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list | events
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list | relations
list |
|---|---|---|---|---|---|---|
1138
|
20515563
|
[
{
"id": "1139",
"type": "title",
"text": [
"Correlation between thymidylate synthase gene variants, RNA and protein levels in primary colorectal adenocarcinomas."
],
"offsets": [
[
0,
117
]
]
},
{
"id": "1140",
"type": "abstract",
"text": [
"This study was designed to compare thymidylate synthase (TS) genotype, mRNA and protein levels in primary colorectal adenocarcinoma, and to examine the correlation between microsatellite instability (MSI) and TS expression. The TS genotype of 68 patients with colorectal cancer was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis in peripheral blood mononuclear cells and tumour tissue. The TS mRNA levels in tumour tissue were measured by reverse-transcription PCR, and TS protein levels and MSI status were assessed using immunohistochemistry. Significantly higher mRNA and protein levels were observed in patients with the TS 3R/3R versus the 2R/2R and 2R/3R genotypes. There was no correlation between TS single nucleotide polymorphism and TS expression. Individuals homozygous for the six base-pair insertion in the 3'-untranslated region had significantly higher TS mRNA levels than heterozygous and homozygous wild type individuals. The TS mRNA and protein levels were significantly higher in microsatellite unstable tumours compared with microsatellite stable tumours. There was a significant association between the number of TS enhancer region repeats (in blood) and intratumoural TS mRNA and protein levels. A larger case series investigating the role of TS gene polymorphisms as predictors of sensitivity to 5-fluorouracil-based chemotherapy is required."
],
"offsets": [
[
118,
1536
]
]
}
] |
[] |
[] |
[] |
[] |
1141
|
20227423
|
[
{
"id": "1146",
"type": "title",
"text": [
"A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome."
],
"offsets": [
[
0,
111
]
]
},
{
"id": "1147",
"type": "abstract",
"text": [
"AIMS: Disrupted-in schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and major depressive disorder (MDD). Patients with chronic fatigue syndrome (CFS) report having continuous severe fatigue and many overlapping symptoms with MDD; however, the mechanism and effective treatment of CFS are still unclear. We focused on the overlapping symptoms between CFS and MDD and performed an association study of the functional single-nucleotide polymorphism (SNP) in the DISC1 gene with CFS. MAIN METHODS: Venous blood was drawn from CFS patients and controls and genomic DNA was extracted from the whole blood according to standard procedures. Ser704Cys DISC1 SNP was genotyped using the TaqMan 5'-exonuclease allelic discrimination assay. KEY FINDINGS: We found that the Cys704 allele of Ser704Cys SNP was associated with an increased risk of CFS development compared with the Ser704 allele. SIGNIFICANCE: DISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS. Some patients with CFS showed a phenotype similar to that of patients with MDD, but further studies are needed to clarify the biological mechanism, because this study is of a rather preliminary nature. Despite the variety of patients with CFS, DISC1 Ser704Cys has an association with CFS, which may also suggest that DISC1 plays a central role in the induction of various psychiatric diseases."
],
"offsets": [
[
112,
1655
]
]
}
] |
[
{
"id": "1142",
"type": "ProteinMutation",
"text": [
"Ser704Cys"
],
"offsets": [
[
884,
893
]
],
"normalized": []
},
{
"id": "1143",
"type": "ProteinMutation",
"text": [
"Ser704Cys"
],
"offsets": [
[
1029,
1038
]
],
"normalized": []
},
{
"id": "1144",
"type": "ProteinMutation",
"text": [
"Ser704Cys"
],
"offsets": [
[
1153,
1162
]
],
"normalized": []
},
{
"id": "1145",
"type": "ProteinMutation",
"text": [
"Ser704Cys"
],
"offsets": [
[
1512,
1521
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1148
|
20143913
|
[
{
"id": "1152",
"type": "title",
"text": [
"Large deletion involving exon 5 of the arylsulfatase B gene caused apparent homozygosity in a mucopolysaccharidosis type VI patient."
],
"offsets": [
[
0,
132
]
]
},
{
"id": "1153",
"type": "abstract",
"text": [
"Apparent homozygosity for the mutation p.R315X present on exon 5 of the arylsulfatase B (ARSB) gene in a mucopolysaccharidosis type VI patient was solved in this study by further testing for a second mutation. Patient cDNA analysis revealed that the entire exon 5 of the ARSB gene was lacking; this new mutation was identified as c.899-1142del. As the genomic DNA sequencing excluded the presence of splicing mutations, polymerase chain reaction analysis was performed for polymorphisms listed in the NCBI SNP database for the ARSB gene. This allowed the mutation at the genomic DNA level to be identified as g.99367-102002del; this gross deletion, involving the entire exon 5 of the gene and parts of introns 4 and 5 led to a frameshift starting at amino acid 300 and resulting in a protein with 39% amino acids different from the normal enzyme. We stress that extensive DNA analysis needs to be performed in case of apparent homozygosity to avoid potential errors in genetic counseling."
],
"offsets": [
[
133,
1121
]
]
}
] |
[
{
"id": "1149",
"type": "ProteinMutation",
"text": [
"p.R315X"
],
"offsets": [
[
172,
179
]
],
"normalized": []
},
{
"id": "1150",
"type": "DNAMutation",
"text": [
"c.899-1142del"
],
"offsets": [
[
463,
476
]
],
"normalized": []
},
{
"id": "1151",
"type": "DNAMutation",
"text": [
"g.99367-102002del"
],
"offsets": [
[
742,
759
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1154
|
20086182
|
[
{
"id": "1161",
"type": "title",
"text": [
"The six-nucleotide deletion/insertion variant in the CASP8 promoter region is inversely associated with risk of squamous cell carcinoma of the head and neck."
],
"offsets": [
[
0,
157
]
]
},
{
"id": "1162",
"type": "abstract",
"text": [
"Caspase 8 (CASP8) is an apoptosis-related cysteine peptidase involved in the death receptor pathway and likely in the mitochondrial pathway. A CASP8 promoter region six-nucleotide deletion/insertion (-652 6N ins/del) variant and a coding region D302H polymorphism are reportedly important in cancer development, but no reported study has assessed the associations of these genetic variations with risk of head and neck cancer. In a hospital-based study of non-Hispanic whites, we genotyped CASP8 -652 6N del and 302H variants in 1,023 patients with squamous cell carcinoma of the head and neck (SCCHN) and 1,052 cancer-free controls. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models. The CASP8 -652 6N del variant genotypes or haplotypes were inversely associated with SCCHN risk (adjusted OR, 0.70; 95% CI, 0.57-0.85 for the ins/del + del/del genotypes compared with the ins/ins genotype; adjusted OR, 0.73; 95% CI, 0.55-0.97 for the del-D haplotype compared with the ins-D haplotype). Furthermore, the number of the CASP8 -652 6N del (but not 302H) variant allele tended to correlate with increased levels of camptothecin-induced p53-mediated apoptosis in T lymphocytes from 170 cancer-free controls. We concluded that the CASP8 -652 6N del variant allele may contribute to the risk of developing SCCHN in non-Hispanic white populations. Further validation by population-based case-control studies and rigorous mechanistic studies is warranted."
],
"offsets": [
[
158,
1687
]
]
}
] |
[
{
"id": "1155",
"type": "DNAMutation",
"text": [
"-652 6N ins/del"
],
"offsets": [
[
358,
373
]
],
"normalized": []
},
{
"id": "1156",
"type": "ProteinMutation",
"text": [
"D302H"
],
"offsets": [
[
403,
408
]
],
"normalized": []
},
{
"id": "1157",
"type": "DNAMutation",
"text": [
"-652 6N del"
],
"offsets": [
[
654,
665
]
],
"normalized": []
},
{
"id": "1158",
"type": "DNAMutation",
"text": [
"-652 6N del"
],
"offsets": [
[
935,
946
]
],
"normalized": []
},
{
"id": "1159",
"type": "DNAMutation",
"text": [
"-652 6N del"
],
"offsets": [
[
1265,
1276
]
],
"normalized": []
},
{
"id": "1160",
"type": "DNAMutation",
"text": [
"-652 6N del"
],
"offsets": [
[
1472,
1483
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1163
|
20026870
|
[
{
"id": "1166",
"type": "title",
"text": [
"Angiotensin-converting enzyme insertion/deletion and angiotensin type 1 receptor A1166C polymorphisms as genetic risk factors in benign prostatic hyperplasia and prostate cancer."
],
"offsets": [
[
0,
178
]
]
},
{
"id": "1167",
"type": "abstract",
"text": [
"INTRODUCTION: Prostate cancer is one of the most common malignant neoplasias in developed countries. In 2003, 6,536 new cases and 4,602 related deaths were reported in Mexico. The renin-angiotensin system has been shown to play a role in prostate cancer pathology. Two previous studies investigated the association of prostate cancer with the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene; both studies reported an association between prostate cancer and the DD genotype. The present study was aimed at searching for an association of prostate cancer and benign prostatic hyperplasia with the I/D polymorphism in the ACE gene and the A1166C polymorphism in the angiotensin type 1 receptor (AGT1R) gene and at comparing allele frequencies between both groups and the general population. MATERIALS AND METHODS: DNA was extracted from 20 samples from individuals with a prostate cancer diagnosis and from 20 samples from individuals with a benign prostatic hyperplasia diagnosis. Genotyping was performed by PCR-RFLP analysis. Polymorphism frequency results obtained for the test groups were compared with the frequencies in 66 individuals from the general population, which were previously obtained at the same molecular medicine laboratory in the context of other studies. RESULTS: The comparative analysis of the three groups revealed significant differences for allele frequencies in the two genes in patients groups (prostate cancer and benign prostatic hyperplasia) versus the general population. The D allele in the ACE gene was closely associated with a significant higher risk of developing both benign prostatic hyperplasia (odds ratio [OR]=21.87; 95% confidence interval [CI]=2.314-206.479) or prostate cancer (OR=31.66; 95% CI=0.091-1.272), and the AGT1R A1166 allele in the homozygote state was identified as a risk genotype for benign prostatic hyperplasia (OR=56.07). CONCLUSIONS: Genotypes in ACE and AGT1R polymorphisms could be considered as genetic risk markers for benign prostatic hyperplasia or prostate cancer."
],
"offsets": [
[
179,
2249
]
]
}
] |
[
{
"id": "1164",
"type": "DNAMutation",
"text": [
"A1166C"
],
"offsets": [
[
81,
87
]
],
"normalized": []
},
{
"id": "1165",
"type": "DNAMutation",
"text": [
"A1166C"
],
"offsets": [
[
853,
859
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1168
|
19958188
|
[
{
"id": "1176",
"type": "title",
"text": [
"Molecular analysis of gamma-globin promoters, HS-111 and 3'HS1, in beta-thalassemia intermedia patients associated with high levels of Hb F."
],
"offsets": [
[
0,
140
]
]
},
{
"id": "1177",
"type": "abstract",
"text": [
"The nucleotide (nt) variations in the promoter region of the gamma-globin genes, HS-111 and 3'HS1 regions, were studied in Iranian patients with beta-thalassemia intermedia (beta-TI), beta-thalassemia major (beta-TM) and healthy individuals. Of the five nt variations at the 5' end of the (A)gamma-globin gene, -369 (C>G), -611 (-T) and -603/604 (GA>AG) were found in all samples, whereas -588 (A>G) and -AAGC at -222 to -225 were found at different frequencies in the studied groups. Therefore, the -369, -611 and -603/604 variations were considered common mutations in this population, and the difference with respect to the -AAGC deletion was not significant. However, the A allele of the -588 variation and [+] allele of the XmnI polymorphism were more frequent in beta-TI patients, especially those who had the IVS-II-1(G>A)/IVS-II-1(G>A) genotype. The + allele of XmnI also had complete correlation with the A allele of -588 variation. The HS-111 (-21 A) variation also showed association with beta-TI patients who had high levels of Hb F. Bearing in mind that the -588 variation lies within the postulated adult-specific silencer region and that the majority of beta-TI patients had allele A, then it can be envisaged that this allele could have a role in altering the repressor function at this region. Therefore, the A allele of -588, [+] allele of XmnI and HS-111 (-21 A) variation are useful genetic markers to differentiate between beta-TM and beta-TI patients. However, these nt changes alone may not be the only elements raising the level of Hb F, other regulatory and modifying factors also play a role in Hb F production."
],
"offsets": [
[
141,
1778
]
]
}
] |
[
{
"id": "1169",
"type": "DNAMutation",
"text": [
"-369 (C>G)"
],
"offsets": [
[
452,
462
]
],
"normalized": []
},
{
"id": "1170",
"type": "DNAMutation",
"text": [
"-611 (-T)"
],
"offsets": [
[
464,
473
]
],
"normalized": []
},
{
"id": "1171",
"type": "DNAMutation",
"text": [
"-603/604 (GA>AG)"
],
"offsets": [
[
478,
494
]
],
"normalized": []
},
{
"id": "1172",
"type": "DNAMutation",
"text": [
"-588 (A>G)"
],
"offsets": [
[
530,
540
]
],
"normalized": []
},
{
"id": "1173",
"type": "DNAMutation",
"text": [
"-AAGC at -222 to -225"
],
"offsets": [
[
545,
566
]
],
"normalized": []
},
{
"id": "1174",
"type": "DNAMutation",
"text": [
"IVS-II-1(G>A)"
],
"offsets": [
[
957,
970
]
],
"normalized": []
},
{
"id": "1175",
"type": "DNAMutation",
"text": [
"IVS-II-1(G>A)"
],
"offsets": [
[
971,
984
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1178
|
19929939
|
[
{
"id": "1181",
"type": "title",
"text": [
"Multiple trichoepitheliomas--a novel mutation in the CYLD gene."
],
"offsets": [
[
0,
63
]
]
},
{
"id": "1182",
"type": "abstract",
"text": [
"BACKGROUND: Trichoepitheliomas are benign neoplasms with follicular differentiation. They may present as a solitary lesion or as multiple lesions. Multiple trichoepitheliomas are inherited in an autosomal dominant pattern within families, with both variable penetrance and expressivity. Recent investigations support that mutations in CYLD, the gene affected in familial cylindromatosis as well as in Brooke-Spiegler syndrome, are also responsible for multiple trichoepitheliomas. OBJECTIVE: The authors report the case of a 9-year-old African girl with multiple facial trichoepitheliomas in whom a mutation in the CYLD gene was hypothesised. MATERIALS AND METHODS: After genomic DNA extraction from the peripheral blood, a molecular analysis of the CYLD gene was performed by PCR, DHPLC and automated sequencing. RESULTS: A novel heterozygous mutation in exon 18 of the CYLD gene (c.2449delT) was identified, with a deletion of one nucleotide resulting in a premature translational termination codon at amino acid position 831 on the affected allele (p.Cys817Valfs X15). CONCLUSIONS: The predominating tumours define the classification of these three entities. Nevertheless, studies suggest that they can simply represent phenotypic variations of the same disease spectrum, sharing common genetic mutations."
],
"offsets": [
[
64,
1372
]
]
}
] |
[
{
"id": "1179",
"type": "DNAMutation",
"text": [
"c.2449delT"
],
"offsets": [
[
946,
956
]
],
"normalized": []
},
{
"id": "1180",
"type": "ProteinMutation",
"text": [
"p.Cys817Valfs X15"
],
"offsets": [
[
1116,
1133
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1183
|
19918264
|
[
{
"id": "1186",
"type": "title",
"text": [
"FGFR4 Gly388Arg polymorphism and prostate cancer risk in Scottish men."
],
"offsets": [
[
0,
70
]
]
},
{
"id": "1187",
"type": "abstract",
"text": [
"Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth receptor family, was recently reported to be more abundantly expressed in malignant than benign prostate cells. A single nucleotide polymorphism at position 388 of the FGFR4 amino-acid sequence results in the substitution of glycine (Gly) with arginine (Arg) and higher frequency of the ArgArg genotype was previously found in prostate cancer patients. DNA was extracted from the blood drawn from 399 prostate cancer patients, 150 BPH patients and 294 healthy community controls. Polymerase chain reaction was carried out and single nucleotide polymorphisms of FGFR4 were identified by restriction enzyme digestion. No overall association is detectable between the Arg allele and increased prostate cancer risk. Subgroup analysis shows a higher incidence of the heterozygous ArgGly genotype in cancer cases than in the combined group of BPH and controls (P<0.05); this difference is statistically significant between cancer and BPH patients but not between cancer cases and community controls. The single nucleotide polymorphism Gly(388)Arg in FGFR4 is not associated with increased risk of prostate cancer in Scottish men. This observation is in contrast with results from two previous studies conducted in the USA and Japan."
],
"offsets": [
[
71,
1376
]
]
}
] |
[
{
"id": "1184",
"type": "ProteinMutation",
"text": [
"Gly388Arg"
],
"offsets": [
[
6,
15
]
],
"normalized": []
},
{
"id": "1185",
"type": "ProteinMutation",
"text": [
"Gly(388)Arg"
],
"offsets": [
[
1179,
1190
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1188
|
19880293
|
[
{
"id": "1195",
"type": "title",
"text": [
"Polymorphisms in the FOXP3 gene in Han Chinese psoriasis patients."
],
"offsets": [
[
0,
66
]
]
},
{
"id": "1196",
"type": "abstract",
"text": [
"BACKGROUND: Psoriasis is a common dermatological disorder, in which autoimmunity plays an important role. CD4(+)CD25(+) regulatory T cells (T-regs) have been suggested to be involved in the pathogenesis of some autoimmune diseases. T-regs express the fork head/winged helix transcription factor, FOXP3, which appears to be of key importance in the development and function of T-regs. Studies have found that single-nucleotide polymorphisms (SNPs) in the FOXP3 gene contribute to susceptibility to some autoimmune disorders. However, information about FOXP3 gene in psoriasis is limited. OBJECTIVE: This study evaluated the association between FOXP3 gene SNPs and susceptibility to psoriasis in a Han Chinese population. METHODS: In a hospital-based case-control study, 524 patients with psoriasis and 549 psoriasis-free controls were recruited according to age and gender. We investigated four SNPs in the FOXP3 gene (-6054, deletion/ATT; -3279, A/C; -924, A/G; IVS9+459, A/G) in psoriatic patients, and assessed allele and genotype frequencies in psoriatic patients (237 females, 287 males) and normal controls (272 females, 277 males). The polymorphisms were genotyped using the PCR sequence-specific primer (PCR-SSP) technique and PCR-restriction fragment length polymorphism (RFLP) analysis. RESULTS: We found that increased risk of psoriasis was associated with the FOXP3 -3279 AC genotype (adjusted OR, 1.32; 95% CI, 1.01-1.74) and the combined AC+AA genotype (adjusted OR, 1.38; 95% CI, 1.07-1.78), compared with the -3279 CC genotype. We also found that an increased risk of psoriasis was associated with the FOXP3 IVS9+459 GG genotype (adjusted OR, 2.24; 95% CI, 1.41-3.58). However, the combined GA+GG genotype showed no such tendency (adjusted OR=1.28; 95% CI, 1.00-1.64), compared with the IVS9+459 AA genotype. There was no evidence of an increased risk associated with the FOXP3-6054 deletion/ATT or FOXP3-924 A/G genotype. In combined genotype analyses, the FOXP3-3279 AC+AA genotype was more obviously associated in males (adjusted OR=1.60, 95% CI=1.11-2.31) and severe psoriasis patients (PASI score >20; adjusted OR=1.97, 95% CI=1.41-2.75). Meanwhile, the FOXP3 IVS9+459 GA+GG genotype was also associated with severe psoriasis patients (adjusted OR=1.69, 95% CI=1.21-2.36). CONCLUSIONS: FOXP3 polymorphisms appear to contribute to the risk of psoriasis in a Han Chinese population. Larger studies are needed to confirm these findings."
],
"offsets": [
[
67,
2520
]
]
}
] |
[
{
"id": "1189",
"type": "DNAMutation",
"text": [
"-6054, deletion/ATT"
],
"offsets": [
[
985,
1004
]
],
"normalized": []
},
{
"id": "1190",
"type": "DNAMutation",
"text": [
"-3279, A/C"
],
"offsets": [
[
1006,
1016
]
],
"normalized": []
},
{
"id": "1191",
"type": "DNAMutation",
"text": [
"-924, A/G"
],
"offsets": [
[
1018,
1027
]
],
"normalized": []
},
{
"id": "1192",
"type": "DNAMutation",
"text": [
"IVS9+459, A/G"
],
"offsets": [
[
1029,
1042
]
],
"normalized": []
},
{
"id": "1193",
"type": "DNAMutation",
"text": [
"-6054 deletion/ATT"
],
"offsets": [
[
1959,
1977
]
],
"normalized": []
},
{
"id": "1194",
"type": "DNAMutation",
"text": [
"-924 A/G"
],
"offsets": [
[
1986,
1994
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1197
|
19804530
|
[
{
"id": "1198",
"type": "title",
"text": [
"A LDR-PCR approach for multiplex polymorphisms genotyping of severely degraded DNA with fragment sizes <100 bp."
],
"offsets": [
[
0,
111
]
]
},
{
"id": "1199",
"type": "abstract",
"text": [
"Reducing amplicon sizes has become a major strategy for analyzing degraded DNA typical of forensic samples. However, amplicon sizes in current mini-short tandem repeat-polymerase chain reaction (PCR) and mini-sequencing assays are still not suitable for analysis of severely degraded DNA. In this study, we present a multiplex typing method that couples ligase detection reaction with PCR that can be used to identify single nucleotide polymorphisms and small-scale insertion/deletions in a sample of severely fragmented DNA. This method adopts thermostable ligation for allele discrimination and subsequent PCR for signal enhancement. In this study, four polymorphic loci were used to assess the ability of this technique to discriminate alleles in an artificially degraded sample of DNA with fragment sizes <100 bp. Our results showed clear allelic discrimination of single or multiple loci, suggesting that this method might aid in the analysis of extremely degraded samples in which allelic drop out of larger fragments is observed."
],
"offsets": [
[
112,
1148
]
]
}
] |
[] |
[] |
[] |
[] |
1200
|
19728872
|
[
{
"id": "1204",
"type": "title",
"text": [
"A MANBA mutation resulting in residual beta-mannosidase activity associated with severe leukoencephalopathy: a possible pseudodeficiency variant."
],
"offsets": [
[
0,
145
]
]
},
{
"id": "1205",
"type": "abstract",
"text": [
"BACKGROUND: beta-Mannosidosis (OMIM 248510) is a rare inborn lysosomal storage disorder caused by the deficient activity of beta-mannosidase, an enzyme encoded by a single gene (MANBA) located on chromosome 4q22-25. To date, only 20 cases of this autosomal recessive disorder have been described and 14 different MANBA mutations were incriminated in the disease. These are all null mutations or missense mutations that abolish beta-mannosidase activity. In this study, we characterized the molecular defect of a new case of beta-mannosidosis, presenting with a severe neurological disorder. METHODS: Genomic DNA was isolated from peripheral blood leukocytes of the patient to allow MANBA sequencing. The identified mutation was engineered by site-directed mutagenesis and the mutant protein was expressed through transient transfection in HEK293T cells. The beta-mannosidase expression and activity were respectively assessed by Western blot and fluorometric assay in both leukocytes and HEK293T cells. RESULTS: A missense disease-associated mutation, c.1922G>A (p.Arg641His), was identified for which the patient was homozygous. In contrast to previously described missense mutations, this substitution does not totally abrogate the enzyme activity but led to a residual activity of about 7% in the patient's leukocytes, 11% in lymphoblasts and 14% in plasma. Expression studies in transfected cells also resulted in 7% residual activity. CONCLUSION: Correlations between MANBA mutations, residual activity of beta-mannosidase and the severity of the ensuing neurological disorder are discussed. Whether the c.1922G>A mutation is responsible for a yet undescribed pseudodeficiency of beta-mannosidase is also discussed."
],
"offsets": [
[
146,
1866
]
]
}
] |
[
{
"id": "1201",
"type": "DNAMutation",
"text": [
"c.1922G>A"
],
"offsets": [
[
1198,
1207
]
],
"normalized": []
},
{
"id": "1202",
"type": "ProteinMutation",
"text": [
"p.Arg641His"
],
"offsets": [
[
1209,
1220
]
],
"normalized": []
},
{
"id": "1203",
"type": "DNAMutation",
"text": [
"c.1922G>A"
],
"offsets": [
[
1755,
1764
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1206
|
19664890
|
[
{
"id": "1208",
"type": "title",
"text": [
"Screening of the LIX1 gene in Japanese and Malaysian patients with SMA and/or SMA-like disorder."
],
"offsets": [
[
0,
96
]
]
},
{
"id": "1209",
"type": "abstract",
"text": [
"BACKGROUND: The majority of spinal muscular atrophy (SMA) patients showed homozygous deletion or other mutations of SMN1. However, the genetic etiology of a significant number of SMA patients has not been clarified. Recently, mutation in the gene underlying cat SMA, limb expression 1 (LIX1), has been reported. Similarity in clinical and pathological features of cat and human SMA may give an insight into possible similarity of the genetic etiology. PATIENTS AND METHODS: In this study, we screened for a mutation in LIX1 using direct DNA sequencing in our SMA and/or SMA-like patients who retained SMN1. A total of 33 patients were enrolled in this study, of which 22 were Japanese and 11 were Malaysians. All these patients possessed at least two copies of SMN1. RESULTS: We did not identify any pathogenic mutations in the coding regions or splice sites of LIX1 in the patients. In addition, we described a polymorphism within LIX1 intron 3, c.387+107A>T. We found that A-allele is significantly more frequent in SMA patients compared to normal individuals. CONCLUSION: Molecular genetic analysis of our SMA and/or SMA-like patients suggests that LIX1 is not associated with the development of their disorders. However, the number of patients analyzed in this study was very limited, and a larger study with bigger sample size is needed to confirm this result."
