, and is caused by mutations in the proteolipid protein gene (PLP) which encodes two myelin proteins, PLP and DM20. While narrowing the genetic interval containing SPG2 in a large pedigree, we found that PLP was the closest marker to the disease locus, implicating PLP as a possible candidate gene. We have found that a point mutation (His139Tyr) in exon 3B of an affected male produces a mutant PLP but a normal DM20, and segregates with the disease (Zmax = 6. 63, theta = 0. 00). It appears, therefore, that SPG2 and PMD are allelic disorders 
8012387	0	27	X-linked spastic paraplegia	SpecificDisease	OMIM:312920
8012387	32	60	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
8012387	65	82	allelic disorders	DiseaseClass	D030342
8012387	132	159	X-linked spastic paraplegia	SpecificDisease	OMIM:312920
8012387	161	164	SPG	SpecificDisease	OMIM:312920
8012387	279	311	X-linked dysmyelinating disorder	DiseaseClass	D020279
8012387	343	371	Pelizaeus-Merzbacher disease	SpecificDisease	OMIM:312080
8012387	373	376	PMD	SpecificDisease	OMIM:312080
8012387	930	933	PMD	SpecificDisease	OMIM:312080
8012387	938	955	allelic disorders	DiseaseClass	D030342