],
"offsets": [
[
97,
1462
]
]
}
] |
[
{
"id": "1207",
"type": "DNAMutation",
"text": [
"c.387+107A>T"
],
"offsets": [
[
1044,
1056
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1210
|
19645056
|
[
{
"id": "1211",
"type": "title",
"text": [
"Single nucleotide polymorphism discovery in TBX1 in individuals with and without 22q11.2 deletion syndrome."
],
"offsets": [
[
0,
107
]
]
},
{
"id": "1212",
"type": "abstract",
"text": [
"BACKGROUND: Children with 22q11.2 deletion syndrome (22q11.2DS) have a wide range of clinical features. TBX1 has been proposed as a candidate gene for some of the features in this condition. Polymorphisms in the nondeleted TBX1, which may affect the function of the sole TBX1 gene in individuals with the 22q11.2DS, may be a key to understanding the phenotypic variability among individuals with a shared deletion. Comprehensive single nucleotide polymorphism (SNP) discovery by resequencing candidate genes can identify genetic variants that influence a given phenotype. The purpose of this study was to further characterize the sequence variability in TBX1 by identifying all common SNPs in this gene. METHODS: We resequenced TBX1 in 29 children with a documented 22q11.2 deletion and 95 nondeleted, healthy individuals. We estimated allele frequencies, performed tagSNP selection, and inferred haplotypes. We also compared SNP frequencies between 22q11.2DS and control samples. RESULTS: We identified 355 biallelic markers among the 190 chromosomes resequenced in the control panel. The vast majority of the markers identified were SNPs (n = 331), and the remainder indels (n = 24). We did not identify SNPs or indels in the cis- regulatory element (FOX-binding site) upstream of TBX1. In children with 22q11.2DS we detected 187 biallelic markers, six of which were indels. Four of the seven coding SNPs identified in the controls were identified in children with 22q11.2DS. CONCLUSIONS: This comprehensive SNP discovery data can be used to select SNPs to genotype for future association studies assessing the role of TBX1 and phenotypic variability in individuals with 22q11.2DS."
],
"offsets": [
[
108,
1791
]
]
}
] |
[] |
[] |
[] |
[] |
1213
|
19592582
|
[
{
"id": "1220",
"type": "title",
"text": [
"Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms."
],
"offsets": [
[
0,
131
]
]
},
{
"id": "1221",
"type": "abstract",
"text": [
"Mutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C>A and c.468C>T in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency."
],
"offsets": [
[
132,
1418
]
]
}
] |
[
{
"id": "1214",
"type": "ProteinMutation",
"text": [
"P686fs"
],
"offsets": [
[
498,
504
]
],
"normalized": []
},
{
"id": "1215",
"type": "DNAMutation",
"text": [
"2172_2173insCCCC"
],
"offsets": [
[
571,
587
]
],
"normalized": []
},
{
"id": "1216",
"type": "DNAMutation",
"text": [
"c.467C>A"
],
"offsets": [
[
715,
723
]
],
"normalized": []
},
{
"id": "1217",
"type": "DNAMutation",
"text": [
"c.468C>T"
],
"offsets": [
[
728,
736
]
],
"normalized": []
},
{
"id": "1218",
"type": "ProteinMutation",
"text": [
"A118D"
],
"offsets": [
[
781,
786
]
],
"normalized": []
},
{
"id": "1219",
"type": "ProteinMutation",
"text": [
"A118D"
],
"offsets": [
[
1025,
1030
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1222
|
19521089
|
[
{
"id": "1227",
"type": "title",
"text": [
"Serotonin transporter gene polymorphic element 5-HTTLPR increases the risk of sporadic Parkinson's disease in Italy."
],
"offsets": [
[
0,
116
]
]
},
{
"id": "1228",
"type": "abstract",
"text": [
"Parkinson's disease (PD) is a neurodegenerative disorder causing muscular rigidity, resting tremor and bradykinesia. We conducted an association study assessing how PD risk in Italy was influenced by the serotonin transporter gene (SLC6A4) polymorphic region 5-HTTLPR, consisting of an insertion/deletion (long allele-L/short allele-S) of 43 bp in the SLC6A4 promoter region. The SLC6A4 promoter single nucleotide polymorphism rs25531(A-->G) was evaluated too. We collected 837 independent subjects (393 PD, 444 controls). An association between the 5-HTTLPR polymorphism and risk of PD (S/S genotype OR [95% CI]: 1.7[1.2-2.5], p = 0.002) was found. The rs25531 and the haplotype 5-HTTLPR/rs25531 did not associate with risk of PD. Our data indicate that the 5-HTTLPR polymorphic element within the SLC6A4 promoter may govern the genetic risk of PD in Italians."
],
"offsets": [
[
117,
978
]
]
}
] |
[
{
"id": "1223",
"type": "SNP",
"text": [
"rs25531"
],
"offsets": [
[
544,
551
]
],
"normalized": []
},
{
"id": "1224",
"type": "DNAMutation",
"text": [
"A-->G"
],
"offsets": [
[
552,
557
]
],
"normalized": []
},
{
"id": "1225",
"type": "SNP",
"text": [
"rs25531"
],
"offsets": [
[
771,
778
]
],
"normalized": []
},
{
"id": "1226",
"type": "SNP",
"text": [
"rs25531"
],
"offsets": [
[
806,
813
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1229
|
19484664
|
[
{
"id": "1230",
"type": "title",
"text": [
"Angiotensin converting enzyme gene polymorphism in Turkish asthmatic patients."
],
"offsets": [
[
0,
78
]
]
},
{
"id": "1231",
"type": "abstract",
"text": [
"Asthma is a chronic inflammatory disease of the airways. Several candidate genes have been identified with a potential role in the pathogenesis of asthma, including the angiotensin converting enzyme (ACE) gene. We aimed to investigate the frequency of an ACE gene polymorphism in Turkish asthmatic patients and to determine its impact on clinical parameters and disease severity. Ninety-seven asthmatic patients (M/F 25/72, mean age 39 +/- 13 years) and 96 healthy subjects (M/F 26/70, mean age 38 +/- 12 years) were included. At baseline, all participants completed a questionnaire on demographics, symptoms, triggering factors, severity of asthma, and the presence of atopism. Blood samples were obtained from all patients and genomic DNA was isolated. The frequency of the ACE genotypes (I = insertion and D = deletion) among asthmatics and controls were compared: asthmatics showed a 40.2% prevalence of the DD genotype (n = 39), ID was 45.4% (n = 44), and II was 14.4% (n = 14.4). In the control subjects, the frequency of DD was 18.8% (n = 18), ID was 50% (n = 48) and II was 31.3% (n = 30). The DD ACE genotype was significantly more frequent in asthmatics compared with controls (p < 0.001). Asthmatics with the ID ACE genotype showed a higher frequency of drug allergies, although this was not statistically significant (p = 0.08). Asthmatics with the DD genotype appeared to have a higher incidence of asthmatic episode exacerbations due to viral infections, but again this was not statistically significant (p = 0.08). Patients with mild or moderate-severe asthma had similar frequencies of these mutations. We found a higher frequency of the ACE DD gene mutation in Turkish asthmatic patients compared with non-asthmatics, suggesting that this ACE gene polymorphism may be a risk factor for asthma but does not increase the severity of the disease."
],
"offsets": [
[
79,
1939
]
]
}
] |
[] |
[] |
[] |
[] |
1232
|
19476483
|
[
{
"id": "1241",
"type": "title",
"text": [
"The role of the CCR5 Delta32 polymorphism in abdominal aortic aneurysms."
],
"offsets": [
[
0,
72
]
]
},
{
"id": "1242",
"type": "abstract",
"text": [
"BACKGROUND: C-C chemokine receptor 5 (CCR5) is involved in the regulation of the inflammatory response. Abdominal aortic aneurysms (AAA) may arise as the result of a chronic inflammatory process which is influenced by genetic predisposition. The CCR5 gene is associated with a 32 base pair deletion (the Delta32 polymorphism). The aim of this study was to investigate the role of the CCR5 Delta32 polymorphism in the development of AAA. METHODS: A case-control study was conducted including 285 patients with AAA and 273 control subjects. A blood sample was taken from each individual and DNA was extracted. CCR5 genotype was determined using the polymerase chain reaction (PCR). Flow cytometry was used to investigate the biological activity of the Delta32 polymorphism. RESULTS: There was no significant difference between the AAA and the control group in relation to the Delta32 allele frequency (AAA group 10%, control group = 12%, P = 0.82, chi-squared analysis). Genotype analysis revealed no significant difference between the groups (AAA vs. controls, wild-type homozygotes = 82% vs. 77%, heterozygotes = 16% vs. 21%, vs. Delta32 homozygotes = 2% and 2%, respectively, P = 0.33, chi-squared analysis). The polymorphism was shown to be biologically active with the number of Delta32 alleles correlating with cell expression of ccr5 as detected with flow cytometry (P < or = 0.05). CONCLUSION: This study demonstrates that the ccr5 Delta32 is a biologically active genetic polymorphism; however, there is no association between this polymorphism and AAA."
],
"offsets": [
[
73,
1633
]
]
}
] |
[
{
"id": "1233",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
21,
28
]
],
"normalized": []
},
{
"id": "1234",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
377,
384
]
],
"normalized": []
},
{
"id": "1235",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
462,
469
]
],
"normalized": []
},
{
"id": "1236",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
823,
830
]
],
"normalized": []
},
{
"id": "1237",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
947,
954
]
],
"normalized": []
},
{
"id": "1238",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
1203,
1210
]
],
"normalized": []
},
{
"id": "1239",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
1355,
1362
]
],
"normalized": []
},
{
"id": "1240",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
1511,
1518
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1243
|
19473658
|
[
{
"id": "1244",
"type": "title",
"text": [
"Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion)."
],
"offsets": [
[
0,
98
]
]
},
{
"id": "1245",
"type": "abstract",
"text": [
"We report a novel apolipoprotein A-I (apoA-I) mutation identified in a 64-year-old patient with marked plasma high density lipoprotein (HDL) cholesterol (4 mg/dl) and apoA-I (5mg/dl) deficiency, prior myocardial infarction, and moderate corneal opacities. Coronary angiography revealed extensive atherosclerosis in all three major vessels. Genomic DNA sequencing of the proband revealed a homozygous novel deletion of two successive adenine residues in codon 138 in the apoA-I gene, resulting in a frameshift mutation at amino acid residues 138-178, which we have designated as apoA-I Tomioka. His elder brother was also homozygous for apoA-I Tomioka with marked HDL cholesterol and apoA-I deficiency, but had no clinical evidence of coronary heart disease. Other family members including three siblings and two sons were heterozygous for the mutation, and had approximately 50% of normal plasma HDL cholesterol, and apoA-I. Analysis of apoA-I-containing HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I HDL particles in the homozygotes, while in heterozygotes, the mean concentrations of apoA-I in large alpha-1 and very small prebeta-1 HDL subpopulations were significantly decreased at about 35% of normal. Thus, apoA-I Tomioka, a novel deletion mutation in codon 138 of the apoA-I gene, is the causative defect in this case of HDL deficiency."
],
"offsets": [
[
99,
1478
]
]
}
] |
[] |
[] |
[] |
[] |
1246
|
19448408
|
[
{
"id": "1252",
"type": "title",
"text": [
"Correlation of polymorphism of the coding region of glutathione S- transferase M1 to susceptibility of nasopharyngeal carcinoma in South China population."
],
"offsets": [
[
0,
154
]
]
},
{
"id": "1253",
"type": "abstract",
"text": [
"BACKGROUND AND OBJECTIVE: Glutathione S-transferase M1 (GSTM1) deficiency may increase the risk of nasopharyngeal carcinoma (NPC). This study was to evaluate the correlation of the single nucleotide polymorphism (SNP) in the coding region of GSTM1 gene to NPC susceptibility in southern China population. METHODS: In total 239 NPC patients and 286 age-matched healthy controls were entered into the study. Among them, 225 out of 239 NPC patients and 273 out of 286 controls were used for statistical analysis. SNP screening of all exons, relevant intron-exon boundaries, and the promoter region of GSTM1, in total 4739bp, was performed by PCR direct sequencing. The loci T1270533G and C1256088C were selected for the case-control study using the tetra-Primer ARMS-PCR, as well as the sequencing method. RESULTS: In total 29 SNPs of GSTM1 were identified by sequencing. Missense mutation occurred in the polymorphic loci of T1270533G and C1256088C. However, no evident relationships between the variants of T1270533G and clinical phenotypes of NPC were observed in the NPC group and healthy control group (OR = 0.170, 95%CI = 0.95-0.306 for homozygote TT). The deletion frequency of C1256088C was 45% (45/100) for NPC patients and 42% (42/100) for controls. CONCLUSIONS: The polymorphism of T1270533G does not affect the detoxification function of GSTM1. The T1270533G locus has no apparent association with genetic susceptibility to NPC in the southern China population. The loss rate of C1256088C is high in this study."
],
"offsets": [
[
155,
1675
]
]
}
] |
[
{
"id": "1247",
"type": "DNAMutation",
"text": [
"T1270533G"
],
"offsets": [
[
826,
835
]
],
"normalized": []
},
{
"id": "1248",
"type": "DNAMutation",
"text": [
"T1270533G"
],
"offsets": [
[
1078,
1087
]
],
"normalized": []
},
{
"id": "1249",
"type": "DNAMutation",
"text": [
"T1270533G"
],
"offsets": [
[
1161,
1170
]
],
"normalized": []
},
{
"id": "1250",
"type": "DNAMutation",
"text": [
"T1270533G"
],
"offsets": [
[
1445,
1454
]
],
"normalized": []
},
{
"id": "1251",
"type": "DNAMutation",
"text": [
"T1270533G"
],
"offsets": [
[
1513,
1522
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1254
|
19435819
|
[
{
"id": "1255",
"type": "title",
"text": [
"High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray."
],
"offsets": [
[
0,
122
]
]
},
{
"id": "1256",
"type": "abstract",
"text": [
"Glioblastoma multiforme (GBM) is an extremely malignant brain tumor. To identify new genomic alterations in GBM, genomic DNA of tumor tissue/explants from 55 individuals and 6 GBM cell lines were examined using single nucleotide polymorphism DNA microarray (SNP-Chip). Further gene expression analysis relied on an additional 56 GBM samples. SNP-Chip results were validated using several techniques, including quantitative PCR (Q-PCR), nucleotide sequencing, and a combination of Q-PCR and detection of microsatellite markers for loss of heterozygosity with normal copy number [acquired uniparental disomy (AUPD)]. Whole genomic DNA copy number in each GBM sample was profiled by SNP-Chip. Several signaling pathways were frequently abnormal. Either the p16(INK4A)/p15(INK4B)-CDK4/6-pRb or p14(ARF)-MDM2/4-p53 pathways were abnormal in 89% (49 of 55) of cases. Simultaneous abnormalities of both pathways occurred in 84% (46 of 55) samples. The phosphoinositide 3-kinase pathway was altered in 71% (39 of 55) GBMs either by deletion of PTEN or amplification of epidermal growth factor receptor and/or vascular endothelial growth factor receptor/platelet-derived growth factor receptor alpha. Deletion of chromosome 6q26-27 often occurred (16 of 55 samples). The minimum common deleted region included PARK2, PACRG, QKI, and PDE10A genes. Further reverse transcription Q-PCR studies showed that PARK2 expression was decreased in another collection of GBMs at a frequency of 61% (34 of 56) of samples. The 1p36.23 region was deleted in 35% (19 of 55) of samples. Notably, three samples had homozygous deletion encompassing this site. Also, a novel internal deletion of a putative tumor suppressor gene, LRP1B, was discovered causing an aberrant protein. AUPDs occurred in 58% (32 of 55) of the GBM samples and five of six GBM cell lines. A common AUPD was found at chromosome 17p13.3-12 (included p53 gene) in 13 of 61 samples and cell lines. Single-strand conformational polymorphism and nucleotide sequencing showed that 9 of 13 of these samples had homozygous p53 mutations, suggesting that mitotic recombination duplicated the abnormal p53 gene, probably providing a growth advantage to these cells. A significantly shortened survival time was found in patients with 13q14 (RB) deletion or 17p13.1 (p53) deletion/AUPD. Taken together, these results suggest that this technique is a rapid, robust, and inexpensive method to profile genome-wide abnormalities in GBM."
],
"offsets": [
[
123,
2589
]
]
}
] |
[] |
[] |
[] |
[] |
1257
|
19404517
|
[
{
"id": "1260",
"type": "title",
"text": [
"A large Swiss family with Bernard-Soulier syndrome - Correlation phenotype and genotype."
],
"offsets": [
[
0,
88
]
]
},
{
"id": "1261",
"type": "abstract",
"text": [
"Bernard-Soulier syndrome (BSS) is a rare, autosomal recessive inherited bleeding disorder associated with thrombocytopenia, thrombocytopathy and giant platelets. BSS is caused by genetic alterations of the glycoprotein (GP) Ib/V/IX complex. We report on a large Swiss family of whom four family members suffer from BSS. Here, a homozygous missense mutation in position 1829 (A(R)G) of the GPIX gene constituting a N45S substitution is the cause for the bleeding symptoms. A total of 38 family members within two generations were analyzed regarding the N45S mutation by DNA sequencing and restriction fragment length polymorphism. The laboratory parameters which are characteristically for BSS such as platelet count, platelet volume and the expression of CD42a (GPIX), CD42b (GPIbalpha) and CD41 (GPIIb) were measured for all 38 individuals. The four homozygous patients showed bleeding symptoms, thrombocytopenia and giant platelets. In these patients, the expression of CD42a (GPIX), CD42b (GPIbalpha) was diminished. Interestingly, the intensity of the bleeding symptoms of the 4 homozygous family members seemed to vary although they carry the same mutation. The 24 heterozygous carriers did not differ significantly from their 10 wildtype family members regarding bleeding symptoms and laboratory analysis."
],
"offsets": [
[
89,
1400
]
]
}
] |
[
{
"id": "1258",
"type": "ProteinMutation",
"text": [
"N45S"
],
"offsets": [
[
503,
507
]
],
"normalized": []
},
{
"id": "1259",
"type": "ProteinMutation",
"text": [
"N45S"
],
"offsets": [
[
641,
645
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1262
|
19370764
|
[
{
"id": "1275",
"type": "title",
"text": [
"Identification and molecular characterization of six novel mutations in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTG) gene in patients with mucolipidosis III gamma."
],
"offsets": [
[
0,
189
]
]
},
{
"id": "1276",
"type": "abstract",
"text": [
"Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense (p.T286M) and nonsense (p.W111X) mutations and a transition in the obligate AG-dinucleotide of the intron 8 acceptor splice site (c.610-2A>G). Three microdeletions were also identified, two of which (c.611delG and c.640_667del28) were located within the coding region whereas one (c.609+28_610-16del) was located entirely within intron 8. RT-PCR analysis of the c.610-2A>G transition demonstrated that the change altered splicing, leading to the production of two distinct aberrantly spliced forms, viz. the skipping of exon 9 (p.G204_K247del) or the retention of introns 8 and 9 (p.G204VfsX28). RT-PCR analysis, performed on a patient homozygous for the intronic deletion (c.609+28_610-16del), failed to detect any GNPTG RNA transcripts. To determine whether c.609+28_610-16del allele-derived transcripts were subject to nonsense-mediated mRNA decay (NMD), patient fibroblasts were incubated with the protein synthesis inhibitor anisomycin. An RT-PCR fragment retaining 43 bp of intron 8 was consistently detected suggesting that the 33-bp genomic deletion had elicited NMD. Quantitative real-time PCR and GNPTG western blot analysis confirmed that the homozygous microdeletion p.G204VfsX17 had elicited NMD resulting in failure to synthesize GNPTG protein. Analysis of the sequences surrounding the microdeletion breakpoints revealed either intrinsic repetitivity of the deleted region or short direct repeats adjacent to the breakpoint junctions. This is consistent with these repeats having mediated the microdeletions via replication slippage and supports the view that the mutational spectrum of the GNPTG gene is strongly influenced by the properties of the local DNA sequence environment."
],
"offsets": [
[
190,
2173
]
]
}
] |
[
{
"id": "1263",
"type": "ProteinMutation",
"text": [
"p.T286M"
],
"offsets": [
[
478,
485
]
],
"normalized": []
},
{
"id": "1264",
"type": "ProteinMutation",
"text": [
"p.W111X"
],
"offsets": [
[
501,
508
]
],
"normalized": []
},
{
"id": "1265",
"type": "DNAMutation",
"text": [
"c.610-2A>G"
],
"offsets": [
[
607,
617
]
],
"normalized": []
},
{
"id": "1266",
"type": "DNAMutation",
"text": [
"c.611delG"
],
"offsets": [
[
677,
686
]
],
"normalized": []
},
{
"id": "1267",
"type": "DNAMutation",
"text": [
"c.640_667del28"
],
"offsets": [
[
691,
705
]
],
"normalized": []
},
{
"id": "1268",
"type": "DNAMutation",
"text": [
"c.609+28_610-16del"
],
"offsets": [
[
758,
776
]
],
"normalized": []
},
{
"id": "1269",
"type": "DNAMutation",
"text": [
"c.610-2A>G"
],
"offsets": [
[
839,
849
]
],
"normalized": []
},
{
"id": "1270",
"type": "ProteinMutation",
"text": [
"p.G204_K247del"
],
"offsets": [
[
1005,
1019
]
],
"normalized": []
},
{
"id": "1271",
"type": "ProteinMutation",
"text": [
"p.G204VfsX28"
],
"offsets": [
[
1058,
1070
]
],
"normalized": []
},
{
"id": "1272",
"type": "DNAMutation",
"text": [
"c.609+28_610-16del"
],
"offsets": [
[
1151,
1169
]
],
"normalized": []
},
{
"id": "1273",
"type": "DNAMutation",
"text": [
"c.609+28_610-16del"
],
"offsets": [
[
1237,
1255
]
],
"normalized": []
},
{
"id": "1274",
"type": "ProteinMutation",
"text": [
"p.G204VfsX17"
],
"offsets": [
[
1656,
1668
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1277
|
19353688
|
[
{
"id": "1278",
"type": "title",
"text": [
"Pure monosomy and pure trisomy of 13q21.2-31.1 consequent to a familial insertional translocation: exclusion of PCDH9 as the responsible gene for autosomal dominant auditory neuropathy (AUNA1)."
],
"offsets": [
[
0,
193
]
]
},
{
"id": "1279",
"type": "abstract",
"text": [
"Insertional translocations (IT) are rare structural rearrangements. Offspring of IT balanced carriers are at high risk to have either pure partial trisomy or monosomy for the inserted segment as manifested by \"pure\" phenotypes. We describe an IT between chromosomes 3 and 13 segregating in a three-generation pedigree. Short tandem repeat (STR) segregation analysis and array-comparative genomic hybridization were used to define the IT as a 25.1 Mb segment spanning 13q21.2-q31.1. The phenotype of pure monosomy included deafness, duodenal stenosis, developmental and growth delay, vertebral anomalies, and facial dysmorphisms; the trisomy was manifested by only minor dysmorphisms. As the AUNA1 deafness locus on 13q14-21 overlaps the IT in the PCDH9 (protocadherin-9) gene region, PCDH9 was investigated as a candidate gene for deafness in both families. Genotyping of STRs and single nucleotide polymorphisms defined the AUNA1 breakpoint as 35 kb 5' to PCDH9, with a 2.4 Mb area of overlap with the IT. DNA sequencing of coding regions in the AUNA1 family and in the retained homologue chromosome in the monosomic patient revealed no mutations. We conclude that AUNA1 deafness does not share a common etiology with deafness associated with monosomy 13q21.2-q31.3; deafness may result from monosomy of PCHD9 or another gene in the IT, as has been demonstrated in contiguous gene deletion syndromes. Precise characterization of the breakpoints of the translocated region is useful to identify which genes may be contributing to the phenotype, either through haploinsufficiency or extra dosage effects, in order to define genotype-phenotype correlations."
],
"offsets": [
[
194,
1849
]
]
}
] |
[] |
[] |
[] |
[] |
1280
|
19309272
|
[
{
"id": "1281",
"type": "title",
"text": [
"A simple multiplex real-time PCR methodology for the SMN1 gene copy number quantification."
],
"offsets": [
[
0,
90
]
]
},
{
"id": "1282",
"type": "abstract",
"text": [
"Spinal muscular atrophy (SMA) is an autosomal recessive disease caused, in about 95% of SMA cases, by homozygous deletion of the survival motor neuron 1 (SMN1) gene or its conversion to the highly homologous SMN2 gene. The molecular diagnosis of SMA is usually carried out by a PCR-Restriction fragment length polymorphism (RFLP) approach. However, this approach is not useful for identification of healthy deletion carriers. TaqMan technology is one of the most reliable and widely adopted techniques for the SMN1 copy number evaluation. However, several limitations of this technique have been described. Particularly, DNA extraction methods and accurate template quantification have been shown to be critical for reliable results. In this work, we set up a reliable, highly reproducible, and easy-to-perform TaqMan technology-based protocol to obtain the SMN1 gene copy number assessment. We demonstrate that PCR amplification of both target gene and reference gene in the same reaction mix, instead of separated mixes, greatly reduces reported criticisms of simplex TaqMan technology. The multiplex real-time PCR we describe allows interlaboratory samples and data exchange, without the need to equalize the DNA isolation technique. Further, the protocol described below requires fewer replica tests than the simplex methodology does, leading to reduced overall cost for the diagnostic assay."
],
"offsets": [
[
91,
1487
]
]
}
] |
[] |
[] |
[] |
[] |
1283
|
19218574
|
[
{
"id": "1292",
"type": "title",
"text": [
"Phosphatidylinositol 3-kinase p85alpha regulatory subunit gene Met326Ile polymorphism in women with polycystic ovary syndrome."
],
"offsets": [
[
0,
126
]
]
},
{
"id": "1293",
"type": "abstract",
"text": [
"BACKGROUND: Insulin resistance is a core feature of polycystic ovary syndrome (PCOS). Phosphatidylinositol (PI) 3-kinase is an important enzyme in the early insulin signaling cascade and plays a key role in insulin-mediated glucose transport. In its regulatory subunit, p85alpha, there is a common amino acid substitution (the Met326Ile polymorphism), and this amino acid may be crucial for the function of the p85alpha regulatory subunit and PI3-kinase. METHODS: Analysis of the Met326Ile polymorphism was carried out on DNA samples from 256 PCOS patients and 283 controls. Clinical and biochemical profiles of participants were also compared. RESULTS: The genotype distribution of the Met326Ile polymorphism in the PCOS group was not different from that of the controls (Met326Met/Met326Ile/Ile326Ile rates were 73.4%/23.4%/3.2% and 70.3%/26.1%/3.6% for the PCOS and control groups, respectively, P = 0.72). The PCOS group was divided into two subgroups according to the presence of the variant 326Ile allele. Compared with those carrying at least one variant 326Ile allele, carriers with the Met326Met genotype had higher serum 17-hydroxyprogesterone (17-OHP) {1.1 [95% confidence interval (CI) 1.1-1.3] ng/ml in those with the Met326Met genotype versus 0.8 (95% CI 0.7-1.0) ng/ml in those with Ile326Ile and Met326Ile genotypes, P = 0.0073} and free testosterone levels [1.2 (95% CI 1.1-1.4) pg/ml for Met326Met genotype versus 0.9 (95% CI 0.6-1.3) pg/ml for Ile326Ile and Met326Ile genotypes, P = 0.038]. CONCLUSIONS: Our results suggest that the PI3-kinase gene Met326Ile polymorphism may not be a major determinant for the development of PCOS, but it may modulate the concentrations of serum 17-OHP or free testosterone in PCOS patients."
],
"offsets": [
[
127,
1871
]
]
}
] |
[
{
"id": "1284",
"type": "ProteinMutation",
"text": [
"Met326Ile"
],
"offsets": [
[
63,
72
]
],
"normalized": []
},
{
"id": "1285",
"type": "ProteinMutation",
"text": [
"Met326Ile"
],
"offsets": [
[
454,
463
]
],
"normalized": []
},
{
"id": "1286",
"type": "ProteinMutation",
"text": [
"Met326Ile"
],
"offsets": [
[
607,
616
]
],
"normalized": []
},
{
"id": "1287",
"type": "ProteinMutation",
"text": [
"Met326Ile"
],
"offsets": [
[
814,
823
]
],
"normalized": []
},
{
"id": "1288",
"type": "ProteinMutation",
"text": [
"Met326Ile"
],
"offsets": [
[
910,
919
]
],
"normalized": []
},
{
"id": "1289",
"type": "ProteinMutation",
"text": [
"Met326Ile"
],
"offsets": [
[
1439,
1448
]
],
"normalized": []
},
{
"id": "1290",
"type": "ProteinMutation",
"text": [
"Met326Ile"
],
"offsets": [
[
1604,
1613
]
],
"normalized": []
},
{
"id": "1291",
"type": "ProteinMutation",
"text": [
"Met326Ile"
],
"offsets": [
[
1695,
1704
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1294
|
19144556
|
[
{
"id": "1302",
"type": "title",
"text": [
"Identification of newly polymorphic intron 40 markers of the von Willebrand factor gene in a Japanese population."
],
"offsets": [
[
0,
113
]
]
},
{
"id": "1303",
"type": "abstract",
"text": [
"We investigated a region of repetitive DNA located in intron 40 of the von Willebrand factor (vWF) gene (nucleotides [nt] 1639-2404; i.e., F8VWF). We identified 13 alleles and 33 genotypes in 49 unrelated Japanese individuals. The heterozygosity of the region was 0.897. Direct sequence analyses revealed five single-base substitutions, one tetranucleotide (TTAT) insertion, and seven short tandem repeats (STRs) in the intron; four of the STRs and one single-base substitution had been reported previously. The four new base substitutions we identified were 1849T>A, 2122C>T, 2180C>T, and 2192C>T. The novel TTAT tetranucleotide was inserted between nt 2057 and 2058. The three newly identified STRs were 1978(TATC)(1-2), 2193(ATCT)(5-13), and 2234(TGTA)(5-7). The five single-base substitutions and the TTAT insertion were identified only with 3' downstream of vWA allele 14."
],
"offsets": [
[
114,
991
]
]
}
] |
[
{
"id": "1295",
"type": "DNAMutation",
"text": [
"1849T>A"
],
"offsets": [
[
673,
680
]
],
"normalized": []
},
{
"id": "1296",
"type": "DNAMutation",
"text": [
"2122C>T"
],
"offsets": [
[
682,
689
]
],
"normalized": []
},
{
"id": "1297",
"type": "DNAMutation",
"text": [
"2180C>T"
],
"offsets": [
[
691,
698
]
],
"normalized": []
},
{
"id": "1298",
"type": "DNAMutation",
"text": [
"2192C>T"
],
"offsets": [
[
704,
711
]
],
"normalized": []
},
{
"id": "1299",
"type": "DNAMutation",
"text": [
"1978(TATC)(1-2)"
],
"offsets": [
[
820,
835
]
],
"normalized": []
},
{
"id": "1300",
"type": "DNAMutation",
"text": [
"2193(ATCT)(5-13)"
],
"offsets": [
[
837,
853
]
],
"normalized": []
},
{
"id": "1301",
"type": "DNAMutation",
"text": [
"2234(TGTA)(5-7)"
],
"offsets": [
[
859,
874
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1304
|
19048115
|
[
{
"id": "1305",
"type": "title",
"text": [
"Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations."
],
"offsets": [
[
0,
109
]
]
},
{
"id": "1306",
"type": "abstract",
"text": [
"Ovarian serous carcinoma (OSC) is the most common and lethal histologic type of ovarian epithelial malignancy. Mutations of TP53 and dysfunction of the Brca1 and/or Brca2 tumor-suppressor proteins have been implicated in the molecular pathogenesis of a large fraction of OSCs, but frequent somatic mutations in other well-established tumor-suppressor genes have not been identified. Using a genome-wide screen of DNA copy number alterations in 36 primary OSCs, we identified two tumors with apparent homozygous deletions of the NF1 gene. Subsequently, 18 ovarian carcinoma-derived cell lines and 41 primary OSCs were evaluated for NF1 alterations. Markedly reduced or absent expression of Nf1 protein was observed in 6 of the 18 cell lines, and using the protein truncation test and sequencing of cDNA and genomic DNA, NF1 mutations resulting in deletion of exons and/or aberrant splicing of NF1 transcripts were detected in 5 of the 6 cell lines with loss of NF1 expression. Similarly, NF1 alterations including homozygous deletions and splicing mutations were identified in 9 (22%) of 41 primary OSCs. As expected, tumors and cell lines with NF1 defects lacked mutations in KRAS or BRAF but showed Ras pathway activation based on immunohistochemical detection of phosphorylated MAPK (primary tumors) or increased levels of GTP-bound Ras (cell lines). The TP53 tumor-suppressor gene was mutated in all OSCs with documented NF1 mutation, suggesting that the pathways regulated by these two tumor-suppressor proteins often cooperate in the development of ovarian carcinomas with serous differentiation."
],
"offsets": [
[
110,
1711
]
]
}
] |
[] |
[] |
[] |
[] |
1307
|
18798060
|
[
{
"id": "1308",
"type": "title",
"text": [
"The influence of interstitial collagenase-1 genotype polymorphism on colorectal cancer risk in Iranian population."
],
"offsets": [
[
0,
114
]
]
},
{
"id": "1309",
"type": "abstract",
"text": [
"Interstitial collagenase-1 degrades a variety of extracellular matrix components. A single guanine insertion polymorphism in the promoter has been found that influences on the transcription and expression level of the gene. It is suggested that this polymorphism may enhance susceptibility to some types of cancer. Therefore, this case-control study evaluated the association of this genotype polymorphism with susceptibility to initiation and invasion of colorectal cancer. For this reason, whole blood samples were obtained from 150 CRC patients and 100 control subjects in Tehran. Genomic DNA was extracted and genotyped by PCR-RFLP method. We showed that 2G allele and 2G/2G genotype had higher frequencies in patients (60% and 39%, respectively) than in controls (47% and 23%, respectively). The CRC patients were divided into two groups: with metastasis (M+) and without metastasis (M-) groups. The 2G allele was more frequent in M+ group compared with control group. However, no significantly difference was observed between M-group and control (chi(2) = 0.48, P = 0.78 for 2G/2G genotype). Further stratification analyses showed that only gender (OR = 2.58, 95% CI = 0.89-7.52 for women and OR = 4.12, 95% CI = 1.62-10.42 for men) and smoking (OR = 3.03, 95% CI = 1.28-7.16 for non-smokers and OR = 4.09, 95% CI = 1.18-4.15 for smoker) may modify the risk of colorectal invasion related to 2G/2G genotype. Furthermore, individual with 2G/2G genotype seems to spread metastasis, 3 years earlier than those who were 1G/1G and 1G/2G. In conclusion, to our knowledge, the present epidemiological study for the first time indicates the relationship of 2G/2G genotype polymorphism with invasion risk of colorectal cancer in subgroups of gender and smoking, especially in smoker men."
],
"offsets": [
[
115,
1899
]
]
}
] |
[] |
[] |
[] |
[] |
1310
|
18791947
|
[
{
"id": "1311",
"type": "title",
"text": [
"A case of Bernard-Soulier Syndrome due to a homozygous four bases deletion (TGAG) of GPIbalpha gene: lack of GPIbalpha but absence of bleeding."
],
"offsets": [
[
0,
143
]
]
},
{
"id": "1312",
"type": "abstract",
"text": [
"More than 20 DNA mutations with different inheritance pattern have been described in patients with Bernard-Soulier Syndrome (BSS), leading to abnormal or absent synthesis and/or expression of GPIbalpha. Clinical phenotype shows considerable variation between individuals, such as bleeding, platelet count and the percentage of large platelets. We describe in a BSS patient the first case of homozygous four bases deletion (TGAG) in the gpIbalpha gene coding sequence, leading to a premature stop codon. In the propositus, blood smears revealed giant platelets (30 x 10(9) platelets/L), and platelet agglutination to ristocetin was absent. Propositus' parents are consanguineous. His father and paternal grandmother showed a mild thrombocytopenia (108 x 10(9)/L and 120 x 10(9)/L platelets respectively) while mothers and sister's referred normal platelet counts. The surface expression of GPIbalpha was practically undetectable by flow-cytometry and western blot in the patient and was reduced in the father. Proband's DNA analysis revealed a homozygous four-base-pair deletion (TGAG), starting from the last base of the codon for Ser39, leading to a coding frame shift with a new termination codon after 11 novel amino acids. The same mutation was seen in heterozygosis in both parents. This is the first report of GPIbalpha TGAG deletion in homozygous state even if the defect has already been described in a case of compound heterozygosis. Surprisingly, the propositus does not report any spontaneous bleeding tendency."
],
"offsets": [
[
144,
1666
]
]
}
] |
[] |
[] |
[] |
[] |
1313
|
18790087
|
[
{
"id": "1317",
"type": "title",
"text": [
"Is the European spatial distribution of the HIV-1-resistant CCR5-Delta32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion?"
],
"offsets": [
[
0,
160
]
]
},
{
"id": "1318",
"type": "abstract",
"text": [
"We studied the possible effects of the expansion of ancient Mediterranean civilizations during the five centuries before and after Christ on the European distribution of the mutant allele for the chemokine receptor gene CCR5 which has a 32-bp deletion (CCR5-Delta32). There is a strong evidence for the unitary origin of the CCR5-Delta32 mutation, this it is found principally in Europe and Western Asia, with generally a north-south downhill cline frequency. Homozygous carriers of this mutation show a resistance to HIV-1 infection and a slower progression towards AIDS. However, HIV has clearly emerged too recently to have been the selective force on CCR5. Our analyses showed strong negative correlations in Europe between the allele frequency and two historical parameters, i.e. the first colonization dates by the great ancient Mediterranean civilizations, and the distances from the Northern frontiers of the Roman Empire in its greatest expansion. Moreover, other studies have shown that the deletion frequencies in both German Bronze Age and Swedish Neolithic populations were similar to those found in the corresponding modern populations, and this deletion has been found in ancient DNA of around 7000 years ago, suggesting that in the past, the deletion frequency could have been relatively high in European populations. In addition, in West Nile virus pathogenesis, CCR5 plays an antimicrobial role showing that host genetic factors are highly pathogen-specific. Our results added to all these previous data suggest that the actual European allele frequency distribution might not be due to genes spreading, but to a negative selection resulting in the spread of pathogens principally during Roman expansion. Indeed, as gene flows from colonizers to European native populations were extremely low, the mutational changes might be associated with vulnerability to imported infections. To date, the nature of the parasites remains unknown; however, zoonoses could be incriminated."
],
"offsets": [
[
161,
2153
]
]
}
] |
[
{
"id": "1314",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
65,
72
]
],
"normalized": []
},
{
"id": "1315",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
419,
426
]
],
"normalized": []
},
{
"id": "1316",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
491,
498
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1319
|
18681856
|
[
{
"id": "1323",
"type": "title",
"text": [
"Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene."
],
"offsets": [
[
0,
144
]
]
},
{
"id": "1324",
"type": "abstract",
"text": [
"OBJECTIVE: To describe clinical and genetic features of a Thai family with non-autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene. PATIENTS: Three affected individuals from the same family (a father and his two children) were studied. Clinical and imaging findings were reviewed and compared. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral blood leukocytes and mutation analysis of the entire coding sequence of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS: A heterozygous germline T to C transition in exon 10 of the TSHR gene (c.1358T-->C) resulting in the substitution of methionine (ATG) by threonine (ACG) at codon 453 (p.M453T) was identified in the father and his two children. They presented with different clinical severity and variable age of onset. In addition to hyperthyroidism, ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers were consistently found in all affected individuals. CONCLUSIONS: Ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers might be characteristic features of NAH because of an activating TSHR germline mutation. In addition, the shortening of the middle phalanges of the fifth fingers has never been previously described, expanding the phenotypic spectrum of the disease."
],
"offsets": [
[
145,
1616
]
]
}
] |
[
{
"id": "1320",
"type": "ProteinMutation",
"text": [
"p.M453T"
],
"offsets": [
[
102,
109
]
],
"normalized": []
},
{
"id": "1321",
"type": "DNAMutation",
"text": [
"c.1358T-->C"
],
"offsets": [
[
803,
814
]
],
"normalized": []
},
{
"id": "1322",
"type": "ProteinMutation",
"text": [
"p.M453T"
],
"offsets": [
[
899,
906
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1325
|
18600483
|
[
{
"id": "1326",
"type": "title",
"text": [
"Identification of rifampin-resistant genotypes in Mycobacterium tuberculosis by PCR-reverse dot blot hybridization."
],
"offsets": [
[
0,
115
]
]
},
{
"id": "1327",
"type": "abstract",
"text": [
"A PCR-reverse dot blot hybridization (RDBH) assay was developed for rapid identification of rifampin (RFP)-resistant genotypes in Mycobacterium tuberculosis clinical isolates. The assay used the rpoB gene as target and was used to evaluate 148 clinical isolates (97 RFP-resistant isolates and 51 RFP-susceptible isolates). At the same time, the isolates were subjected to DNA sequencing and conventional drug susceptibility test. One hundred and forty one (95.3%) and 136 (91.9%) of the 148 strains were correctly identified by DNA sequencing and RDBH assay, respectively. None of the 51 RFP-susceptible isolates examined had alterations in rpoB. The sensitivity and specificity of the DNA sequencing were 92.8% and 100%, and the positive predictive value (PPV) and negative predictive value (NPV) were 100% and 87.9%, respectively. The sensitivity and specificity of the RDBH assay were 87.6% and 100%, and the PPV and NPV were 100% and 81.0%, respectively. Codons 531 and 526 of the rpoB were found to be the most common sites of nucleotide substitutions. Mutations at codons 511, 513, 515, 516, 517, 518, and 533 were also found. There were two-codon mutations in four isolates. No deletion and insertion was found in the rpoB gene. These results indicate that the RDBH assay is a rapid, simple, and reliable method for routine identification of RFP resistance in M. tuberculosis."
],
"offsets": [
[
116,
1499
]
]
}
] |
[] |
[] |
[] |
[] |
1328
|
19808398
|
[
{
"id": "1333",
"type": "title",
"text": [
"Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy."
],
"offsets": [
[
0,
132
]
]
},
{
"id": "1334",
"type": "abstract",
"text": [
"BACKGROUND: Increased susceptibility to dilated cardiomyopathy has been observed in patients carrying mutations in the SCN5A gene, but the underlying mechanism remains unclear. In this study, we identified and characterized, both in vitro and clinically, an SCN5A mutation associated with familial progressive atrioventricular block of adult onset and dilated cardiomyopathy in a Chinese family. METHODS AND RESULTS: Among 32 family members, 5 were initially diagnosed with atrioventricular block after age 30; 4 were studied, 3 of whom later developed dilated cardiomyopathy. We found a heterozygous single-nucleotide mutation resulting in an amino acid substitution (A1180V) in all studied patients and in 6 other younger unaffected members but not in 200 control chromosomes. When expressed with the beta1 subunit, the mutated channels exhibited a -4.5-mV shift of inactivation with slower recovery leading to a rate-dependent Na(+) current reduction and a moderate increase in late Na(+) current. Clinical study revealed that although QRS duration decreased with increasing heart rate in noncarrier family members, this change was blunted in unaffected carriers whose ECG and heart function were normal. Resting corrected QT interval of unaffected carriers was significantly longer than that of noncarriers, even though it was still within the normal range. CONCLUSIONS: A1180V expresses a mild Na(+) channel phenotype in vitro and a corresponding clinical phenotype in unaffected mutation carriers, implying that A1180V caused structural heart disease in affected carriers by disturbing Na(+) influx and, hence, cellular Na(+) homeostasis. The high penetrance of A1180V suggests this phenotype as a high risk factor for dilated cardiomyopathy with preceding atrioventricular block."
],
"offsets": [
[
133,
1919
]
]
}
] |
[
{
"id": "1329",
"type": "ProteinMutation",
"text": [
"A1180V"
],
"offsets": [
[
802,
808
]
],
"normalized": []
},
{
"id": "1330",
"type": "ProteinMutation",
"text": [
"A1180V"
],
"offsets": [
[
1508,
1514
]
],
"normalized": []
},
{
"id": "1331",
"type": "ProteinMutation",
"text": [
"A1180V"
],
"offsets": [
[
1651,
1657
]
],
"normalized": []
},
{
"id": "1332",
"type": "ProteinMutation",
"text": [
"A1180V"
],
"offsets": [
[
1801,
1807
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1335
|
18470323
|
[
{
"id": "1341",
"type": "title",
"text": [
"Anticipation in familial lattice corneal dystrophy type I with R124C mutation in the TGFBI (BIGH3) gene."
],
"offsets": [
[
0,
104
]
]
},
{
"id": "1342",
"type": "abstract",
"text": [
"PURPOSE: To report the clinical, ophthalmic, and genetic characteristics for lattice corneal dystrophy type I (LCDI) in a Chilean family. METHODS: Six affected family members were examined clinically including visual acuity, color cornea photography, applanation tonography, and fundoscopy. Genomic DNA was extracted from peripheral leukocytes from six affected and three unaffected members of a family with lattice corneal dystrophy type I. Exon 4 of the transforming growth factor-induced gene (TGFBI) was screened for the most frequent mutation, R124C, in the proband by sequencing. We also designed a rapid polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the same mutation, amplifying exon 4 and digesting with PstI restriction enzyme. Using this strategy, we analyzed the mutation in six affected and three healthy family members. RESULTS: Three generations of family members were positively diagnosed with lattice corneal dystrophy. Six participants demonstrated LCD1 in both eyes, most of whom were symmetric. Age at onset of symptoms was variable (3-42 years old). Moreover, in this family, the age of onset of the disease decreased in succeeding generations, which could be interpreted as anticipation. Visual acuity varied from 1.0 to 0.13. Two patients, ages 69 and 44 years old, demonstrated a degree of severity \"Bad\" according to best-corrected vision and corneal commitment. The exon 4 sequence of TGFBI of the proband exhibits the heterozygous single-nucleotide mutation, C417T, leading to amino acid substitution (R124C) in the encoded TGF-induced protein. Using PCR-RFLP, we confirmed the heterozygous mutation in six affected family members and excluded it in three healthy members. CONCLUSIONS: The R124C mutation in TGFBI cosegregated with LCD type I in the investigated family. This is the first report of a molecular analysis of LCD type I in Chilean patients. The early onset affected persons in the fourth generation raises the possibility of anticipation."
],
"offsets": [
[
105,
2134
]
]
}
] |
[
{
"id": "1336",
"type": "ProteinMutation",
"text": [
"R124C"
],
"offsets": [
[
63,
68
]
],
"normalized": []
},
{
"id": "1337",
"type": "ProteinMutation",
"text": [
"R124C"
],
"offsets": [
[
654,
659
]
],
"normalized": []
},
{
"id": "1338",
"type": "DNAMutation",
"text": [
"C417T"
],
"offsets": [
[
1641,
1646
]
],
"normalized": []
},
{
"id": "1339",
"type": "ProteinMutation",
"text": [
"R124C"
],
"offsets": [
[
1684,
1689
]
],
"normalized": []
},
{
"id": "1340",
"type": "ProteinMutation",
"text": [
"R124C"
],
"offsets": [
[
1872,
1877
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1343
|
18457324
|
[
{
"id": "1349",
"type": "title",
"text": [
"Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer."
],
"offsets": [
[
0,
207
]
]
},
{
"id": "1350",
"type": "abstract",
"text": [
"BACKGROUND: Exposure to anthracyclines as part of cancer therapy has been associated with the development of congestive heart failure (CHF). The potential role of genetic risk factors in anthracycline-related CHF remains to be defined. Thus, in this study, the authors examined whether common polymorphisms in candidate genes involved in the pharmacodynamics of anthracyclines (in particular, the nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 gene NQO1 and the carbonyl reductase 3 gene CBR3) had an impact on the risk of anthracycline-related CHF. METHODS: A nested case-control study was conducted within a cohort of 1979 patients enrolled in the Childhood Cancer Survivor Study who received treatment with anthracyclines and had available DNA. Thirty patients with CHF (cases) and 115 matched controls were genotyped for polymorphisms in NQO1 (NQO1*2) and CBR3 (the CBR3 valine [V] to methionine [M] substitution at position 244 [V244M]). Enzyme activity assays with recombinant CBR3 isoforms (CBR3 V244 and CBR3 M244) and the anthracycline substrate doxorubicin were used to investigate the functional impact of the CBR3 V244M polymorphism. RESULTS: Multivariate analyses adjusted for sex and primary disease recurrence were used to test for associations between the candidate genetic polymorphisms (NQO1*2 and CBR3 V244M) and the risk of CHF. Analyses indicated no association between the NQO1*2 polymorphism and the risk of anthracycline-related CHF (odds ratio [OR], 1.04; P=.97). There was a trend toward an association between the CBR3 V244M polymorphism and the risk of CHF (OR, 8.16; P=.056 for G/G vs A/A; OR, 5.44; P=.092 for G/A vs A/A). In line, recombinant CBR3 V244 (G allele) synthesized 2.6-fold more cardiotoxic doxorubicinol per unit of time than CBR3 M244 (A allele; CBR3 V244 [8.26+/-3.57 nmol/hour.mg] vs CBR3 M244 [3.22+/-0.67 nmol/hour.mg]; P=.01). CONCLUSIONS: The functional CBR3 V244M polymorphism may have an impact on the risk of anthracycline-related CHF among childhood cancer survivors by modulating the intracardiac formation of cardiotoxic anthracycline alcohol metabolites. Larger confirmatory case-control studies are warranted."
],
"offsets": [
[
208,
2397
]
]
}
] |
[
{
"id": "1344",
"type": "ProteinMutation",
"text": [
"V244M"
],
"offsets": [
[
1164,
1169
]
],
"normalized": []
},
{
"id": "1345",
"type": "ProteinMutation",
"text": [
"V244M"
],
"offsets": [
[
1356,
1361
]
],
"normalized": []
},
{
"id": "1346",
"type": "ProteinMutation",
"text": [
"V244M"
],
"offsets": [
[
1551,
1556
]
],
"normalized": []
},
{
"id": "1347",
"type": "ProteinMutation",
"text": [
"V244M"
],
"offsets": [
[
1776,
1781
]
],
"normalized": []
},
{
"id": "1348",
"type": "ProteinMutation",
"text": [
"V244M"
],
"offsets": [
[
2139,
2144
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1351
|
18439317
|
[
{
"id": "1353",
"type": "title",
"text": [
"Association between promoter -1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese."
],
"offsets": [
[
0,
100
]
]
},
{
"id": "1354",
"type": "abstract",
"text": [
"BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the MMP1 gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD. METHODS: Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test. RESULTS: Our results showed substantial evidence of association between -1607 promoter polymorphism of MMP1 and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04-1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01-2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033-2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029-2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele. CONCLUSION: We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of MMP1 are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism."
],
"offsets": [
[
101,
2025
]
]
}
] |
[
{
"id": "1352",
"type": "DNAMutation",
"text": [
"G/D"
],
"offsets": [
[
272,
275
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1355
|
18426832
|
[
{
"id": "1358",
"type": "title",
"text": [
"Association between gynecomastia and aromatase (CYP19) polymorphisms."
],
"offsets": [
[
0,
69
]
]
},
{
"id": "1359",
"type": "abstract",
"text": [
"OBJECTIVE: Aromatase cytochrome P45019 (CYP19) is a key enzyme in estrogen biosynthesis, and polymorphisms within its gene are associated with an increased risk of estrogen-dependent diseases. Enhanced estrogen stimulation of breast tissue in men may lead to gynecomastia. We assessed whether intron 4 (TTTA)n repeat and TCT deletion/insertion polymorphisms and an exon 10 (3'-UTR) C/T single nucleotide polymorphism of CYP19 are associated with gynecomastia. DESIGN/METHODS: We performed a genetic association study of 100 patients referred to the endocrinological outpatient clinic with breast glandular tissue enlargement confirmed by clinical and ultrasound examinations and 99 healthy volunteers without gynecomastia. Microsatellite (TTTA)n and insertion/deletion polymorphisms were studied using capillary electrophoresis, and the C/T polymorphism in the 3'-UTR was analyzed using the TaqMan assay. RESULTS: Significantly increased risk of gynecomastia was found in subjects carrying a CYP19 exon 10 T allele that was previously related to the high aromatase activity. Frequency of the TT genotype was significantly higher in patients when compared with controls (40.6 vs 26.3%; TT versus CT and CC genotypes; P(c)<0.05). We found strong linkage disequilibrium between the alleles of studied polymorphic loci. T allele in the 3'-UTR was in linkage disequilibrium with the long alleles of the intron 4 polymorphism, mainly (TTTA)11. However, our findings did not show significant correlation of alleles having more than nine TTTA repeats with gynecomastia. CONCLUSIONS: The CYP19 polymorphisms might contribute to the incidence of gynecomastia, but further studies in larger groups are needed to confirm these results."
],
"offsets": [
[
70,
1793
]
]
}
] |
[
{
"id": "1356",
"type": "DNAMutation",
"text": [
"C/T"
],
"offsets": [
[
452,
455
]
],
"normalized": []
},
{
"id": "1357",
"type": "DNAMutation",
"text": [
"C/T"
],
"offsets": [
[
907,
910
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1360
|
18410548
|
[
{
"id": "1363",
"type": "title",
"text": [
"Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas."
],
"offsets": [
[
0,
136
]
]
},
{
"id": "1364",
"type": "abstract",
"text": [
"OBJECTIVE: Pituitary adenomas occur rarely in childhood and adolescence. Pituitary adenoma predisposition (PAP) has been recently associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The aim of the study was to examine the proportion of germline AIP mutations in apparently sporadic paediatric pituitary adenomas. DESIGN: Genomic DNA was analysed for mutations in the AIP gene, by PCR amplification and direct sequencing. PATIENTS: A population-based cohort consisting of 36 apparently sporadic paediatric pituitary adenoma patients, referred to two medical centres in Italy, was included in the study. Patients were either less than 18 years at diagnosis, or showed clinical evidence of adenoma development before the age of 18 years. RESULTS: A heterozygous in-frame deletion Y248del (c.742_744delTAC) was identified in one GH-secreting adenoma patient. Loss of heterozygosity (LOH) analysis of tumour DNA revealed the loss of the wild-type allele. First degree relatives carrying the mutation were clinically unaffected. CONCLUSIONS: While mutations were absent in non-GH-secreting adenoma patients, germline AIP mutations can be found in children and adolescents with GH-secreting tumours, even in the absence of family history. The present study reports the AIP mutation analysis results on patients of a single ethnic origin. Clearly, further studies are needed to improve our knowledge on the role of AIP in paediatric pituitary adenomas."
],
"offsets": [
[
137,
1629
]
]
}
] |
[
{
"id": "1361",
"type": "ProteinMutation",
"text": [
"Y248del"
],
"offsets": [
[
962,
969
]
],
"normalized": []
},
{
"id": "1362",
"type": "DNAMutation",
"text": [
"c.742_744delTAC"
],
"offsets": [
[
971,
986
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1365
|
18408250
|
[
{
"id": "1369",
"type": "title",
"text": [
"A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population."
],
"offsets": [
[
0,
146
]
]
},
{
"id": "1370",
"type": "abstract",
"text": [
"OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, which regulate the production of proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to systemic lupus erythaematosus (SLE) in Caucasian and Asian populations, but their involvement in other autoimmune diseases is still uncertain. Here, we assessed the genetic role of IRF5 in susceptibility to rheumatoid arthritis (RA) in Japanese subjects. METHODS: We selected 13 single nucleotide polymorphisms (SNPs) and a CGGGG insertion-deletion polymorphism in the IRF5 gene. We performed 2 sets of case-control comparisons using Japanese subjects (first set: 830 patients with RA and 658 controls; second set: 1112 patients with RA and 940 controls), and then performed a stratified analysis using human leukocyte antigen (HLA)-DRB1 shared epitope (SE) status. We genotyped the SNPs using TaqMan assays. RESULTS: A significant association of the rs729302 A allele with RA susceptibility was found in both sets (odds ratio (OR) 1.22, 95% CI 1.09 to 1.35, p<0.001 in the combined analysis). When the patients were stratified by the SE, the rs729302 A allele was found to confer increased risk to RA in patients that were SE negative (OR 1.50, 95% CI 1.17 to 1.92, p = 0.001) as compared with patients carrying the SE (OR 1.11, 95% CI 0.93 to 1.33, p = 0.24). In both sets, no genotyped polymorphisms were significantly associated with RA susceptibility, but rs729302 was significantly associated. CONCLUSIONS: These findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative."
],
"offsets": [
[
147,
1912
]
]
}
] |
[
{
"id": "1366",
"type": "SNP",
"text": [
"rs729302"
],
"offsets": [
[
1139,
1147
]
],
"normalized": []
},
{
"id": "1367",
"type": "SNP",
"text": [
"rs729302"
],
"offsets": [
[
1331,
1339
]
],
"normalized": []
},
{
"id": "1368",
"type": "SNP",
"text": [
"rs729302"
],
"offsets": [
[
1649,
1657
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1371
|
18391980
|
[
{
"id": "1372",
"type": "title",
"text": [
"Functional inactivation of the WTX gene is not a frequent event in Wilms' tumors."
],
"offsets": [
[
0,
81
]
]
},
{
"id": "1373",
"type": "abstract",
"text": [
"For many years the precise genetic etiology of the majority of Wilms' tumors has remained unexplained. Recently, the WTX gene, mapped to chromosome Xq11.1, has been reported to be lost or mutated in approximately one-third of Wilms' tumors. Moreover, in female cases, the somatically inactivated alleles were found to invariantly derive from the active chromosome X. Consequently, WTX has been proposed as a 'one-hit' tumor suppressor gene. To provide further insights on the contribution of WTX to the development of the disease, we have examined 102 Wilms' tumors, obtained from 43 male and 57 female patients. Quantitative PCR analyses detected WTX deletions in 5 of 45 (11%) tumors from males, whereas loss of heterozygosity at WTX-linked microsatellites was observed in 9 tumors from 50 informative females (19%). However, in the latter group, using a combination of HUMARA assay and bisulfite-modified DNA sequencing, we found that the deletion affected the active chromosome X only in two cases (4%). Sequence analyses detected an inactivating somatic mutation of WTX in a single tumor, in which a strongly reduced expression of the mutant allele respect to the wild-type allele was observed, a finding not consistent with its localization on the active chromosome X. Overall, a functional somatic nullizygosity of the WTX gene was ascertained only in seven of the Wilms' tumors included in the study (approximately 7%). Our findings indicate that previously reported estimates on the proportion of Wilms' tumors due to WTX alterations should be reconsidered."
],
"offsets": [
[
82,
1648
]
]
}
] |
[] |
[] |
[] |
[] |
1374
|
18385794
|
[
{
"id": "1389",
"type": "title",
"text": [
"Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia."
],
"offsets": [
[
0,
129
]
]
},
{
"id": "1390",
"type": "abstract",
"text": [
"PURPOSE: Mutations in the SOX2 and CHX10 genes have been reported in patients with anophthalmia and/or microphthalmia. In this study, we evaluated 34 anophthalmic/microphthalmic patient DNA samples (two sets of siblings included) for mutations and sequence variants in SOX2 and CHX10. METHODS: Conformational sensitive gel electrophoresis (CSGE) was used for the initial SOX2 and CHX10 screening of 34 affected individuals (two sets of siblings), five unaffected family members, and 80 healthy controls. Patient samples containing heteroduplexes were selected for sequence analysis. Base pair changes in SOX2 and CHX10 were confirmed by sequencing bidirectionally in patient samples. RESULTS: Two novel heterozygous mutations and two sequence variants (one known) in SOX2 were identified in this cohort. Mutation c.310 G>T (p. Glu104X), found in one patient, was in the region encoding the high mobility group (HMG) DNA-binding domain and resulted in a change from glutamic acid to a stop codon. The second mutation, noted in two affected siblings, was a single nucleotide deletion c.549delC (p. Pro184ArgfsX19) in the region encoding the activation domain, resulting in a frameshift and premature termination of the coding sequence. The shortened protein products may result in the loss of function. In addition, a novel nucleotide substitution c.*557G>A was identified in the 3'-untranslated region in one patient. The relationship between the nucleotide change and the protein function is indeterminate. A known single nucleotide polymorphism (c. *469 C>A, SNP rs11915160) was also detected in 2 of the 34 patients. Screening of CHX10 identified two synonymous sequence variants, c.471 C>T (p.Ser157Ser, rs35435463) and c.579 G>A (p. Gln193Gln, novel SNP), and one non-synonymous sequence variant, c.871 G>A (p. Asp291Asn, novel SNP). The non-synonymous polymorphism was also present in healthy controls, suggesting non-causality. CONCLUSIONS: These results support the role of SOX2 in ocular development. Loss of SOX2 function results in severe eye malformation. CHX10 was not implicated with microphthalmia/anophthalmia in our patient cohort."
],
"offsets": [
[
130,
2277
]
]
}
] |
[
{
"id": "1375",
"type": "DNAMutation",
"text": [
"c.310 G>T"
],
"offsets": [
[
943,
952
]
],
"normalized": []
},
{
"id": "1376",
"type": "ProteinMutation",
"text": [
"p. Glu104X"
],
"offsets": [
[
954,
964
]
],
"normalized": []
},
{
"id": "1377",
"type": "DNAMutation",
"text": [
"c.549delC"
],
"offsets": [
[
1212,
1221
]
],
"normalized": []
},
{
"id": "1378",
"type": "ProteinMutation",
"text": [
"p. Pro184ArgfsX19"
],
"offsets": [
[
1223,
1240
]
],
"normalized": []
},
{
"id": "1379",
"type": "DNAMutation",
"text": [
"c.*557G>A"
],
"offsets": [
[
1476,
1485
]
],
"normalized": []
},
{
"id": "1380",
"type": "DNAMutation",
"text": [
"c. *469 C>A"
],
"offsets": [
[
1677,
1688
]
],
"normalized": []
},
{
"id": "1381",
"type": "SNP",
"text": [
"rs11915160"
],
"offsets": [
[
1694,
1704
]
],
"normalized": []
},
{
"id": "1382",
"type": "DNAMutation",
"text": [
"c.471 C>T"
],
"offsets": [
[
1813,
1822
]
],
"normalized": []
},
{
"id": "1383",
"type": "ProteinMutation",
"text": [
"p.Ser157Ser"
],
"offsets": [
[
1824,
1835
]
],
"normalized": []
},
{
"id": "1384",
"type": "SNP",
"text": [
"rs35435463"
],
"offsets": [
[
1837,
1847
]
],
"normalized": []
},
{
"id": "1385",
"type": "DNAMutation",
"text": [
"c.579 G>A"
],
"offsets": [
[
1853,
1862
]
],
"normalized": []
},
{
"id": "1386",
"type": "ProteinMutation",
"text": [
"p. Gln193Gln"
],
"offsets": [
[
1864,
1876
]
],
"normalized": []
},
{
"id": "1387",
"type": "DNAMutation",
"text": [
"c.871 G>A"
],
"offsets": [
[
1931,
1940
]
],
"normalized": []
},
{
"id": "1388",
"type": "ProteinMutation",
"text": [
"p. Asp291Asn"
],
"offsets": [
[
1942,
1954
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1391
|
18257781
|
[
{
"id": "1396",
"type": "title",
"text": [
"Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease."
],
"offsets": [
[
0,
132
]
]
},
{
"id": "1397",
"type": "abstract",
"text": [
"BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians. MATERIALS AND METHODS: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. RESULTS: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. CONCLUSIONS: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation."
],
"offsets": [
[
133,
1794
]
]
}
] |
[
{
"id": "1392",
"type": "DNAMutation",
"text": [
"c.1445T > G"
],
"offsets": [
[
559,
570
]
],
"normalized": []
},
{
"id": "1393",
"type": "ProteinMutation",
"text": [
"p.F482C"
],
"offsets": [
[
718,
725
]
],
"normalized": []
},
{
"id": "1394",
"type": "DNAMutation",
"text": [
"IVS21-2delAG"
],
"offsets": [
[
783,
795
]
],
"normalized": []
},
{
"id": "1395",
"type": "ProteinMutation",
"text": [
"p.F482C"
],
"offsets": [
[
1535,
1542
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1398
|
18241046
|
[
{
"id": "1402",
"type": "title",
"text": [
"A human phospholamban promoter polymorphism in dilated cardiomyopathy alters transcriptional regulation by glucocorticoids."
],
"offsets": [
[
0,
123
]
]
},
{
"id": "1403",
"type": "abstract",
"text": [
"Depressed calcium handling by the sarcoplasmic reticulum (SR) Ca-ATPase and its regulator phospholamban (PLN) is a key characteristic of human and experimental heart failure. Accumulating evidence indicates that increases in the relative levels of PLN to Ca-ATPase in failing hearts and resulting inhibition of Ca sequestration during diastole, impairs contractility. Here, we identified a genetic variant in the PLN promoter region, which increases its expression and may serve as a genetic modifier in dilated cardiomyopathy (DCM). The variant AF177763.1:g.203A>C (at position -36 bp relative to the PLN transcriptional start site) was found only in the heterozygous form in 1 out of 296 normal subjects and in 22 out of 381 cardiomyopathy patients (heart failure at age of 18-44 years, ejection fraction=22+/-9%). In vitro analysis, using luciferase as a reporter gene in rat neonatal cardiomyocytes, indicated that the PLN-variant increased activity by 24% compared to the wild type. Furthermore, the g.203A>C substitution altered the specific sequence of the steroid receptor for the glucocorticoid nuclear receptor (GR)/transcription factor in the PLN promoter, resulting in enhanced binding to the mutated DNA site. These findings suggest that the g.203A>C genetic variant in the human PLN promoter may contribute to depressed contractility and accelerate functional deterioration in heart failure."
],
"offsets": [
[
124,
1529
]
]
}
] |
[
{
"id": "1399",
"type": "DNAMutation",
"text": [
"g.203A>C"
],
"offsets": [
[
681,
689
]
],
"normalized": []
},
{
"id": "1400",
"type": "DNAMutation",
"text": [
"g.203A>C"
],
"offsets": [
[
1129,
1137
]
],
"normalized": []
},
{
"id": "1401",
"type": "DNAMutation",
"text": [
"g.203A>C"
],
"offsets": [
[
1379,
1387
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1404
|
18235024
|
[
{
"id": "1405",
"type": "title",
"text": [
"Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2."
],
"offsets": [
[
0,
92
]
]
},
{
"id": "1406",
"type": "abstract",
"text": [
"PURPOSE: Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized by reduced visual acuity, color vision defects, and specific alterations of ERG responses that feature elevated scotopic b-wave amplitudes at high luminance intensities. Mutations in PDE6H and in KCNV2 have been described in CDSRR. A combined clinical and genetic study was conducted in a cohort of patients with CDSRR, to substantiate these prior RESULTS: <AbstractText Label=\"METHODS\" NlmCategory=\"METHODS\">Seventeen patients from 13 families underwent a detailed ophthalmic examination including color vision testing, Goldmann visual fields, fundus photography, Ganzfeld and multifocal ERGs, and optical coherence tomography. The coding sequences and flanking intron/UTR sequences of PDE6C and KCNV2 were screened for mutations by means of DHPLC and direct DNA sequencing of PCR-amplified genomic DNA. results. Whereas no mutations were detected in the PDE6H gene, mutations in KCNV2 were identified in all patients, in either the homozygous or compound heterozygous state. Ten of the 11 identified mutations were novel, including three missense and six truncating mutations and one gross deletion. The mutations concordantly segregate in all available families according a recessive mode of inheritance. The CDSRR phenotype was associated with reduced visual acuity of variable degree and color vision defects. Macular defects ranging from mild pigmentary changes to distinct foveal atrophy were present in nine patients. Progression of the disease was observed in only three of seven patients with follow-up data. CONCLUSIONS: The phenotype of cone dystrophy with supernormal rod response is tightly linked with mutations in KCNV2."
],
"offsets": [
[
93,
1843
]
]
}
] |
[] |
[] |
[] |
[] |
1407
|
18202102
|
[
{
"id": "1408",
"type": "title",
"text": [
"SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer."
],
"offsets": [
[
0,
129
]
]
},
{
"id": "1409",
"type": "abstract",
"text": [
"Deletion of chromosome 6q14-q22 is common in multiple human cancers including prostate cancer, and chromosome 6 transferred into cancer cells induces senescence and reduces cell growth, tumorigenicity and metastasis, indicating the existence of one or more tumor-suppressor genes in 6q. To identify the 6q tumor-suppressor gene, we first narrowed the common region of deletion to a 2.5 Mb interval at 6q14-15. Of the 11 genes located in this minimal deletion region and expressed in normal prostates, only snoRNA U50 was mutated, demonstrated transcriptional downregulation and inhibited colony formation in prostate cancer cells. The mutation, a homozygous 2 bp (TT) deletion, was found in two of 30 prostate cancer cell lines/xenografts and nine of 89 localized prostate cancers (eleven of 119 or 9% cancers). Two of 89 (2%) patients with prostate cancer also showed the same mutation in their germline DNA, but none of 104 cancer-free control men did. The homozygous deletion abolished U50 function in a colony formation assay. Analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, although a germline heterozygous genotype of the deletion was detected in both patients and controls at similar frequencies, the homozygosity of the deletion was significantly associated with clinically significant prostate cancer (odds ratio 2.9; 95% confidence interval 1.17-7.21). These findings establish snoRNA U50 as a reasonable candidate for the 6q tumor-suppressor gene in prostate cancer and likely in other types of cancers."
],
"offsets": [
[
130,
1734
]
]
}
] |
[] |
[] |
[] |
[] |
1410
|
18050247
|
[
{
"id": "1413",
"type": "title",
"text": [
"Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform."
],
"offsets": [
[
0,
151
]
]
},
{
"id": "1414",
"type": "abstract",
"text": [
"OBJECTIVE: Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents. METHODS: Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections. RESULTS: Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P = 5.74 x 10(-6)) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P = 9.58 x 10(-6)). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis. CONCLUSION: SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases."
],
"offsets": [
[
152,
2033
]
]
}
] |
[
{
"id": "1411",
"type": "ProteinMutation",
"text": [
"N673S"
],
"offsets": [
[
1029,
1034
]
],
"normalized": []
},
{
"id": "1412",
"type": "ProteinMutation",
"text": [
"C203S"
],
"offsets": [
[
1104,
1109
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1415
|
17994380
|
[
{
"id": "1416",
"type": "title",
"text": [
"Screening of Iranian thalassemic families for the most common deletions of the beta-globin gene cluster."
],
"offsets": [
[
0,
104
]
]
},
{
"id": "1417",
"type": "abstract",
"text": [
"Deltabeta-thalassemia (thal) is a disorder, characterized by increased levels of fetal hemoglobin (Hb F) in adult life. A considerable number of deletions of variable size and position in the beta-globin gene cluster are associated with the clinical manifestation of deltabeta-thal. In this study we have determined the presence of the eight most common deletions in Iranian patients. Thirty-two patients from 19 families were referred to the Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran (a private genetics center), within the past 3 years with elevated levels of Hb F and low mean corpuscular volume (MCV). After obtaining their informed consent, DNA was extracted from whole blood by the salting-out method. Detection of eight deletions was performed using polymerase chain reaction (PCR). These deletions included the hereditary persistence of fetal Hb (HPFH) 1 (Black) and 3 (Indian), Spanish (-114 kb), Sicilian (-13,377 bp), Chinese (G)gamma((A)gammadeltabeta)(0)-thal (-100 kb), Asian-Indian inversion-deletion (G)gamma((A)gammadeltabeta)(0)-thal, and the Turkish form of inversion-deletion (deltabeta)(0)-thal, as well as the Hbs Lepore, which are characterized by unequal crossovers between the delta- and beta-globin genes. We found the Sicilian (-13,377 bp) and Hb Lepore deletions as well as the Asian-Indian (G)gamma((A)gammadeltabeta)(0)-thal in 11 (57.89%), three (15.78%) and five (26.31%) families, respectively. None of the aforementioned deletions were found in one of the patients. This is the first study of the deletions involved in deltabeta-thal in Iranian patients. Our study highlights the importance of detecting these mutations for prenatal diagnosis carrier detection and genotype/phenotype prediction."
],
"offsets": [
[
105,
1858
]
]
}
] |
[] |
[] |
[] |
[] |
1418
|
17990063
|
[
{
"id": "1420",
"type": "title",
"text": [
"Clinical and molecular characterization of Italian patients affected by Cohen syndrome."
],
"offsets": [
[
0,
87
]
]
},
{
"id": "1421",
"type": "abstract",
"text": [
"Cohen syndrome is an autosomal recessive disorder with variability in the clinical manifestations, characterized by developmental delay, visual disability, facial dysmorphisms and intermittent neutropenia. We described a cohort of 10 patients affected by Cohen syndrome from nine Italian families ranging from 5 to 52 years at assessment. Characteristic age related facial changes were well documented. Visual anomalies, namely retinopathy and myopia, were present in 9/10 patients (retinopathy in 9/10 and myopia in 8/10). Truncal obesity has been described in all patients older than 6 years (8/8). DNA samples from all patients were analyzed for mutations in COH1 by DHPLC. We detected 15 COH1 alterations most of them were truncating mutations, only one being a missense change. Partial gene deletions have been found in two families. Most mutations were private. Two were already reported in the literature just once. A single base deletion leading to p.T3708fs3769, never reported before, was found in three apparently unrelated families deriving from a restricted area of the Veneto's lowland, between Padova town and Tagliamento river, in heterozygous state. Given the geographical conformation of this region, which is neither geographically or culturally isolated, a recent origin of the mutation could be hypothesized."
],
"offsets": [
[
88,
1417
]
]
}
] |
[
{
"id": "1419",
"type": "ProteinMutation",
"text": [
"p.T3708fs3769"
],
"offsets": [
[
1045,
1058
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1422
|
17962394
|
[
{
"id": "1427",
"type": "title",
"text": [
"Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene."
],
"offsets": [
[
0,
122
]
]
},
{
"id": "1428",
"type": "abstract",
"text": [
"AIMS: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. METHODS: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. RESULTS: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. CONCLUSIONS: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females."
],
"offsets": [
[
123,
1334
]
]
}
] |
[
{
"id": "1423",
"type": "ProteinMutation",
"text": [
"p.R229G"
],
"offsets": [
[
77,
84
]
],
"normalized": []
},
{
"id": "1424",
"type": "DNAMutation",
"text": [
"c.686C>G"
],
"offsets": [
[
725,
733
]
],
"normalized": []
},
{
"id": "1425",
"type": "ProteinMutation",
"text": [
"p.R229G"
],
"offsets": [
[
837,
844
]
],
"normalized": []
},
{
"id": "1426",
"type": "ProteinMutation",
"text": [
"p.R229G"
],
"offsets": [
[
1179,
1186
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1429
|
17959715
|
[
{
"id": "1431",
"type": "title",
"text": [
"Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma."
],
"offsets": [
[
0,
88
]
]
},
{
"id": "1432",
"type": "abstract",
"text": [
"BACKGROUND AND OBJECTIVE: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. METHODS: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. CONCLUSIONS: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested."
],
"offsets": [
[
89,
2316
]
]
}
] |
[
{
"id": "1430",
"type": "SNP",
"text": [
"rs1800734"
],
"offsets": [
[
634,
643
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1433
|
17910065
|
[
{
"id": "1438",
"type": "title",
"text": [
"A novel missense mutation in the paired domain of human PAX9 causes oligodontia."
],
"offsets": [
[
0,
80
]
]
},
{
"id": "1439",
"type": "abstract",
"text": [
"PAX9 and MSX1 are transcription factors that play essential roles in craniofacial and limb development. In humans, mutations in both genes are associated with nonsyndromic and syndromic oligodontia, respectively. We screened one family with nonsyndromic oligodontia for mutations in PAX9 and MSX1. Single stranded conformational polymorphism (SSCP) analysis and sequencing revealed a novel heterozygous C139T transition in PAX9 in the affected members of the family. There were no mutations detected in the entire coding sequence of MSX1. The C139T mutation, predicted to result in the substitution of an arginine by a tryptophan (R47W) in the N-terminal subdomain, affected conserved residues in the PAX9 paired domain. To elucidate the pathogenic mechanism producing oligodontia phenotype caused by this mutation, we analyzed the binding of wild-type and mutant PAX9 paired domain protein to double-stranded DNA targets. The R47W mutation dramatically reduced DNA binding suggesting that the mutant protein with consequent haploinsufficiency results in a clinical phenotype."
],
"offsets": [
[
81,
1157
]
]
}
] |
[
{
"id": "1434",
"type": "DNAMutation",
"text": [
"C139T"
],
"offsets": [
[
484,
489
]
],
"normalized": []
},
{
"id": "1435",
"type": "DNAMutation",
"text": [
"C139T"
],
"offsets": [
[
624,
629
]
],
"normalized": []
},
{
"id": "1436",
"type": "ProteinMutation",
"text": [
"R47W"
],
"offsets": [
[
712,
716
]
],
"normalized": []
},
{
"id": "1437",
"type": "ProteinMutation",
"text": [
"R47W"
],
"offsets": [
[
1008,
1012
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1440
|
17876530
|
[
{
"id": "1442",
"type": "title",
"text": [
"Role of homozygous DC-SIGNR 5/5 tandem repeat polymorphism in HIV-1 exposed seronegative North Indian individuals."
],
"offsets": [
[
0,
114
]
]
},
{
"id": "1443",
"type": "abstract",
"text": [
"Despite multiple sexual exposures to HIV-1 virus, some individuals remain HIV-1 seronegative. Although several genetic factors have been related to HIV-1 resistance, the homozygosity for a mutation in CCR5 gene (the 32-bp deletion, i.e., CCR5-Delta32 allele) is presently considered the most relevant one. The C-type lectins, DC-SIGN (present on dendritic cells and macrophages) and DC-SIGNR (present on endothelial cells in liver and lymph nodes) efficiently bind and transmit HIV-1 to susceptible cell in trans, thereby augmenting the infection. A potential association of the DC-SIGN and DC-SIGNR neck domain repeat polymorphism and risk of HIV-1 infection is currently under debate. To determine the influence of host genetic factors on HIV-1 resistance, we conducted genetic risk association study in HIV-1-exposed seronegative (n = 47) individuals, HIV-1 seronegative (n = 262) healthy control, and HIV-1-infected seropositive patients (n = 168) for polymorphism in neck domain of DC-SIGN and DC-SIGNR genes. The DC-SIGN and DC-SIGNR genotypes were identified by polymerase chain reaction method in DNA extracted from peripheral blood and confirmed by sequencing. Fisher exact or chi (2) test was used for static analysis. DC-SIGN genotype and allele distribution was fairly similar in HIV-1-exposed seronegative, HIV-1 seropositive, and HIV-1 seronegative control. There was no statistical significance in the differences in the distribution of DC-SIGN genotypes. A total of 13 genotypes were found in DC-SIGNR neck repeat region polymorphism. Among all the genotypes, only 5/5 homozygous showed significant reduced risk of HIV-1 infection in HIV-1-exposed seronegative individuals (p = 0.009). A unique genotype 8/5 heterozygous was also found in HIV-1 seropositive individual, which is not reported elsewhere."
],
"offsets": [
[
115,
1933
]
]
}
] |
[
{
"id": "1441",
"type": "DNAMutation",
"text": [
"Delta32"
],
"offsets": [
[
358,
365
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1444
|
17710578
|
[
{
"id": "1446",
"type": "title",
"text": [
"Angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensin II type 1 receptor (AT1R) gene polymorphism and its association with preeclampsia in Chinese women."
],
"offsets": [
[
0,
174
]
]
},
{
"id": "1447",
"type": "abstract",
"text": [
"OBJECTIVE: To investigate whether polymorphisms of angiotensin converting enzyme gene (ACE) and angiotensin II receptor type 1 gene (AT1R) are associated with etiology of preeclampsia and renal impact in women with preeclampsia. METHODS: DNA was extracted from peripheral blood of 133 patients with preeclampsia and 105 healthy pregnant women. The I/D polymorphism of the ACE gene was assessed by polymerase chain reaction, and the A1166C polymorphism of the AT(1)R gene was additionally assessed by DdeI digestion. The level of proteinuria, fasting serum urea, creatinine and uric acid were investigated according to different genotypes of ACE and AT1R genes. RESULTS: The frequency of genotypes of the ACE gene and the AT1R gene was similar in preeclampsia and normal pregnancy. DD and ID genotype predominated in patients with severe proteinuria, as well as increased serum urea and uric acid. Serum creatinine was also increased, but no significant difference was found among three genotypes. The level of proteinuria, serum uric acid, urea, and creatinine did not vary between different AT1R genotypes. Compared with patients without renal dysfunction, the frequency of DD and ID genotypes of ACE gene was much higher in those with renal dysfunction, but AC and CC genotypes of AT1R gene were not. CONCLUSION: We found no association of the two gene polymorphisms with preeclampsia. However, ACE gene I/D polymorphisms were associated with the severe proteinuria and renal dysfunction seen in preeclampsia. Preeclampsia patients carrying the D allele may be susceptible to renal dysfunction."
],
"offsets": [
[
175,
1771
]
]
}
] |
[
{
"id": "1445",
"type": "DNAMutation",
"text": [
"A1166C"
],
"offsets": [
[
607,
613
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1448
|
17683901
|
[
{
"id": "1456",
"type": "title",
"text": [
"An improved tetra-primer PCR approach for the detection of the FGFR3 G380R mutation responsible for achondroplasia."
],
"offsets": [
[
0,
115
]
]
},
{
"id": "1457",
"type": "abstract",
"text": [
"Achondroplasia is the most common form of dwarfism and has an incidence of approximately 1/7500. In more than 98% of cases, the disease is associated with a G to A or G to C substitution at nucleotide position 1138 (p.G380R) of the fibroblast growth factor receptor 3 (FGFR3) gene. We have developed a sensitive single tube tetra-primer PCR assay to detect both the c.1138G>A and c.1138G>C mutations and can successfully distinguish DNA samples that are homozygous and heterozygous for the c.1138G>A mutation. Titration studies showed that the assay could reliably detect one copy of the mutant allele in a mix of 100 wild-type alleles. The assay has been tested in 50 healthy controls, 3 known patients with achondroplasia, and 5 amniotic fluids suspected of having achondroplasia and for whom we had previously determined the genotypes for the c.1138G>A mutation by PCR-RFLP. We have observed complete concordance between methods. Our tetra-primer PCR assay is sensitive, low-cost, and easy to use method for FGFR3 p.G380R genotyping, which could be used even in \"low-tech\" laboratories."
],
"offsets": [
[
116,
1205
]
]
}
] |
[
{
"id": "1449",
"type": "ProteinMutation",
"text": [
"G380R"
],
"offsets": [
[
69,
74
]
],
"normalized": []
},
{
"id": "1450",
"type": "ProteinMutation",
"text": [
"p.G380R"
],
"offsets": [
[
332,
339
]
],
"normalized": []
},
{
"id": "1451",
"type": "DNAMutation",
"text": [
"c.1138G>A"
],
"offsets": [
[
482,
491
]
],
"normalized": []
},
{
"id": "1452",
"type": "DNAMutation",
"text": [
"c.1138G>C"
],
"offsets": [
[
496,
505
]
],
"normalized": []
},
{
"id": "1453",
"type": "DNAMutation",
"text": [
"c.1138G>A"
],
"offsets": [
[
606,
615
]
],
"normalized": []
},
{
"id": "1454",
"type": "DNAMutation",
"text": [
"c.1138G>A"
],
"offsets": [
[
962,
971
]
],
"normalized": []
},
{
"id": "1455",
"type": "ProteinMutation",
"text": [
"p.G380R"
],
"offsets": [
[
1133,
1140
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1458
|
17671968
|
[
{
"id": "1459",
"type": "title",
"text": [
"Association study between Gilles de la Tourette Syndrome and two genes in the Robo-Slit pathway located in the chromosome 11q24 linked/associated region."
],
"offsets": [
[
0,
153
]
]
},
{
"id": "1460",
"type": "abstract",
"text": [
"Gilles de la Tourette Syndrome (GTS) is an inherited neuropsychiatric disorder characterized by the presence of motor and phonic tics. Previous genetic studies have identified linkage and association between GTS and the 11q24 chromosomal region. We selected for study, within this region, two possible susceptibility genes for GTS, the ROBO3 and ROBO4 genes. These two genes were selected because of the recent identification of SLITRK1 as a potential susceptibility gene for GTS based on a translocation breakpoint and the further finding of two mutations in the SLITRK1 gene in three patients with GTS. While thus far, the SLITRK1 gene appears to account for only a few cases of GTS, these findings, if confirmed, point to other genes in these pathways that may contribute to GTS. Based on this, we examined two genes in the Slit-Robo pathway involved in cell migration, axonal pathfinding, and/or neuronal differentiation because of their location in 11q24, a region previously identified as linked and associated with GTS. We selected six haplotype tagging single nucleotide polymorphisms (SNPs) for ROBO3 and four for ROBO4 and genotyped them in our sample of trios and sibpair families diagnosed with GTS. Based on 155 nuclear families with 255 affected children, we did not find evidence for association between GTS and either the ROBO3 or ROBO4 genes. Thus, these two genes are unlikely to be the susceptibility genes contributing to GTS on 11q24."
],
"offsets": [
[
154,
1609
]
]
}
] |
[] |
[] |
[] |
[] |
1461
|
17671735
|
[
{
"id": "1471",
"type": "title",
"text": [
"Coincidence of mutations in different connexin genes in Hungarian patients."
],
"offsets": [
[
0,
75
]
]
},
{
"id": "1472",
"type": "abstract",
"text": [
"Mutations in the GJB2 gene are the most common cause of hereditary prelingual sensorineural hearing impairment in Europe. Several studies indicate that different members of the connexin protein family interact to form gap junctions in the inner ear. Mutations in different connexin genes may accumulate and, consequently lead to hearing impairment. Therefore, we screened 47 Hungarian GJB2- heterozygous (one mutation in coding exon of the GJB2 gene) patients with hearing impairment for DNA changes in two further connexin genes (GJB6 and GJB3) and in the 5' non-coding region of GJB2 including the splice sites. Eleven out of 47 GJB2-heterozygous patients analyzed carried the splice site mutation -3170G>A in the 5'UTR region of GJB2. One out of these 11 patients showed homozygous -3170G>A genotype in combination with p.R127H. Next to the GJB2 mutations we noted 2 cases of deletion in GJB6 [Delta(GJB6-D13S1830)] and 3 (2 new and 1 described) base substitutions in GJB3 [c.357C>T, c.798C>T and c.94C>T (p.R32W)] which are unlikely disease-causing. Our results suggest the importance of routine screening for the rather frequent -3170G>A mutation (in addition to c.35delG) in patients with hearing impairment."
],
"offsets": [
[
76,
1290
]
]
}
] |
[
{
"id": "1462",
"type": "DNAMutation",
"text": [
"-3170G>A"
],
"offsets": [
[
776,
784
]
],
"normalized": []
},
{
"id": "1463",
"type": "DNAMutation",
"text": [
"-3170G>A"
],
"offsets": [
[
861,
869
]
],
"normalized": []
},
{
"id": "1464",
"type": "ProteinMutation",
"text": [
"p.R127H"
],
"offsets": [
[
899,
906
]
],
"normalized": []
},
{
"id": "1465",
"type": "DNAMutation",
"text": [
"c.357C>T"
],
"offsets": [
[
1053,
1061
]
],
"normalized": []
},
{
"id": "1466",
"type": "DNAMutation",
"text": [
"c.798C>T"
],
"offsets": [
[
1063,
1071
]
],
"normalized": []
},
{
"id": "1467",
"type": "DNAMutation",
"text": [
"c.94C>T"
],
"offsets": [
[
1076,
1083
]
],
"normalized": []
},
{
"id": "1468",
"type": "ProteinMutation",
"text": [
"p.R32W"
],
"offsets": [
[
1085,
1091
]
],
"normalized": []
},
{
"id": "1469",
"type": "DNAMutation",
"text": [
"-3170G>A"
],
"offsets": [
[
1210,
1218
]
],
"normalized": []
},
{
"id": "1470",
"type": "DNAMutation",
"text": [
"c.35delG"
],
"offsets": [
[
1244,
1252
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1473
|
17614823
|
[
{
"id": "1474",
"type": "title",
"text": [
"Characterisation of a large complex intragenic re-arrangement in the FVII gene (F7) avoiding misdiagnosis in inherited factor VII deficiency."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "1475",
"type": "abstract",
"text": [
"Inherited factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder mostly caused by point mutations. Large genomic re-arrangements at F7 locus could account for a fraction of mutant alleles that remain unidentified after DNA sequencing, because they escape conventional polymerase chain reaction (PCR)-based techniques. We report the first systematic screening of F7 for large re-arrangements, by semi-quantitative multiplex PCR of fluorescent fragments targeting the 9 exons and the promoter region. A well-characterised cohort of 43 unrelated patients either apparently homozygous for a F7 point mutation or carrying at least one unidentified F7 mutant allele participated in this study. Two large F7 re-arrangements were identified in two FVII-deficient pedigrees, including a discontinuous deletion involving two distinct portions of F7 whose proximal and distal end junctions were characterised. A simple and efficient method for the routine detection of gross alterations of F7, which accounted for 2.3% of mutant alleles in our sample, is now available in inherited FVII deficiency. This test should complement conventional PCR-based techniques not only in unsolved cases, but also where inheritance pattern analysis is not achievable."
],
"offsets": [
[
142,
1404
]
]
}
] |
[] |
[] |
[] |
[] |
1476
|
17549393
|
[
{
"id": "1480",
"type": "title",
"text": [
"A novel IRF6 nonsense mutation (Y67X) in a German family with Van der Woude syndrome."
],
"offsets": [
[
0,
85
]
]
},
{
"id": "1481",
"type": "abstract",
"text": [
"Van der Woude syndrome (VWS) is the most common type of syndromic orofacial cleft, which accounts for approximately 2% of all cleft lip and palate cases. It is characterised by variable association of lower lip pits, cleft lip and cleft palate, and hypodontia. VWS arises as the result of mutations in the gene encoding interferon regulatory factor 6 (IRF6). The disorder is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity. Very recently, mutations of the IRF6 gene in exons 2-9 have been found in VWS patients, suggesting that this gene plays an important role in orofacial development. We report a novel mutation of the IRF6 gene in a German family. Five out of the 12 persons affected were able to be investigated. The mutation produced a stop codon within exon 4 of the IRF6 gene. All 5 patients were heterozygous for a base substitution c.201C>A changing the tyrosine codon at amino acid position 67 into a stop codon (p.Y67X) in exon 4. The premature stop codon was responsible for a truncated protein lacking parts of the DNA- binding domain and the complete Smad-interferon regulatory factor-binding domain probably essential for interactions with the Smad transcription factors."
],
"offsets": [
[
86,
1317
]
]
}
] |
[
{
"id": "1477",
"type": "ProteinMutation",
"text": [
"Y67X"
],
"offsets": [
[
32,
36
]
],
"normalized": []
},
{
"id": "1478",
"type": "DNAMutation",
"text": [
"c.201C>A"
],
"offsets": [
[
972,
980
]
],
"normalized": []
},
{
"id": "1479",
"type": "ProteinMutation",
"text": [
"p.Y67X"
],
"offsets": [
[
1054,
1060
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1482
|
17392687
|
[
{
"id": "1483",
"type": "title",
"text": [
"Subfertility in mice harboring a mutation in betaB2-crystallin."
],
"offsets": [
[
0,
63
]
]
},
{
"id": "1484",
"type": "abstract",
"text": [
"PURPOSE: betaB2-crystallin is one of the most abundant proteins of the adult ocular lens of mammals although it is expressed at lower levels in several extralenticular locations. While mutations in betaB2-crystallin are known to result in lens opacities, alterations in tissues besides the lens have not been previously investigated in these mutants. Since we found mice harboring the Crybb2Phil mutation bred poorly, here we assess the contribution of betaB2-crystallin to mouse fertility and determine the expression pattern of betaB2-crystallin in the testis. METHODS: The expression pattern of betaB2-crystallin in the testis was analyzed by rt-PCR, western blotting, and immunohistochemistry. The fecundity of wildtype and Crybb2Phil mice was analyzed by quantitative fertility testing. The morphology of testes and ovaries was assessed by hematoxylin and eosin staining. RESULTS: In the mouse testis, betaB2-crystallin mRNA is found at low levels at birth, but its expression upregulates in this tissue as the testis is primed to initiate spermatogenesis. Western blotting detected betaB2-crystallin protein in sperm obtained from mice, cattle, and humans while immunolocalization detected this protein in developing sperm from the spermatocyte stage onward. Male and female mice homozygous for a 12 nucleotide inframe deletion mutation in betaB2-crystallin are subfertile when analyzed on a Swiss Webster derived background due to defects in egg and sperm production. However, mice harboring the same mutation on the C57Bl/6 genetic background did not exhibit any defects in reproductive function. CONCLUSIONS: betaB2-crystallin is expressed in developing and mature sperm and mice of both sexes harboring the Philly mutation in the betaB2-crystallin gene are subfertile when analyzed on a Swiss Webster genetic background. While these data are suggestive of a role for betaB2-crystallin in fertility, definitive determination of this will await the creation of a betaB2-crystallin null mouse."
],
"offsets": [
[
64,
2064
]
]
}
] |
[] |
[] |
[] |
[] |
1485
|
17356395
|
[
{
"id": "1486",
"type": "title",
"text": [
"Monitoring the isochromosome i(7)(q10) in the bone marrow of patients with Shwachman syndrome by real-time quantitative PCR."
],
"offsets": [
[
0,
124
]
]
},
{
"id": "1487",
"type": "abstract",
"text": [
"Clonal chromosome anomalies may be found in the bone marrow (BM) of patients with Shwachman syndrome, who are at risk to develop myelodysplastic syndromes and/or acute myeloid leukemias. In particular, an isochromosome i(7)(q10) is frequent, and is usually monitored by chromosome analyses. We tested an approach by real-time quantitative polymerase chain reaction (RQ-PCR) on a chromosome 7 polymorphism. Five DNA samples of 2 Shwachman syndrome patients with clonal i(7)(q10) in the BM were used. Both were heterozygous for the diallelic indel polymorphism MID1064, which maps in 7q35. The percentage of i(7)(q10)-positive cells was extrapolated from the ratio of the 2 alleles measured by means of an allele-specific RQ-PCR assay. The results were compared with cytogenetic analyses on the same material used for RQ-PCR. In 1 patient, the RQ-PCR results matched well with those of chromosome analyses, whereas in the other one RQ-PCR showed that around 40% of the BM cells were abnormal, while they resulted to be nearly 80% with conventional monitoring assays. As the results obtained by RQ-PCR refer to the DNA of around 128,000 BM cells, our method proved to be feasible and more efficient in the quantitative evaluation of the i(7)(q10)-positive clone than conventional ones."
],
"offsets": [
[
125,
1407
]
]
}
] |
[] |
[] |
[] |
[] |
1488
|
17353905
|
[
{
"id": "1489",
"type": "title",
"text": [
"DFF45/ICAD restores cisplatin-induced nuclear fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells."
],
"offsets": [
[
0,
120
]
]
},
{
"id": "1490",
"type": "abstract",
"text": [
"We have previously defined a homozygously deleted region at chromosome 1p36.2-p36.3 in human neuroblastoma cell lines, NB-1 and NB-C201, and identified six genes including DFF45/ICAD within this region. In this study, we found that NB-C201 cells are much more resistant to various genotoxic stresses such as cisplatin (CDDP) than CHP134 and SH-SY5Y cells that do not have the homozygous deletion. To examine a role(s) of DFF45 in the regulation of apoptosis in response to CDDP, we have established stably DFF45-expressing NB-C201 cell clones (DFF45-1 and DFF45-3) and a control cell clone (NB-C201-C) using a retrovirus-mediated gene transfer. In contrast to NB-C201-C cells, DFF45-3 cells displayed apoptotic nuclear fragmentation in response to CDDP. Although CDDP-induced proteolytic cleavage of procaspase-3 and DFF45 in DFF45-3 cells, we could not detect a typical apoptotic DNA fragmentation. Additionally, deletion analysis revealed that C-terminal region of DFF45 is required for inducing nuclear fragmentation. Unexpectedly, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that DFF45 has undetectable effect on CDDP sensitivity of NB-C201 cells. Taken together, our present results suggest that DFF45/DFF40 system may be sufficient for CDDP-induced nuclear fragmentation but not DNA cleavage."
],
"offsets": [
[
121,
1463
]
]
}
] |
[] |
[] |
[] |
[] |
1491
|
17327131
|
[
{
"id": "1495",
"type": "title",
"text": [
"Molecular analysis of the CYP2F1 gene: identification of a frequent non-functional allelic variant."
],
"offsets": [
[
0,
99
]
]
},
{
"id": "1496",
"type": "abstract",
"text": [
"The CYP2F1 is a human cytochrome P450 that is selectively expressed in lung tissue and involved in the metabolism of various pneumotoxicants with potential carcinogenic effects. In the present study, we report the first systematic investigation of the genetic polymorphism of this enzyme. We analyzed the nucleotidic sequence of the CYP2F1 gene in DNA samples from 90 French Caucasians consisting in 44 patients with lung cancer and 46 control individuals, using single-strand conformation polymorphism analysis of PCR products (PCR-SSCP). We identified 24 novel mutations distributed in the promoter region of the gene, as well as in the coding regions and their flanking intronic sequences. In addition to the wild-type CYP2F1*1 allele, seven allelic variant, CYP2F1*2A, *2B, *3, *4, *5A, *5B and *6, were characterized. The most frequent allelic variant, CYP2F1*2A (25.6%), harbors a combination of 9 mutations, including 2 missense mutations (Asp218Asn and Gln266His) and a 1-bp insertion (c.14_15insC) that creates a premature stop codon in exon 2, probably leading to the synthesis of a severely truncated protein with no catalytic activity. The identification of around 7% of homozygotes for the frameshift mutation in our Caucasian population suggests the existence of an interindividual variation of the CYP2F1 activity and, consequently, the possibility of interindividual differences in the toxic response to some pneumotoxicants and in the susceptibility to certain chemically induced diseases. However, our preliminary results did not show any evidence that the CYP2F1 genetic polymorphism has implications in the pathogenesis of lung cancer."
],
"offsets": [
[
100,
1755
]
]
}
] |
[
{
"id": "1492",
"type": "ProteinMutation",
"text": [
"Asp218Asn"
],
"offsets": [
[
1047,
1056
]
],
"normalized": []
},
{
"id": "1493",
"type": "ProteinMutation",
"text": [
"Gln266His"
],
"offsets": [
[
1061,
1070
]
],
"normalized": []
},
{
"id": "1494",
"type": "DNAMutation",
"text": [
"c.14_15insC"
],
"offsets": [
[
1094,
1105
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1497
|
17273972
|
[
{
"id": "1499",
"type": "title",
"text": [
"Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions."
],
"offsets": [
[
0,
106
]
]
},
{
"id": "1500",
"type": "abstract",
"text": [
"Deletion 22q11.2 syndrome is the most frequent known microdeletion syndrome and is associated with a highly variable phenotype, including DiGeorge and Shprintzen (velocardiofacial) syndromes. Although haploinsufficiency of the T-box transcription factor gene TBX1 is thought to cause the phenotype, to date, only four different point mutations in TBX1 have been reported in association with six of the major features of 22q11.2 deletion syndrome. Although, for the two truncating mutations, loss of function was previously shown, the pathomechanism of the missense mutations remains unknown. We report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions."
],
"offsets": [
[
107,
1135
]
]
}
] |
[
{
"id": "1498",
"type": "ProteinMutation",
"text": [
"H194Q"
],
"offsets": [
[
749,
754
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1501
|
17250667
|
[
{
"id": "1502",
"type": "title",
"text": [
"A possible bichromatid mutation in a male gamete giving rise to a female mosaic for two different mutations in the X-linked gene WAS."
],
"offsets": [
[
0,
133
]
]
},
{
"id": "1503",
"type": "abstract",
"text": [
"In genetic disorders caused by point mutations or small frameshift mutations, affected members of the same family are expected to have the same mutation in the causative gene. We have recently evaluated a family in which this was not the case. Maternal cousins with Wiskott-Aldrich syndrome (WAS; MIM 301000) had two different but contiguous single base pair deletions in WAS. The proband had an A deletion in codon 242 in exon 7 of WAS; his two cousins had a C deletion in codon 241. The mother of the proband was heterozygous for the A deletion allele, but her three sisters, including the mother of the affected cousins, were heterozygous for the C deletion. Both deletions occurred on the haplotype from the unaffected maternal great-grandfather. The maternal grandmother, who was a carrier of WAS, based on a non-random pattern of X chromosome inactivation in T cells, was mosaic for both deletions. These findings are most consistent with the mutations originating in a male gamete with different mutations on the two strands of DNA, a bichromatid mutation."
],
"offsets": [
[
134,
1197
]
]
}
] |
[] |
[] |
[] |
[] |
1504
|
17250663
|
[
{
"id": "1511",
"type": "title",
"text": [
"A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1."
],
"offsets": [
[
0,
150
]
]
},
{
"id": "1512",
"type": "abstract",
"text": [
"We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H (c.G1714C), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N (c.G1714A). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H, in comparison with that caused by p.D572N, may reflect a correlation of DFNA36 phenotype with TMC1 genotype."
],
"offsets": [
[
151,
1154
]
]
}
] |
[
{
"id": "1505",
"type": "ProteinMutation",
"text": [
"p.D572H"
],
"offsets": [
[
678,
685
]
],
"normalized": []
},
{
"id": "1506",
"type": "DNAMutation",
"text": [
"c.G1714C"
],
"offsets": [
[
687,
695
]
],
"normalized": []
},
{
"id": "1507",
"type": "ProteinMutation",
"text": [
"p.D572N"
],
"offsets": [
[
824,
831
]
],
"normalized": []
},
{
"id": "1508",
"type": "DNAMutation",
"text": [
"c.G1714A"
],
"offsets": [
[
833,
841
]
],
"normalized": []
},
{
"id": "1509",
"type": "ProteinMutation",
"text": [
"p.D572H"
],
"offsets": [
[
1037,
1044
]
],
"normalized": []
},
{
"id": "1510",
"type": "ProteinMutation",
"text": [
"p.D572N"
],
"offsets": [
[
1080,
1087
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1513
|
17192049
|
[
{
"id": "1516",
"type": "title",
"text": [
"Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer."
],
"offsets": [
[
0,
78
]
]
},
{
"id": "1517",
"type": "abstract",
"text": [
"CYP1A1 activates environmental procarcinogens and catalyzes oxidative metabolism of estrogens and is likely to play an important role in the etiology of prostate cancer. To evaluate this phenomenon, the association between two single nucleotide polymorphisms (A to G transition in exon7 leading to amino acid substitution Ile462Val and T3801C at 3'UTR) of CYP1A1 gene in prostate cancer were analyzed in a case-control study of 100 individuals in South Indian population. The estimated relative risk was significantly high for individuals with w1/m1 genotype at 3'UTR of CYP1A1 gene (OR-4.64; 95%CI = 1.51-14.86; P < 0.01) whereas the CYP1A1 Ile/Val genotype (w2/m2) on exon 7 was found to be associated with a decreased risk for prostate cancer (OR-0.17; 95%CI = 0.02-0.89; P=0.03). A Stratified analysis of the genotypes with age of onset and tumor grade showed the w1/m1 genotype to be significantly associated with an early age of onset; however the tumor grades did not have significant association with the variant genotypes. Thus the present study indicates that individuals with the variant w1/m1 genotype exhibit an increased risk while those with w2/m2 genotype exhibit a decreased risk for prostate cancer."
],
"offsets": [
[
79,
1296
]
]
}
] |
[
{
"id": "1514",
"type": "ProteinMutation",
"text": [
"Ile462Val"
],
"offsets": [
[
401,
410
]
],
"normalized": []
},
{
"id": "1515",
"type": "DNAMutation",
"text": [
"T3801C"
],
"offsets": [
[
415,
421
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1518
|
17175380
|
[
{
"id": "1519",
"type": "title",
"text": [
"Multipoint interphase FISH in childhood T-acute lymphoblastic leukemia detects subpopulations that carry different chromosome 3 aberrations."
],
"offsets": [
[
0,
140
]
]
},
{
"id": "1520",
"type": "abstract",
"text": [
"We examined chromosome 3 in 32 childhood acute lymphoblastic leukemia (ALL) bone marrow samples. Using interphase multipoint FISH (mp-FISH), which was developed by our group, with 42 chromosome 3-specific probes, we detected clonal chromosome 3 aberrations in 4 T-cell ALL (T-ALL) cases. Four out of seven T-ALL cases carried 3q trisomies. One T-ALL case carried either trisomy 3 (in 15% of the cells) or a 23-megabase (Mb) 3p13 approximately p12 deletion in a different subpopulation of cells of 32%. Another T-ALL case had either 3q trisomy in 11% or a 12-Mb 3p12 approximately p13 deletion in 19% of the cells. The deletions were overlapping. In both cases, the majority of the bone marrow cells (47 and 70%, respectively) were normal chromosome 3 disomics. The interstitial deletions detected harbor a known homozygous deletion region between 72.6 and 78.8 Mb, which has been described in lung and breast tumors and contains the DUTT1/ROBO1 tumor suppressor gene. These deletions detected by mp-FISH would have remained unnoticed by conventional cytogenetics and multiplex FISH, as well as by current methods based on total tumor DNA analysis such as comparative genomic hybridization (CGH), array CGH, and loss of heterozygosity (LOH)."
],
"offsets": [
[
141,
1381
]
]
}
] |
[] |
[] |
[] |
[] |
1521
|
17169596
|
[
{
"id": "1525",
"type": "title",
"text": [
"Single-base substitution at the last nucleotide of exon 6 (c.671G>A), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene."
],
"offsets": [
[
0,
186
]
]
},
{
"id": "1526",
"type": "abstract",
"text": [
"Succinyl-CoA:3-ketoacid CoA transferase (SCOT, EC 2.8.3.5) is the key enzyme for ketone body utilization. Hereditary SCOT deficiency (MIM 245050) causes episodes of severe ketoacidosis. We identified a homozygous point mutation (c.671G>A) , which is a single-base substitution at the last nucleotide of exon 6, in a Turkish patient (GS12) with SCOT deficiency. This point mutation resulted in the skipping of exon 6, and exons 6 and 7 in human SCOT genes. To understand why the c.671G>A causes exons 6 and 7 skipping, nuclear RNA was separated from cytoplasmic RNA and both were analyzed by RT-PCR. In nuclear RNA, SCOT mRNA with exon 6 skipping was predominant and mRNA with exons 6 and 7 skipping was hardly detected, whereas the latter became one of major mRNA species in cytoplasmic RNA. This discrepancy was interpreted as follows: exon 6 skipping causes a frameshift and nonsense-mediated RNA decay in the cytosol, so mRNA with exon 6 skipping was unstable. On the other hand, SCOT mRNA with exons 6 and 7 is a minor transcript but it retains the reading-frame and is stable in cytosol. As a result, the latter mRNA is more abundant under steady-state conditions as compared to the former mRNA."
],
"offsets": [
[
187,
1387
]
]
}
] |
[
{
"id": "1522",
"type": "DNAMutation",
"text": [
"c.671G>A"
],
"offsets": [
[
59,
67
]
],
"normalized": []
},
{
"id": "1523",
"type": "DNAMutation",
"text": [
"c.671G>A"
],
"offsets": [
[
416,
424
]
],
"normalized": []
},
{
"id": "1524",
"type": "DNAMutation",
"text": [
"c.671G>A"
],
"offsets": [
[
665,
673
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1527
|
17083016
|
[
{
"id": "1528",
"type": "title",
"text": [
"Genetic polymorphism of the binding domain of surfactant protein-A2 increases susceptibility to meningococcal disease."
],
"offsets": [
[
0,
118
]
]
},
{
"id": "1529",
"type": "abstract",
"text": [
"BACKGROUND: Meningococcal disease occurs after colonization of the nasopharynx with Neisseria meningitidis. Surfactant protein (SP)-A and SP-D are pattern-recognition molecules of the respiratory tract that activate inflammatory and phagocytic defences after binding to microbial sugars. Variation in the genes of the surfactant proteins affects the expression and function of these molecules. METHODS: Allele frequencies of SP-A1, SP-A2, and SP-D were determined by polymerase chain reaction in 303 patients with microbiologically proven meningococcal disease, including 18 patients who died, and 222 healthy control subjects. RESULTS: Homozygosity of allele 1A1 of SP-A2 increased the risk of meningococcal disease (odds ratio [OR], 7.4; 95% confidence interval [CI], 1.3-42.4); carriage of 1A5 reduced the risk (OR, 0.3; 95% CI, 0.1-0.97). An analysis of the multiple single-nucleotide polymorphisms in SP-A demonstrated that homozygosity for alleles encoding lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223 in the carbohydrate recognition domain was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4-31.5). Carriage of alleles encoding lysine at residue 223 was found in 61% of patients who died, compared with 35% of those who survived (OR adjusted for age, 2.9; 95% CI, 1.1-7.7). Genetic variation of SP-A1 and SP-D was not associated with meningococcal disease. CONCLUSIONS: Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death."
],
"offsets": [
[
119,
1765
]
]
}
] |
[] |
[] |
[] |
[] |
1530
|
17050029
|
[
{
"id": "1531",
"type": "title",
"text": [
"Nucleotide change of codon 38 in the X gene of hepatitis B virus genotype C is associated with an increased risk of hepatocellular carcinoma."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "1532",
"type": "abstract",
"text": [
"BACKGROUND/AIMS: The hepatitis B virus (HBV) genotype C is associated with the development of hepatocellular carcinoma (HCC). In addition, the HBV X gene, which encodes the pleiotropic transactivator HBx, has also been associated with the development of HCC. In this study, we investigated whether nucleotide changes in the X gene of genotype C are associated with the development of HCC. METHODS/RESULTS: We sequenced the X gene in age- and sex-matched 39 HBV-infected patients with HCC and 36 HBV-infected patients without HCC. A novel nucleotide change that resulted in a proline to serine substitution at codon 38 in HBx (codon-38 change) was preferentially found in patients with HCC. Then, sera were collected from a new group of age- and sex-matched 52 patients with HCC and 51 patients without HCC. In this cohort also, the codon-38 change was associated with HCC. Multiple logistic regression analysis showed the prevalence of the codon-38 change was significantly associated with HCC in all patients (P=0.001, odds ratio: 4.89). CONCLUSION: The codon-38 change in genotype C is an independent risk factor for the development of HCC and may serve as a useful molecular marker for predicting the clinical outcomes in patients infected with HBV."
],
"offsets": [
[
142,
1394
]
]
}
] |
[] |
[] |
[] |
[] |
1533
|
17000021
|
[
{
"id": "1542",
"type": "title",
"text": [
"No independent role of the -1123 G>C and+2740 A>G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations."
],
"offsets": [
[
0,
172
]
]
},
{
"id": "1543",
"type": "abstract",
"text": [
"INTRODUCTION: The PTPN22 is a negative regulator of the T cell response. Its +1858C>T (R620W) polymorphism has been shown to associate with a risk for multiple autoimmune diseases, including type 1 diabetes (T1D) and juvenile idiopathic arthritis (JIA). The minor (susceptibility) allele is absent in Asian populations, but a recent study suggested an independent involvement of another polymorphism located within the promoter -1123 nucleotides relative to the translational start site. AIMS: We aimed to analyse the association of three PTPN22 polymorphisms in two distinct Caucasian populations, the Czechs (with T1D and with JIA) and Azeri (with T1D). METHODS: The single nucleotide polymorphisms (SNP) at positions -1123 (rs2488457), +1858 (rs2476601, the R620W substitution), and +2740 (rs1217412) were genotyped using TaqMan assays in 372 subjects with childhood-onset T1D, 130 subjects with JIA, and 400 control subjects of Czech origin, and in 160 subjects with T1D and 271 healthy controls of Azeri origin. RESULTS: In the Czechs, all three SNPs were in a tight linkage disequlibrium, while in the Azeri, the linkage disequlibrium was limited to between the promoter and 3'-UTR polymorphism, D'(-1123, +2740)=0.99, r(2)=0.72. Haplotype reconstruction via the expectation-maximization algorithm showed in both populations that only the haplotype containing the minor (W) allele at codon 620 was associated with T1D (OR=2.26, 95% CI 1.68-3.02 in Czechs, OR=14.8, 95% CI 2.0-651 in Azeri) or JIA (OR=2.43, 95% CI 1.66-3.56 in Czechs). The haplotypes having the wild-type (R) allele at codon 620 and minor alleles at -1123 and/or +2740 were neutral as to the risk of autoimmune conditions in both populations. CONCLUSIONS: In two different Caucasian populations, the Czechs and the Azeri, no independent contribution can be detected either of the -1123 promoter SNP or the +2740 3'-UTR SNP, and only the minor allele at PTPN22 codon 620 contributes to the risk of autoimmunity."
],
"offsets": [
[
173,
2156
]
]
}
] |
[
{
"id": "1534",
"type": "DNAMutation",
"text": [
"-1123 G>C"
],
"offsets": [
[
27,
36
]
],
"normalized": []
},
{
"id": "1535",
"type": "DNAMutation",
"text": [
"+2740 A>G"
],
"offsets": [
[
40,
49
]
],
"normalized": []
},
{
"id": "1536",
"type": "DNAMutation",
"text": [
"+1858C>T"
],
"offsets": [
[
250,
258
]
],
"normalized": []
},
{
"id": "1537",
"type": "ProteinMutation",
"text": [
"R620W"
],
"offsets": [
[
260,
265
]
],
"normalized": []
},
{
"id": "1538",
"type": "SNP",
"text": [
"rs2488457"
],
"offsets": [
[
900,
909
]
],
"normalized": []
},
{
"id": "1539",
"type": "SNP",
"text": [
"rs2476601"
],
"offsets": [
[
919,
928
]
],
"normalized": []
},
{
"id": "1540",
"type": "ProteinMutation",
"text": [
"R620W"
],
"offsets": [
[
934,
939
]
],
"normalized": []
},
{
"id": "1541",
"type": "SNP",
"text": [
"rs1217412"
],
"offsets": [
[
966,
975
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1544
|
16970763
|
[
{
"id": "1547",
"type": "title",
"text": [
"Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity."
],
"offsets": [
[
0,
127
]
]
},
{
"id": "1548",
"type": "abstract",
"text": [
"BACKGROUND: To examine the contribution of mutations within the Norrie disease (NDP) gene to the clinically similar retinal diseases Norrie disease, X-linked familial exudative vitreoretinopathy (FEVR), Coat's disease and retinopathy of prematurity (ROP). METHODS: A dataset comprising 13 Norrie-FEVR, one Coat's disease, 31 ROP patients and 90 ex-premature babies of <32 weeks' gestation underwent an ophthalmologic examination and were screened for mutations within the NDP gene by direct DNA sequencing, denaturing high-performance liquid chromatography or gel electrophoresis. Controls were only screened using denaturing high-performance liquid chromatography and gel electrophoresis. Confirmation of mutations identified was obtained by DNA sequencing. RESULTS: Evidence for two novel mutations in the NDP gene was presented: Leu103Val in one FEVR patient and His43Arg in monozygotic twin Norrie disease patients. Furthermore, a previously described 14-bp deletion located in the 5' unstranslated region of the NDP gene was detected in three cases of regressed ROP. A second heterozygotic 14-bp deletion was detected in an unaffected ex-premature girl. Only two of the 13 Norrie-FEVR index cases had the full features of Norrie disease with deafness and mental retardation. CONCLUSION: Two novel mutations within the coding region of the NDP gene were found, one associated with a severe disease phenotypes of Norrie disease and the other with FEVR. A deletion within the non-coding region was associated with only mild-regressed ROP, despite the presence of low birthweight, prematurity and exposure to oxygen. In full-term children with retinal detachment only 15% appear to have the full features of Norrie disease and this is important for counselling parents on the possible long-term outcome."
],
"offsets": [
[
128,
1932
]
]
}
] |
[
{
"id": "1545",
"type": "ProteinMutation",
"text": [
"Leu103Val"
],
"offsets": [
[
960,
969
]
],
"normalized": []
},
{
"id": "1546",
"type": "ProteinMutation",
"text": [
"His43Arg"
],
"offsets": [
[
994,
1002
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1549
|
16849419
|
[
{
"id": "1550",
"type": "title",
"text": [
"Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria."
],
"offsets": [
[
0,
101
]
]
},
{
"id": "1551",
"type": "abstract",
"text": [
"CONTEXT: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia and rickets/osteomalacia with increased serum 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] resulting in hypercalciuria. OBJECTIVE: Our objective was to determine whether mutations in the SLC34A3 gene, which encodes sodium-phosphate cotransporter type IIc, are responsible for the occurrence of HHRH. DESIGN AND SETTING: Mutation analysis of exons and adjacent introns in the SLC34A3 gene was conducted at an academic research laboratory and medical center. PATIENTS OR OTHER PARTICIPANTS: Members of two unrelated families with HHRH participated in the study. RESULTS: Two affected siblings in one family were homozygous for a 101-bp deletion in intron 9. Haplotype analysis of the SLC34A3 locus in the family showed that the two deletions are on different haplotypes. An unrelated individual with HHRH was a compound heterozygote for an 85-bp deletion in intron 10 and a G-to-A substitution at the last nucleotide in exon 7. The intron 9 deletion (and likely the other two mutations) identified in this study causes aberrant RNA splicing. Sequence analysis of the deleted regions revealed the presence of direct repeats of homologous sequences. CONCLUSION: HHRH is caused by biallelic mutations in the SLC34A3 gene. Haplotype analysis suggests that the two intron 9 deletions arose independently. The identification of three independent deletions in introns 9 and 10 suggests that the SLC34A3 gene may be susceptible to unequal crossing over because of sequence misalignment during meiosis."
],
"offsets": [
[
102,
1724
]
]
}
] |
[] |
[] |
[] |
[] |
1552
|
16843501
|
[
{
"id": "1561",
"type": "title",
"text": [
"DNA damage and repair in gastric cancer--a correlation with the hOGG1 and RAD51 genes polymorphisms."
],
"offsets": [
[
0,
100
]
]
},
{
"id": "1562",
"type": "abstract",
"text": [
"The cell's susceptibility to mutagens and its ability to repair DNA lesions are important for cancer induction, promotion and progression. Both the mutagens' sensitivity and the efficacy of DNA repair may be affected by variation in several genes, including DNA repair genes. The hOGG1 gene encodes glycosylase of base excision repair and RAD51 specifies a key protein in homologues recombination repair. Both can be involved in the repair of oxidative DNA lesions, which can contribute to stomach cancer. In the present work we determined the level of basal and oxidative DNA damage and the kinetics of removal of DNA damage induced by hydrogen peroxide in peripheral blood lymphocytes of 30 gastric cancer patients and 30 healthy individuals. The metrics from DNA damage and repair study were correlated with the genotypes of common polymorphisms of the hOGG1 and RAD51 genes: a G-->C transversion at 1245 position of the hOGG1 gene producing a Ser-->Cys substitution at the codon 326 (the Ser326Cys polymorphism) and a G-->C substitution at position 135 (5'-untranslated region) of the RAD51 gene (the G135C polymorphism). DNA damage and repair were evaluated by alkaline single cell gel electrophoresis (comet assay) assisted by DNA repair enzymes: endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg), preferentially recognizing oxidized DNA bases. The genotypes of the polymorphism were determined by restriction fragment length polymorphism PCR. We observed a strong association between gastric cancer occurrence, impaired DNA repair in human lymphocytes and the G/C genotype of the G135C polymorphism of the RAD51 gene. Moreover, there was a strong correlation between that genotype and stomach cancer occurrence in subjects with high level of oxidatively damaged DNA. We did not observe any correlation between the Ser1245Cys polymorphism of the hOGG1 gene and gastric cancer, including subjects with impaired DNA repair and/or high levels of endogenous oxidative DNA lesions. Therefore, our result suggest that the G135C polymorphism of the RAD51 gene may be linked with gastric cancer by the modulation of the cellular response to oxidative stress and this polymorphism may be a useful additional marker in this disease along with the genetic or/and environmental indicators of oxidative stress."
],
"offsets": [
[
101,
2423
]
]
}
] |
[
{
"id": "1553",
"type": "DNAMutation",
"text": [
"G-->C transversion at 1245 position"
],
"offsets": [
[
982,
1017
]
],
"normalized": []
},
{
"id": "1554",
"type": "ProteinMutation",
"text": [
"Ser-->Cys substitution at the codon 326"
],
"offsets": [
[
1048,
1087
]
],
"normalized": []
},
{
"id": "1555",
"type": "ProteinMutation",
"text": [
"Ser326Cys"
],
"offsets": [
[
1093,
1102
]
],
"normalized": []
},
{
"id": "1556",
"type": "DNAMutation",
"text": [
"G-->C substitution at position 135"
],
"offsets": [
[
1123,
1157
]
],
"normalized": []
},
{
"id": "1557",
"type": "DNAMutation",
"text": [
"G135C"
],
"offsets": [
[
1206,
1211
]
],
"normalized": []
},
{
"id": "1558",
"type": "DNAMutation",
"text": [
"G135C"
],
"offsets": [
[
1707,
1712
]
],
"normalized": []
},
{
"id": "1559",
"type": "ProteinMutation",
"text": [
"Ser1245Cys"
],
"offsets": [
[
1941,
1951
]
],
"normalized": []
},
{
"id": "1560",
"type": "DNAMutation",
"text": [
"G135C"
],
"offsets": [
[
2142,
2147
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1563
|
16822828
|
[
{
"id": "1574",
"type": "title",
"text": [
"Genotyping of five chinese patients with 17alpha-hydroxylase deficiency diagnosed through high-performance liquid chromatography serum adrenal profile: identification of two novel CYP17 mutations."
],
"offsets": [
[
0,
196
]
]
},
{
"id": "1575",
"type": "abstract",
"text": [
"CONTEXT: 17alpha-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia caused by CYP17 gene mutations. OBJECTIVE: Five Chinese patients with 17alpha-hydroxylase deficiency were genotyped. PATIENTS: The five patients derived from four families living in Shandong Province, China. The diagnosis of 17alpha-hydroxylase deficiency was initially established through HPLC serum adrenal profiles in Qilu Hospital, China, from 1983-1993. RESULTS: Three CYP17 gene mutations were identified from these patients. Among them, V311fs and Y329fs are two novel frame-shifting mutations. V311fs is an 8-bp nucleotide (TTAAATGG) deletion in exon 5. Y329fs is a deletion-insertion combined mutation (TAC-->AA) at codon 329 in exon 6. Two homozygotes for Y329fs and one compound heterozygote for Y329fs and V311fs were identified from three different families. Two homozygous sisters for the D487_S488_F489 deletion were identified. CONCLUSION: The results confirmed the diagnostic value of the HPLC serum adrenal profile for 17alpha-hydroxylase deficiency. The D487_S488_F489 deletion had been identified in two previously genotyped Chinese families. In our present study, a third Chinese family with this mutation was identified, suggesting that this mutation is a prevalent CYP17 mutation in the Chinese population. The identification of Y329fs mutation in addition to three previously identified mutations at codon 329 suggests that codon 329 is an unstable point of the CYP17 gene. The mutations identified from our five patients appear to be random, but the recurrence of the Y329fs mutation may be attributed to a founder effect. Our studies suggest that 17alpha-hydroxylase deficiency may not be rare in the Chinese population."
],
"offsets": [
[
197,
1932
]
]
}
] |
[
{
"id": "1564",
"type": "ProteinMutation",
"text": [
"V311fs"
],
"offsets": [
[
730,
736
]
],
"normalized": []
},
{
"id": "1565",
"type": "ProteinMutation",
"text": [
"Y329fs"
],
"offsets": [
[
741,
747
]
],
"normalized": []
},
{
"id": "1566",
"type": "ProteinMutation",
"text": [
"V311fs"
],
"offsets": [
[
788,
794
]
],
"normalized": []
},
{
"id": "1567",
"type": "ProteinMutation",
"text": [
"Y329fs"
],
"offsets": [
[
848,
854
]
],
"normalized": []
},
{
"id": "1568",
"type": "DNAMutation",
"text": [
"(TAC-->AA) at codon 329"
],
"offsets": [
[
897,
920
]
],
"normalized": []
},
{
"id": "1569",
"type": "ProteinMutation",
"text": [
"Y329fs"
],
"offsets": [
[
952,
958
]
],
"normalized": []
},
{
"id": "1570",
"type": "ProteinMutation",
"text": [
"Y329fs"
],
"offsets": [
[
993,
999
]
],
"normalized": []
},
{
"id": "1571",
"type": "ProteinMutation",
"text": [
"V311fs"
],
"offsets": [
[
1004,
1010
]
],
"normalized": []
},
{
"id": "1572",
"type": "ProteinMutation",
"text": [
"Y329fs"
],
"offsets": [
[
1538,
1544
]
],
"normalized": []
},
{
"id": "1573",
"type": "ProteinMutation",
"text": [
"Y329fs"
],
"offsets": [
[
1779,
1785
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1576
|
16628674
|
[
{
"id": "1578",
"type": "title",
"text": [
"A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus."
],
"offsets": [
[
0,
131
]
]
},
{
"id": "1579",
"type": "abstract",
"text": [
"A single nucleotide polymorphism characterized by the substitution of valine for glutamate (V1188E) in exon 25 of the multidrug resistance protein 2 gene was found in a group of patients with primary biliary cirrhosis. This heterozygous mutation was significantly associated with the presence of pruritus."
],
"offsets": [
[
132,
437
]
]
}
] |
[
{
"id": "1577",
"type": "ProteinMutation",
"text": [
"V1188E"
],
"offsets": [
[
224,
230
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1580
|
16601880
|
[
{
"id": "1627",
"type": "title",
"text": [
"Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy."
],
"offsets": [
[
0,
92
]
]
},
{
"id": "1628",
"type": "abstract",
"text": [
"Glycine encephalopathy, or nonketotic hyperglycinaemia (NKH; Mckusick 238300) is a severe autosomal recessive disease due to a defect in the glycine cleavage system (GCS), which is a complex of four subunits: P-, T-, H- and L-proteins. A P-protein (glycine decarboxylase or GLDC) deficiency was reported in about 80% of NKH patients. We performed mutation analysis of the complete coding sequence of the GLDC gene in 28 unrelated patients with neonatal NKH using denaturing high-performance liquid chromatography (DHPLC) and sequencing. Forty different gene alterations were identified, confirming the large molecular heterogeneity of the GLDC gene. Eighteen alterations were clearly disease-causing: two large deletions, four one-base deletions (c.28delC, c.1175delC, c.2186delC, c.2422delA), one 1-base insertion (c.1002_1003insT), one 4-base insertion (c.1285_1286insCAAA), one insertion/deletion (c.2153_2155delinsTCCTGGTTTA), five nonsense mutations (p.E153X, p.R236X, p.E270X, p.R337X, p.R424X) and four splice site mutations (c.861+1G > T, c.1402-1C > G, c.2316-1G > A, c.2919+1G > A). Additionally, we identified one intronic mutation outside the consensus splice sites (c.2838+5G > A) and 21 nucleotide substitutions leading to amino acid change (including three previously described mutations: p.T269M, p.R461Q, p.G771R), the pathogenicity of which should be confirmed by expression studies (p.S132W, p.Y138F, p.G171A, p.T187K, p.R212K, p.T269M, p.R373W, p.I440N, p.R461Q, p.N533Y, p.C644F, p.H651R, p.V705M, p.N732K, p.G771R, p.H775R, p.T830M, p.A841P, p.D880V, p.S957P and p.R966G). Mutation analysis allowed us to identify sequence alterations in both alleles for 19 patients and in one allele for 7 patients One patient was carrying three mutations (p.Y138F, p.T269M and p.E153X) and one patient was carrying two amino acid substitutions on the same allele (p.V705M and p.R212K) and an unidentified mutation on the other allele. No mutation could be found in two patients, suggesting possible defects in the H-protein or gene alterations that could not be identified by our technique. The potential use of genotype determination for prenatal diagnosis is emphasized."
],
"offsets": [
[
93,
2273
]
]
}
] |
[
{
"id": "1581",
"type": "DNAMutation",
"text": [
"c.28delC"
],
"offsets": [
[
840,
848
]
],
"normalized": []
},
{
"id": "1582",
"type": "DNAMutation",
"text": [
"c.1175delC"
],
"offsets": [
[
850,
860
]
],
"normalized": []
},
{
"id": "1583",
"type": "DNAMutation",
"text": [
"c.2186delC"
],
"offsets": [
[
862,
872
]
],
"normalized": []
},
{
"id": "1584",
"type": "DNAMutation",
"text": [
"c.2422delA"
],
"offsets": [
[
874,
884
]
],
"normalized": []
},
{
"id": "1585",
"type": "DNAMutation",
"text": [
"c.1002_1003insT"
],
"offsets": [
[
909,
924
]
],
"normalized": []
},
{
"id": "1586",
"type": "DNAMutation",
"text": [
"c.1285_1286insCAAA"
],
"offsets": [
[
949,
967
]
],
"normalized": []
},
{
"id": "1587",
"type": "DNAMutation",
"text": [
"c.2153_2155delinsTCCTGGTTTA"
],
"offsets": [
[
994,
1021
]
],
"normalized": []
},
{
"id": "1588",
"type": "ProteinMutation",
"text": [
"p.E153X"
],
"offsets": [
[
1049,
1056
]
],
"normalized": []
},
{
"id": "1589",
"type": "ProteinMutation",
"text": [
"p.R236X"
],
"offsets": [
[
1058,
1065
]
],
"normalized": []
},
{
"id": "1590",
"type": "ProteinMutation",
"text": [
"p.E270X"
],
"offsets": [
[
1067,
1074
]
],
"normalized": []
},
{
"id": "1591",
"type": "ProteinMutation",
"text": [
"p.R337X"
],
"offsets": [
[
1076,
1083
]
],
"normalized": []
},
{
"id": "1592",
"type": "ProteinMutation",
"text": [
"p.R424X"
],
"offsets": [
[
1085,
1092
]
],
"normalized": []
},
{
"id": "1593",
"type": "DNAMutation",
"text": [
"c.861+1G > T"
],
"offsets": [
[
1126,
1138
]
],
"normalized": []
},
{
"id": "1594",
"type": "DNAMutation",
"text": [
"c.1402-1C > G"
],
"offsets": [
[
1140,
1153
]
],
"normalized": []
},
{
"id": "1595",
"type": "DNAMutation",
"text": [
"c.2316-1G > A"
],
"offsets": [
[
1155,
1168
]
],
"normalized": []
},
{
"id": "1596",
"type": "DNAMutation",
"text": [
"c.2919+1G > A"
],
"offsets": [
[
1170,
1183
]
],
"normalized": []
},
{
"id": "1597",
"type": "DNAMutation",
"text": [
"c.2838+5G > A"
],
"offsets": [
[
1272,
1285
]
],
"normalized": []
},
{
"id": "1598",
"type": "ProteinMutation",
"text": [
"p.T269M"
],
"offsets": [
[
1397,
1404
]
],
"normalized": []
},
{
"id": "1599",
"type": "ProteinMutation",
"text": [
"p.R461Q"
],
"offsets": [
[
1406,
1413
]
],
"normalized": []
},
{
"id": "1600",
"type": "ProteinMutation",
"text": [
"p.G771R"
],
"offsets": [
[
1415,
1422
]
],
"normalized": []
},
{
"id": "1601",
"type": "ProteinMutation",
"text": [
"p.S132W"
],
"offsets": [
[
1495,
1502
]
],
"normalized": []
},
{
"id": "1602",
"type": "ProteinMutation",
"text": [
"p.Y138F"
],
"offsets": [
[
1504,
1511
]
],
"normalized": []
},
{
"id": "1603",
"type": "ProteinMutation",
"text": [
"p.G171A"
],
"offsets": [
[
1513,
1520
]
],
"normalized": []
},
{
"id": "1604",
"type": "ProteinMutation",
"text": [
"p.T187K"
],
"offsets": [
[
1522,
1529
]
],
"normalized": []
},
{
"id": "1605",
"type": "ProteinMutation",
"text": [
"p.R212K"
],
"offsets": [
[
1531,
1538
]
],
"normalized": []
},
{
"id": "1606",
"type": "ProteinMutation",
"text": [
"p.T269M"
],
"offsets": [
[
1540,
1547
]
],
"normalized": []
},
{
"id": "1607",
"type": "ProteinMutation",
"text": [
"p.R373W"
],
"offsets": [
[
1549,
1556
]
],
"normalized": []
},
{
"id": "1608",
"type": "ProteinMutation",
"text": [
"p.I440N"
],
"offsets": [
[
1558,
1565
]
],
"normalized": []
},
{
"id": "1609",
"type": "ProteinMutation",
"text": [
"p.R461Q"
],
"offsets": [
[
1567,
1574
]
],
"normalized": []
},
{
"id": "1610",
"type": "ProteinMutation",
"text": [
"p.N533Y"
],
"offsets": [
[
1576,
1583
]
],
"normalized": []
},
{
"id": "1611",
"type": "ProteinMutation",
"text": [
"p.C644F"
],
"offsets": [
[
1585,
1592
]
],
"normalized": []
},
{
"id": "1612",
"type": "ProteinMutation",
"text": [
"p.H651R"
],
"offsets": [
[
1594,
1601
]
],
"normalized": []
},
{
"id": "1613",
"type": "ProteinMutation",
"text": [
"p.V705M"
],
"offsets": [
[
1603,
1610
]
],
"normalized": []
},
{
"id": "1614",
"type": "ProteinMutation",
"text": [
"p.N732K"
],
"offsets": [
[
1612,
1619
]
],
"normalized": []
},
{
"id": "1615",
"type": "ProteinMutation",
"text": [
"p.G771R"
],
"offsets": [
[
1621,
1628
]
],
"normalized": []
},
{
"id": "1616",
"type": "ProteinMutation",
"text": [
"p.H775R"
],
"offsets": [
[
1630,
1637
]
],
"normalized": []
},
{
"id": "1617",
"type": "ProteinMutation",
"text": [
"p.T830M"
],
"offsets": [
[
1639,
1646
]
],
"normalized": []
},
{
"id": "1618",
"type": "ProteinMutation",
"text": [
"p.A841P"
],
"offsets": [
[
1648,
1655
]
],
"normalized": []
},
{
"id": "1619",
"type": "ProteinMutation",
"text": [
"p.D880V"
],
"offsets": [
[
1657,
1664
]
],
"normalized": []
},
{
"id": "1620",
"type": "ProteinMutation",
"text": [
"p.S957P"
],
"offsets": [
[
1666,
1673
]
],
"normalized": []
},
{
"id": "1621",
"type": "ProteinMutation",
"text": [
"p.R966G"
],
"offsets": [
[
1678,
1685
]
],
"normalized": []
},
{
"id": "1622",
"type": "ProteinMutation",
"text": [
"p.Y138F"
],
"offsets": [
[
1857,
1864
]
],
"normalized": []
},
{
"id": "1623",
"type": "ProteinMutation",
"text": [
"p.T269M"
],
"offsets": [
[
1866,
1873
]
],
"normalized": []
},
{
"id": "1624",
"type": "ProteinMutation",
"text": [
"p.E153X"
],
"offsets": [
[
1878,
1885
]
],
"normalized": []
},
{
"id": "1625",
"type": "ProteinMutation",
"text": [
"p.V705M"
],
"offsets": [
[
1965,
1972
]
],
"normalized": []
},
{
"id": "1626",
"type": "ProteinMutation",
"text": [
"p.R212K"
],
"offsets": [
[
1977,
1984
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1629
|
16418600
|
[
{
"id": "1632",
"type": "title",
"text": [
"Genetic investigation of the TSPYL1 gene in sudden infant death syndrome."
],
"offsets": [
[
0,
73
]
]
},
{
"id": "1633",
"type": "abstract",
"text": [
"BACKGROUND: Sudden infant death syndrome (SIDS) constitutes the most frequent cause of death in the postperinatal period in Germany. Recently, a lethal phenotype characterized by sudden infant death with dysgenesis of the testes syndrome (SIDDT) was identified to be caused by loss of function mutations in the TSPYL1 gene. PURPOSE: The study's purpose was to reveal a possible role of TSPYL1 in SIDS. METHODS: DNA samples of 126 SIDS cases and 261 controls were investigated. RESULTS: We found five sequence variations, each of them causing an amino acid substitution. No Hardy Weinberg disequilibrium and no significant difference in allele frequencies between patients and controls were observed for any variation. In one female patient a p.F366L amino acid polymorphism was found heterozygous, which could not be displayed in controls. A pathogenic implication of this substitution, which is conserved in primates and rodents, cannot be ruled out completely. Because SIDDT is the result of homozygous TSPYL1 mutations, this heterozygous exchange cannot solely explain the sudden death in this child. The reported mutation associated with SIDDT (457_458insG) was not detectable in our cohort. CONCLUSION: No association of sequence variations in the TSPYL1 gene and SIDS has been found in a German cohort. Genetic analysis of TSPYL1 seems to be of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes."
],
"offsets": [
[
74,
1517
]
]
}
] |
[
{
"id": "1630",
"type": "ProteinMutation",
"text": [
"p.F366L"
],
"offsets": [
[
816,
823
]
],
"normalized": []
},
{
"id": "1631",
"type": "DNAMutation",
"text": [
"457_458insG"
],
"offsets": [
[
1223,
1234
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1634
|
16379540
|
[
{
"id": "1639",
"type": "title",
"text": [
"Indirect CFTR mutation identification by PCR/OLA anomalous electropherograms."
],
"offsets": [
[
0,
77
]
]
},
{
"id": "1640",
"type": "abstract",
"text": [
"Mutations of CFTR gene are responsible for cystic fibrosis (CF) and other clinical conditions such as congenital absence of the vas deferens (CAVD), chronic pancreatitis (IP), and idiopathic disseminated bronchiectasis (DBE) classified as CFTR-related disorders. The PCR/OLA assay is designed to detect 31 known mutations including the 24 most common CF mutations worldwide, as identified by the CF Consortium. In order to define the CFTR genotype a series of 1812 individuals from central-southern Italy with and without CF manifestations were screened by using the PCR/OLA assay. Here we report the description of five cases of anomalous electropherograms obtained after PCR/OLA analysis, that led to the identification, in the homozygous state, of two point mutations (D110H and S589N) not included in the assay test panel, a large gene deletion (CFTRdel14b_17b), and an exonic polymorphism (c.4002A > G). Haplotype and real time PCR analysis were also performed in the subject carrying the large CFTR deletion. The study demonstrates that the PCR/OLA assay, besides being an efficient and user-friendly method to screen known mutations in the CFTR gene, may also function as a mutation/polymorphism-scanning assay, at least for certain nucleotide changes located in some critical regions of the gene."
],
"offsets": [
[
78,
1382
]
]
}
] |
[
{
"id": "1635",
"type": "ProteinMutation",
"text": [
"D110H"
],
"offsets": [
[
850,
855
]
],
"normalized": []
},
{
"id": "1636",
"type": "ProteinMutation",
"text": [
"S589N"
],
"offsets": [
[
860,
865
]
],
"normalized": []
},
{
"id": "1637",
"type": "DNAMutation",
"text": [
"del14b_17b"
],
"offsets": [
[
932,
942
]
],
"normalized": []
},
{
"id": "1638",
"type": "DNAMutation",
"text": [
"c.4002A > G"
],
"offsets": [
[
973,
984
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1641
|
16321363
|
[
{
"id": "1643",
"type": "title",
"text": [
"Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation."
],
"offsets": [
[
0,
89
]
]
},
{
"id": "1644",
"type": "abstract",
"text": [
"We describe a new cause of congenital disorder of glycosylation-Ic (CDG-Ic) in a young girl with a rather mild CDG phenotype. Her cells accumulated lipid-linked oligosaccharides lacking three glucose residues, and sequencing of the ALG6 gene showed what initially appeared to be a homozygous novel point mutation (338G>A). However, haplotype analysis showed that the patient does not carry any paternal DNA markers extending 33kb in the telomeric direction from the ALG6 region, and microsatellite analysis extended the abnormal region to at least 2.5Mb. We used high-resolution karyotyping to confirm a deletion (10-12Mb) [del(1)(p31.2p32.3)] and found no structural abnormalities in the father, suggesting a de novo event. Our findings extend the causes of CDG to larger DNA deletions and identify the first Japanese CDG-Ic mutation."
],
"offsets": [
[
90,
925
]
]
}
] |
[
{
"id": "1642",
"type": "DNAMutation",
"text": [
"338G>A"
],
"offsets": [
[
404,
410
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1645
|
16211251
|
[
{
"id": "1653",
"type": "title",
"text": [
"A novel single-nucleotide substitution, Glu 4 Lys, in the leukotriene C4 synthase gene associated with allergic diseases."
],
"offsets": [
[
0,
121
]
]
},
{
"id": "1654",
"type": "abstract",
"text": [
"Cysteinyl leukotrienes (cysLTs) play important roles in bronchial asthma, and can mediate bronchial smooth muscle constriction and increase mucous secretion, vascular permeability and cellular infiltration. We identified a novel heterozygous single-nucleotide substitution 10G>A (Glu 4 Lys) in the first exon of the leukotriene C4 synthase gene (LTC4S). This substitution was detected in 5 of 141 allergic patients, but not in 110 nonallergic subjects. There was a difference in the Glu 4 Lys frequency between the allergic patients and nonallergic subjects (Fisher's exact test, p=0.0460). The five patients with Glu 4 Lys had allergic diseases such as bronchial asthma and/or allergic dermatitis. Furthermore, a familial analysis of Glu 4 Lys revealed a link with allergic diseases. Thus, our results suggest that Glu 4 Lys in the LTC4S might be associated with allergic diseases."
],
"offsets": [
[
122,
1004
]
]
}
] |
[
{
"id": "1646",
"type": "ProteinMutation",
"text": [
"Glu 4 Lys"
],
"offsets": [
[
40,
49
]
],
"normalized": []
},
{
"id": "1647",
"type": "DNAMutation",
"text": [
"10G>A"
],
"offsets": [
[
395,
400
]
],
"normalized": []
},
{
"id": "1648",
"type": "ProteinMutation",
"text": [
"Glu 4 Lys"
],
"offsets": [
[
402,
411
]
],
"normalized": []
},
{
"id": "1649",
"type": "ProteinMutation",
"text": [
"Glu 4 Lys"
],
"offsets": [
[
605,
614
]
],
"normalized": []
},
{
"id": "1650",
"type": "ProteinMutation",
"text": [
"Glu 4 Lys"
],
"offsets": [
[
736,
745
]
],
"normalized": []
},
{
"id": "1651",
"type": "ProteinMutation",
"text": [
"Glu 4 Lys"
],
"offsets": [
[
857,
866
]
],
"normalized": []
},
{
"id": "1652",
"type": "ProteinMutation",
"text": [
"Glu 4 Lys"
],
"offsets": [
[
938,
947
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1655
|
16200390
|
[
{
"id": "1656",
"type": "title",
"text": [
"A genetic analysis of serotonergic biosynthetic and metabolic enzymes in migraine using a DNA pooling approach."
],
"offsets": [
[
0,
111
]
]
},
{
"id": "1657",
"type": "abstract",
"text": [
"Migraine is a common debilitating primary headache disorder with significant mental, physical and social health implications. The brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) is involved in nociceptive pathways and has been implicated in the pathophysiology of migraine. With few genetic studies investigating biosynthetic and metabolic enzymes governing the rate of 5-HT activity and their relationship to migraine, it was the objective of this study to assess genetic variants within the human tryptophan hydroxylase (TPH), amino acid decarboxylase (AADC) and monoamine oxidase A (MAOA) genes in migraine susceptibility. This objective was undertaken using a high-throughput DNA pooling experimental design, which proved to be a very accurate, sensitive and specific method of estimating allele frequencies for single nucleotide polymorphism, insertion deletion and variable number tandem repeat loci. Application of DNA pooling to a wide array of genetic loci provides greater scope in the assessment of population-based genetic association study designs. Despite the application of this high-throughput genotyping method, negative results from the two-stage DNA pooling design used to screen loci within the TPH, AADC and MAOA genes did not support their role in migraine susceptibility."
],
"offsets": [
[
112,
1419
]
]
}
] |
[] |
[] |
[] |
[] |
1658
|
16157158
|
[
{
"id": "1668",
"type": "title",
"text": [
"A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study."
],
"offsets": [
[
0,
179
]
]
},
{
"id": "1669",
"type": "abstract",
"text": [
"Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight."
],
"offsets": [
[
180,
1573
]
]
}
] |
[
{
"id": "1659",
"type": "ProteinMutation",
"text": [
"Cys 23-Ser 23"
],
"offsets": [
[
2,
15
]
],
"normalized": []
},
{
"id": "1660",
"type": "ProteinMutation",
"text": [
"Cys 23 Ser"
],
"offsets": [
[
422,
432
]
],
"normalized": []
},
{
"id": "1661",
"type": "ProteinMutation",
"text": [
"Cys 23 Ser"
],
"offsets": [
[
494,
504
]
],
"normalized": []
},
{
"id": "1662",
"type": "ProteinMutation",
"text": [
"Cys 23 Ser"
],
"offsets": [
[
600,
610
]
],
"normalized": []
},
{
"id": "1663",
"type": "ProteinMutation",
"text": [
"Cys 23 Ser"
],
"offsets": [
[
801,
811
]
],
"normalized": []
},
{
"id": "1664",
"type": "ProteinMutation",
"text": [
"Cys 23 Ser"
],
"offsets": [
[
986,
996
]
],
"normalized": []
},
{
"id": "1665",
"type": "ProteinMutation",
"text": [
"Cys 23 Ser"
],
"offsets": [
[
1222,
1232
]
],
"normalized": []
},
{
"id": "1666",
"type": "ProteinMutation",
"text": [
"Cys 23 Ser"
],
"offsets": [
[
1356,
1366
]
],
"normalized": []
},
{
"id": "1667",
"type": "ProteinMutation",
"text": [
"Cys 23 Ser"
],
"offsets": [
[
1518,
1528
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1670
|
16018252
|
[
{
"id": "1671",
"type": "title",
"text": [
"Two novel mutations in SRY gene form Chinese sex reversal XY females."
],
"offsets": [
[
0,
69
]
]
},
{
"id": "1672",
"type": "abstract",
"text": [
"The SRY gene (sex determining region on Y chromosome) acts as TDF and is required for regulating male sex determination. SRY represents a transcription factor belonging to the superfamily of genes sharing the HMG-box motif (high-mobility group-box), which acts as DNA binding region. Deletion and inactivating mutations of SRY are among the known causes of XY sex reversal. Here, we described the screening of 10 patients who presented with 46,XY sex reversal for mutations in open reading frame (ORF) of SRY gene. DNA was isolated from blood samples using standard techniques. A 609 bp fragment from the central portion of the SRY gene was amplified, using primers XES-2 and XES-7. The amplified PCR fragments were cloned into the pUCm-T vectors, and direct sequencing were carried out on an ABI 377-3 automated DNA sequencer to detect the mutation. PCR-restriction enzyme digestion was applied to detect the results of DNA sequencing. In two patients,de novo mutations led to an amino acid substitution. An A was replaced by a G in codon 38 upstream of the 5' border outside the HMG box of the SRY gene, resulting in the replacement of the amino acid glutamate by glycine. Another heterozygous T to A transition at the nucleotide position +387 which encodes for a Tyrosine (Tyr) instead of a Term, whereas her father was proven to have the wild-type sequence. These point mutations have been confirmed with PCR-restrict enzyme method. As demonstrated by the Human Gene Mutation Database analysis,homology search, and review of the literature, these two mutations were not described previously and brought the total number of SRY gene nucleotide substitutions (missense/nonsense) to 45. These findings indicated that these amino acid substitutions may be responsible for the sex reversal,not only inside the HMG-box but also outside the HMG-box. The two novel mutations in SRY gene provided valuable information for understanding the molecular mechanism of the patient with 46,XY female sex reversal."
],
"offsets": [
[
70,
2071
]
]
}
] |
[] |
[] |
[] |
[] |
1673
|
16000134
|
[
{
"id": "1675",
"type": "title",
"text": [
"Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency."
],
"offsets": [
[
0,
128
]
]
},
{
"id": "1676",
"type": "abstract",
"text": [
"A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis."
],
"offsets": [
[
129,
885
]
]
}
] |
[
{
"id": "1674",
"type": "ProteinMutation",
"text": [
"Glu 272 to stop"
],
"offsets": [
[
722,
737
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1677
|
15851735
|
[
{
"id": "1680",
"type": "title",
"text": [
"Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation."
],
"offsets": [
[
0,
97
]
]
},
{
"id": "1681",
"type": "abstract",
"text": [
"BACKGROUND: Classic neonatal-onset glycine encephalopathy (GE) is devastating and life threatening. Milder, later onset variants have been reported but were usually sporadic and incompletely defined. OBJECTIVE: To determine the clinical and biochemical phenotype and molecular basis of mild GE in nine children from a consanguineous Israeli Bedouin kindred. METHODS: Genomic DNA was screened for GLDC, AMT, and GCSH gene mutations. GLDC expression in lymphoblasts was studied by Northern blot and reverse transcriptase PCR analysis. RESULTS: Clinical features included hypotonia, abnormal movements, convulsions, and moderate mental retardation with relative sparing of gross motor function, activities of daily living skills, and receptive language. Aggression and irritability were prominent. CSF-to-plasma glycine ratio was mildly to moderately elevated. All nine patients were homozygous and their parents heterozygous for a novel, translationally silent GLDC exon 22 transversion c.2607C>A. Lymphoblast GLDC mRNA levels were considerably reduced. Three aberrantly spliced cDNA species were identified: exon 22 and exon 22 to 23 skipping, and insertion of an 87-base pair cryptic exon. Homozygosity for c.2607C>A was also identified in an unrelated but haplotypically identical patient with an unusually favorable outcome despite severe neonatal-onset GE. Mutation analysis enabled prenatal diagnosis of three unaffected and one affected pregnancies. CONCLUSIONS: The mutation in this kindred led to missplicing and reduced GLDC (glycine decarboxylase) expression. The 4 to 6% of normally spliced GLDC mRNA in the patients may account for their relatively favorable clinical outcome compared with patients with classic glycine encephalopathy."
],
"offsets": [
[
98,
1844
]
]
}
] |
[
{
"id": "1678",
"type": "DNAMutation",
"text": [
"c.2607C>A"
],
"offsets": [
[
1083,
1092
]
],
"normalized": []
},
{
"id": "1679",
"type": "DNAMutation",
"text": [
"c.2607C>A"
],
"offsets": [
[
1305,
1314
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1682
|
15837627
|
[
{
"id": "1683",
"type": "title",
"text": [
"Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis."
],
"offsets": [
[
0,
139
]
]
},
{
"id": "1684",
"type": "abstract",
"text": [
"Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase."
],
"offsets": [
[
140,
1000
]
]
}
] |
[] |
[] |
[] |
[] |
1685
|
15827093
|
[
{
"id": "1686",
"type": "title",
"text": [
"Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b."
],
"offsets": [
[
0,
120
]
]
},
{
"id": "1687",
"type": "abstract",
"text": [
"CONTEXT: The central clinical feature of GH insensitivity (GHI) is severe growth failure associated with elevated serum concentrations of GH and abnormally low serum levels of IGF-I. GHI can be the result of an abnormality in the GH receptor or aberrancies downstream of the GH receptor. OBJECTIVE: We investigated the GH-IGF-I axis in a young female GHI subject who presented with a height of 114 cm (-7.8 sd score) at age 16.4 yr. PATIENT: The subject, from a consanguineous pedigree, had circulating levels of GH and GH-binding protein that were normal to elevated, whereas IGF-I (7.2 ng/ml; normal, 242-600), IGF-binding protein-3 (543 ng/ml; normal, 2500-4800), and acid-labile subunit (1.22 microg/ml; normal, 5.6-16) levels were abnormally low and failed to increase during an IGF-I generation test. DESIGN: Dermal fibroblast cultures were established with the consent of the patient and family. Immunoblot analysis of cell lysates and DNA sequencing of her signal transducer and activator of transcription 5b (STAT5b), a critical intermediate of the GH-IGF-I axis, were performed. RESULTS: Sequencing of the STAT5b gene revealed a novel homozygous insertion of a single nucleotide in exon 10. The insertion resulted in a frame shift, leading to early protein termination and consequent lack of immunodetectable STAT5b protein. CONCLUSION: The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth."
],
"offsets": [
[
121,
1673
]
]
}
] |
[] |
[] |
[] |
[] |
1688
|
15818664
|
[
{
"id": "1689",
"type": "title",
"text": [
"Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5'-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate."
],
"offsets": [
[
0,
230
]
]
},
{
"id": "1690",
"type": "abstract",
"text": [
"OBJECTIVE: Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. METHODS: ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. RESULTS: Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5'-untranslated region (5'-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. CONCLUSION: A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5'-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease."
],
"offsets": [
[
231,
2332
]
]
}
] |
[] |
[] |
[] |
[] |
1691
|
15814629
|
[
{
"id": "1692",
"type": "title",
"text": [
"The number of lymph node metastases in gastric cancer correlates with the angiotensin I-converting enzyme gene insertion/deletion polymorphism."
],
"offsets": [
[
0,
143
]
]
},
{
"id": "1693",
"type": "abstract",
"text": [
"PURPOSE: In the present study, we aimed to substantiate the putative significance of angiotensin I-converting enzyme (ACE) on gastric cancer biology by investigating the influence of its gene polymorphism on gastric cancer progression. EXPERIMENTAL DESIGN: Genomic DNA was purified from peripheral blood mononuclear cells or tissue specimens. Amplified ACE gene fragments were separated on agarose gels. D or I alleles were identified by the presence of 190- or 490-bp fragments, respectively. Local expression of ACE was investigated by immunohistochemistry. RESULTS: Twenty-four of 113 (21%) gastric cancer patients had the II, 57 (51%) the ID, and 32 (28%) the DD genotype. The distribution of the ACE genotypes did not differ significantly from the control group of 189 patients without gastric cancer. However, the ACE genotypes correlated with the number of lymph node metastases and the Unio Internationale Contra Cancrum (UICC) tumor stage. Patients with the II genotype had a highly significantly smaller number of lymph node metastases (P < 0.001) and a significantly lower UICC tumor stage (P = 0.01) than patients with the DD genotype. No correlation was found between tumor type, tumor location, local tumor growth, distant metastases, and the ACE genotype. The expression of ACE in gastric cancer was investigated by immunohistochemistry in 100 of 113 patients. ACE was expressed by endothelial cells in all (100%) specimens and by tumor cells in 56 (56%) specimens. CONCLUSIONS: Our study shows that ACE is expressed locally in gastric cancer and that the gene polymorphism influences metastatic behavior."
],
"offsets": [
[
144,
1764
]
]
}
] |
[] |
[] |
[] |
[] |
1694
|
15807692
|
[
{
"id": "1698",
"type": "title",
"text": [
"Identification of novel type VII collagen gene mutations resulting in severe recessive dystrophic epidermolysis bullosa."
],
"offsets": [
[
0,
120
]
]
},
{
"id": "1699",
"type": "abstract",
"text": [
"In this work, we studied the proband in a small nuclear family of Chinese and Dutch/German descent and identified two novel mutations in the type VII collagen gene leading to recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens variant (HS-RDEB). The maternal mutation is a single base pair deletion of a cytosine nucleotide in exon 26, designated 3472delC, resulting in a frameshift and a premature termination codon (PTC) within the same exon, 7 bp downstream of the site of the mutation. The paternal mutation is a G-->A transition located at the 5' donor splice site within intron 51, designated IVS51 + 1G-->A. This mutation leads to the activation of a cryptic splice site, 32 bp downstream of the mutation site and to subsequent aberrant out-of-frame splicing, resulting in two alternative mRNA transcripts and a downstream PTC. To our knowledge, these two mutations have not been previously reported. These findings extend the body of evidence for compound heterozygous mutations leading to HS-RDEB and provide the basis for prenatal diagnosis in this family."
],
"offsets": [
[
121,
1197
]
]
}
] |
[
{
"id": "1695",
"type": "DNAMutation",
"text": [
"3472delC"
],
"offsets": [
[
478,
486
]
],
"normalized": []
},
{
"id": "1696",
"type": "DNAMutation",
"text": [
"G-->A"
],
"offsets": [
[
648,
653
]
],
"normalized": []
},
{
"id": "1697",
"type": "DNAMutation",
"text": [
"IVS51 + 1G-->A"
],
"offsets": [
[
730,
744
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1700
|
15710861
|
[
{
"id": "1703",
"type": "title",
"text": [
"Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new mutation in the ARSA gene."
],
"offsets": [
[
0,
136
]
]
},
{
"id": "1704",
"type": "abstract",
"text": [
"BACKGROUND: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ARSA). Clinically, the disease is heterogeneous with respect to the age of onset, affection of peripheral and central nervous systems, and progression. OBJECTIVES: To analyze mutations in the ARSA gene of a patient with adult-onset MLD with no signs of peripheral polyneuropathy and to emphasize the clinical, neuroradiologic, neuropathologic, and genetic features of the disease. DESIGN: Case study of a patient clinically presenting with rapidly progressive dementia and behavioral abnormalities. We report the findings of clinical evaluation and neurophysiologic and neuropathologic studies of peripheral nerves; we also performed DNA sequence analysis, transfections, metabolic labeling, and immunoprecipitation of mutant ARSA polypeptides. SETTING: Genetic research and clinical unit, university hospital. RESULTS: Genetic analysis revealed homozygosity for a novel mutation in exon 3 of ARSA (F219V). This substitution leads to a misfolded unstable enzyme with a specific activity less than 1% of normal. There were no clinical or neurophysiologic signs of peripheral nervous system dysfunction. Typical neuropathologic signs for MLD were absent from nerve biopsy specimens. CONCLUSIONS: This novel mutation is associated with progressive psychocognitive impairment without clinical or electrophysiologic signs and only minor morphologic signs of peripheral nerve affection. The F219V substitution causes reduction in enzyme activity to an extent unexpected for an adult patient with MLD."
],
"offsets": [
[
137,
1754
]
]
}
] |
[
{
"id": "1701",
"type": "ProteinMutation",
"text": [
"F219V"
],
"offsets": [
[
1159,
1164
]
],
"normalized": []
},
{
"id": "1702",
"type": "ProteinMutation",
"text": [
"F219V"
],
"offsets": [
[
1645,
1650
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1705
|
15642853
|
[
{
"id": "1708",
"type": "title",
"text": [
"Parkin mutations and early-onset parkinsonism in a Taiwanese cohort."
],
"offsets": [
[
0,
68
]
]
},
{
"id": "1709",
"type": "abstract",
"text": [
"BACKGROUND: Loss of function of the parkin gene (PRKN) is the predominant genetic cause of juvenile and early-onset parkinsonism in Japan, Europe, and the United States. OBJECTIVES: To evaluate the frequency of PRKN mutations in Taiwanese (ethnic Chinese) patients with early-onset parkinsonism and to explore genotype-phenotype correlations. DESIGN: Clinical assessment included medical, neurologic, and psychiatric evaluation. Genomic DNA sequencing and quantitative polymerase chain reaction were performed to identify PRKN mutations. Gene expression was examined in patient lymphoblastoid cell lines, in which PRKN mutations were identified. PATIENTS: Forty-one Taiwanese patients with early-onset parkinsonism (aged <50 years at onset). RESULTS: Four of 41 probands had PRKN mutations. One proband had compound heterozygous mutations, with a PRKN exon 2 deletion and an exon 7 G284R substitution. The phenotype resembled typical Parkinson disease. Three patients were mutation carriers. One proband had PRKN exon 2 and exon 3 deletions in the same allele. However, this patient's phenotype was that of classic \"parkin-proven\" autosomal recessive juvenile parkinsonism, characterized by symmetrical foot dystonia at onset, gait disturbance, diurnal change, and very slow progression. The 2 remaining carriers had novel heterozygous exon 11 R396G substitutions. Patients with PRKN mutations were younger at onset than those without mutations, and they required a lower dose of levodopa despite longer disease duration. CONCLUSIONS: Mutations in PRKN are a rare cause of early-onset parkinsonism in Taiwanese individuals. The overall mutation frequency, adjusted for age at onset, was comparable with that reported for white cohorts; however, the point mutations identified seem to be population specific."
],
"offsets": [
[
69,
1876
]
]
}
] |
[
{
"id": "1706",
"type": "ProteinMutation",
"text": [
"G284R"
],
"offsets": [
[
951,
956
]
],
"normalized": []
},
{
"id": "1707",
"type": "ProteinMutation",
"text": [
"R396G"
],
"offsets": [
[
1413,
1418
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1710
|
15623763
|
[
{
"id": "1730",
"type": "title",
"text": [
"TGFBI gene mutations causing lattice and granular corneal dystrophies in Indian patients."
],
"offsets": [
[
0,
89
]
]
},
{
"id": "1731",
"type": "abstract",
"text": [
"PURPOSE: To identify mutations in the TGFBI gene in Indian patients with lattice corneal dystrophy (LCD) or granular corneal dystrophy (GCD) and to look for genotype-phenotype correlations. METHODS: Thirty-seven unrelated patients were studied, 18 with LCD and 19 with GCD. The diagnosis of LCD or GCD was made on the basis of clinical and/or histopathological evaluation. Exons and flanking intron sequences of the TGFBI gene were amplified by PCR with specific primers. PCR products were screened by the method of single-strand conformation polymorphism followed by sequencing. Mutations were confirmed by screening at least 100 unrelated normal control subjects. RESULTS: Mutations were identified in 14 of 18 patients with LCD and in all 19 patients with GCD. In LCD, three novel heterozygous mutations found were glycine-594-valine (Gly594Val) in 2 of 18 patients, valine-539-aspartic acid (Val539Asp) in 1 patient, and deletion of valine 624, valine 625 (Val624-Val625del) in 1 patient. In addition, mutation of arginine 124-to-cysteine (Arg124Cys) was found in 8 of 18 patients and histidine 626-to-arginine (His626Arg) in 2 of 18 patients. Atypical clinical features for LCD were noted in patients with the Gly594Val and Val624-Val625del mutations. In GCD, 18 patients with GCD type I had a mutation of arginine 555-to-tryptophan (Arg555Trp) and 1 patient with GCD type III (Reis-Bucklers dystrophy), had the Arg124Leu mutation. Seven novel single-nucleotide polymorphisms (SNPs) were also found, of which a change of leucine 269 to phenylalanine (Leu269Phe) was found in 12 of 18 patients with the Arg555Trp mutation. CONCLUSIONS: Arg124Cys and Arg555Trp appear to be the predominant mutations causing LCD and GCD, respectively, in the population studied. The novel mutations identified in this study are associated with distinct phenotypes."
],
"offsets": [
[
90,
1940
]
]
}
] |
[
{
"id": "1711",
"type": "ProteinMutation",
"text": [
"glycine-594-valine"
],
"offsets": [
[
908,
926
]
],
"normalized": []
},
{
"id": "1712",
"type": "ProteinMutation",
"text": [
"Gly594Val"
],
"offsets": [
[
928,
937
]
],
"normalized": []
},
{
"id": "1713",
"type": "ProteinMutation",
"text": [
"valine-539-aspartic"
],
"offsets": [
[
960,
979
]
],
"normalized": []
},
{
"id": "1714",
"type": "ProteinMutation",
"text": [
"Val539Asp"
],
"offsets": [
[
986,
995
]
],
"normalized": []
},
{
"id": "1715",
"type": "ProteinMutation",
"text": [
"Val624-Val625del"
],
"offsets": [
[
1051,
1067
]
],
"normalized": []
},
{
"id": "1716",
"type": "ProteinMutation",
"text": [
"arginine 124-to-cysteine"
],
"offsets": [
[
1108,
1132
]
],
"normalized": []
},
{
"id": "1717",
"type": "ProteinMutation",
"text": [
"Arg124Cys"
],
"offsets": [
[
1134,
1143
]
],
"normalized": []
},
{
"id": "1718",
"type": "ProteinMutation",
"text": [
"histidine 626-to-arginine"
],
"offsets": [
[
1179,
1204
]
],
"normalized": []
},
{
"id": "1719",
"type": "ProteinMutation",
"text": [
"His626Arg"
],
"offsets": [
[
1206,
1215
]
],
"normalized": []
},
{
"id": "1720",
"type": "ProteinMutation",
"text": [
"Gly594Val"
],
"offsets": [
[
1305,
1314
]
],
"normalized": []
},
{
"id": "1721",
"type": "ProteinMutation",
"text": [
"Val624-Val625del"
],
"offsets": [
[
1319,
1335
]
],
"normalized": []
},
{
"id": "1722",
"type": "ProteinMutation",
"text": [
"arginine 555-to-tryptophan"
],
"offsets": [
[
1401,
1427
]
],
"normalized": []
},
{
"id": "1723",
"type": "ProteinMutation",
"text": [
"Arg555Trp"
],
"offsets": [
[
1429,
1438
]
],
"normalized": []
},
{
"id": "1724",
"type": "ProteinMutation",
"text": [
"Arg124Leu"
],
"offsets": [
[
1507,
1516
]
],
"normalized": []
},
{
"id": "1725",
"type": "ProteinMutation",
"text": [
"leucine 269 to phenylalanine"
],
"offsets": [
[
1616,
1644
]
],
"normalized": []
},
{
"id": "1726",
"type": "ProteinMutation",
"text": [
"Leu269Phe"
],
"offsets": [
[
1646,
1655
]
],
"normalized": []
},
{
"id": "1727",
"type": "ProteinMutation",
"text": [
"Arg555Trp"
],
"offsets": [
[
1697,
1706
]
],
"normalized": []
},
{
"id": "1728",
"type": "ProteinMutation",
"text": [
"Arg124Cys"
],
"offsets": [
[
1730,
1739
]
],
"normalized": []
},
{
"id": "1729",
"type": "ProteinMutation",
"text": [
"Arg555Trp"
],
"offsets": [
[
1744,
1753
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1732
|
15481887
|
[
{
"id": "1739",
"type": "title",
"text": [
"Two new beta-chain variants: Hb Tripoli [beta26(B8)Glu-->Ala] and Hb Tizi-Ouzou [beta29(B11)Gly-->Ser]."
],
"offsets": [
[
0,
103
]
]
},
{
"id": "1740",
"type": "abstract",
"text": [
"Two new beta-globin chain variants: Hb Tripoli: codon 26, GAG-->GCG [beta26(B8)Glu-->Ala] and Hb Tizi-Ouzou: codon 29, GGC-->AGC [beta29(B11)Gly-->Ser] are described on the first exon of the beta-globin gene. The two variants are characterized by DNA sequencing and mass spectrometry (MS). Hematological abnormalities were found in the two carriers. The presence of microcytosis and hypochromia is explained by an additional homozygous 3.7 kb alpha(+) thalassemic deletion for the carrier of Hb Tizi-Ouzou. Hb Tizi-Ouzou showed a slight instability in vitro. The same hematological abnormalities associated with anemia are difficult to explain for Hb Tripoli's carrier in the absence of an alpha-globin genes abnormality and could suggest a possible abnormal splicing."
],
"offsets": [
[
104,
872
]
]
}
] |
[
{
"id": "1733",
"type": "ProteinMutation",
"text": [
"Glu-->Ala"
],
"offsets": [
[
51,
60
]
],
"normalized": []
},
{
"id": "1734",
"type": "ProteinMutation",
"text": [
"Gly-->Ser"
],
"offsets": [
[
92,
101
]
],
"normalized": []
},
{
"id": "1735",
"type": "DNAMutation",
"text": [
"codon 26, GAG-->GCG"
],
"offsets": [
[
152,
171
]
],
"normalized": []
},
{
"id": "1736",
"type": "ProteinMutation",
"text": [
"Glu-->Ala"
],
"offsets": [
[
183,
192
]
],
"normalized": []
},
{
"id": "1737",
"type": "DNAMutation",
"text": [
"codon 29, GGC-->AGC"
],
"offsets": [
[
213,
232
]
],
"normalized": []
},
{
"id": "1738",
"type": "ProteinMutation",
"text": [
"Gly-->Ser"
],
"offsets": [
[
245,
254
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1741
|
15459183
|
[
{
"id": "1743",
"type": "title",
"text": [
"CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B."
],
"offsets": [
[
0,
158
]
]
},
{
"id": "1744",
"type": "abstract",
"text": [
"We previously reported association of FCGR2B-Ile232Thr with systemic lupus erythematosus (SLE) in three Asian populations. Because polymorphism of CD72, another inhibitory receptor of B cells, was associated with murine SLE, we identified human CD72 polymorphisms, tested their association with SLE and examined genetic interaction with FCGR2B in the Japanese (160 SLE, 277 controls), Thais (87 SLE, 187 controls) and Caucasians (94 families containing SLE members). Four polymorphisms and six rare variations were detected. The former constituted two major haplotypes that contained one or two repeats of 13 nucleotides in intron 8 (designated as *1 and *2, respectively). Although association with susceptibility to SLE was not detected, the *1 allele was significantly associated with nephritis among the Japanese patients (P=0.024). RT-PCR identified a novel alternatively spliced (AS) transcript that was expressed at the protein level in COS-7 transfectants. The ratio of AS/common isoforms was strikingly increased in individuals with *2/*2 genotype when compared with *1/*1 (P=0.000038) or *1/*2 (P=0.0085) genotypes. Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P=0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2). Minigene assays demonstrated that the 13-nucleotide repeat and 4 bp deletion within the same haplotype of intron 8 could regulate alternative splicing. The AS isoform lacks exon 8, and is deduced to contain 49 amino acid changes in the membrane-distal portion of the extracellular domain, where considerable amino acid changes are known in CD72(c) allele associated with murine SLE. These results indicated that the presence of CD72-*2 allele decreases risk for human SLE conferred by FCGR2B-232Thr, possibly by increasing the AS isoform of CD72."
],
"offsets": [
[
159,
2050
]
]
}
] |
[
{
"id": "1742",
"type": "ProteinMutation",
"text": [
"Ile232Thr"
],
"offsets": [
[
204,
213
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1745
|
15377356
|
[
{
"id": "1748",
"type": "title",
"text": [
"Features of epidermolysis bullosa simplex due to mutations in the ectodomain of type XVII collagen."
],
"offsets": [
[
0,
99
]
]
},
{
"id": "1749",
"type": "abstract",
"text": [
"BACKGROUND: Mutations in COL17A1, coding for type XVII collagen, cause junctional epidermolysis bullosa with an ultrastructural plane of cleavage through the lamina lucida of the epidermal basement membrane. OBJECTIVES: To identify the COL17A1 mutations in a child with reduced type XVII collagen expression and intraepidermal blister formation. PATIENT AND METHODS: Protein expression and level of tissue separation were studied by immunofluorescence and electron microscopy. The mutations were identified by analysing the patient's DNA and mRNA. RESULTS: Immunofluorescence microscopy performed on nonlesional skin demonstrated absence of the type XVII collagen endodomain and presence, although reduced, of the shed ectodomain. Electron microscopy showed that the plane of cleavage was through the basal cells, not through the lamina lucida. Two heterozygous mutations were identified in COL17A1: a new 3'-acceptor splice-site mutation in intron 21 (1877-2A-->C), and a deletion in exon 48 (3432delT). The splice-site mutation in intron 21 results in alternative transcripts of which two are in-frame, with deletions of the first nine codons of exon 22 and the entire exon 22, respectively. By Western blot analysis, a type XVII collagen molecule was detected that was slightly smaller than normal. CONCLUSIONS: Occasionally mutations in the COL17A1 gene may result in split levels suggesting epidermolysis bullosa simplex rather than junctional epidermolysis bullosa."
],
"offsets": [
[
100,
1571
]
]
}
] |
[
{
"id": "1746",
"type": "DNAMutation",
"text": [
"1877-2A-->C"
],
"offsets": [
[
1053,
1064
]
],
"normalized": []
},
{
"id": "1747",
"type": "DNAMutation",
"text": [
"3432delT"
],
"offsets": [
[
1094,
1102
]
],
"normalized": []
}
] |
[] |
[] |
[] |
1750
|
15282322
|
[
{
"id": "1751",
"type": "title",
"text": [
"Deletion of mouse rad9 causes abnormal cellular responses to DNA damage, genomic instability, and embryonic lethality."
],
"offsets": [
[
0,
118
]
]
},
{
"id": "1752",
"type": "abstract",
"text": [
"The fission yeast Schizosaccharomyces pombe rad9 gene promotes cell survival through activation of cell cycle checkpoints induced by DNA damage. Mouse embryonic stem cells with a targeted deletion of Mrad9, the mouse ortholog of this gene, were created to evaluate its function in mammals. Mrad9(-/-) cells demonstrated a marked increase in spontaneous chromosome aberrations and HPRT mutations, indicating a role in the maintenance of genomic integrity. These cells were also extremely sensitive to UV light, gamma rays, and hydroxyurea, and heterozygotes were somewhat sensitive to the last two agents relative to Mrad9(+/+) controls. Mrad9(-/-) cells could initiate but not maintain gamma-ray-induced G(2) delay and retained the ability to delay DNA synthesis rapidly after UV irradiation, suggesting that checkpoint abnormalities contribute little to the radiosensitivity observed. Ectopic expression of Mrad9 or human HRAD9 complemented Mrad9(-/-) cell defects, indicating that the gene has radioresponse and genomic maintenance functions that are evolutionarily conserved. Mrad9(+/-) mice were generated, but heterozygous intercrosses failed to yield Mrad9(-/-) pups, since embryos died at midgestation. Furthermore, Mrad9(-/-) mouse embryo fibroblasts were not viable. These investigations establish Mrad9 as a key mammalian genetic element of pathways that regulate the cellular response to DNA damage, maintenance of genomic integrity, and proper embryonic development."
],
"offsets": [
[
119,
1597
]
]
}
] |
[] |
[] |
[] |
[] |
1753
|
15272913
|
[
{
"id": "1754",
"type": "title",
"text": [
"Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS?"
],
"offsets": [
[
0,
90
]
]
},
{
"id": "1755",
"type": "abstract",
"text": [
"OBJECTIVE: Endometriosis is a steroid-dependent disease with a particular genetic background, but the locations of possible genomic aberrations are still poorly clarified. We have investigated the potential association between endometriosis and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor (PR) gene, which has been reported previously to segregate with this disease. DESIGN: In a case-control study, we examined the PROGINS polymorphism of the progesterone receptor gene in 131 Italian women affected by endometriosis diagnosed according to published criteria for the definition of the definite disease. Control subjects were represented by 127 Italian women without laparoscopic evidence of the disease. MEASUREMENTS: Peripheral blood samples, DNA extraction and polymerase chain reaction (PCR) were used to genotype women for the presence of the PROGINS polymorphism. RESULTS: We found a statistically significant difference in the distribution of PROGINS genotypes between patients with and without endometriosis. The frequency of the PROGINS allele T2 was 17.2% and 11%, respectively, in affected women and in controls [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.0-2.8]. This association was stronger in patients with more severe forms of endometriosis, such as an infiltrating disease or a disease characterized by severe pelvic adhesions (OR 2.4, 95% CI 1.2-4.8; and OR 2.7, 95% CI 1.4-5.3, respectively). Combination of the results from an earlier study and the current data indicates that carrying the allele variant T2 is associated with a twofold increase in the risk of developing endometriosis (OR 2.0, 95% CI 1.3-2.9). CONCLUSIONS: Our results further support the idea that the PROGINS polymorphism of the progesterone receptor may be associated with an increased risk of endometriosis."
],
"offsets": [
[
91,
1947
]
]
}
] |
[] |
[] |
[] |
[] |
1756
|
15258261
|
[
{
"id": "1757",
"type": "title",
"text": [
"Mre11 deficiency in Arabidopsis is associated with chromosomal instability in somatic cells and Spo11-dependent genome fragmentation during meiosis."
],
"offsets": [
[
0,
148
]
]
},
{
"id": "1758",
"type": "abstract",
"text": [
"The Mre11/Rad50/Nbs1 complex is involved in many aspects of chromosome metabolism. Aberrant function of the complex is associated with defects in the DNA checkpoint, double-strand break repair, meiosis, and telomere maintenance. In this article, we report the consequences of Mre11 dysfunction for the stability of mitotic and meiotic chromosomes in Arabidopsis thaliana. Although plants homozygous for a T-DNA insertion in a conserved region of the MRE11 gene are viable, they exhibit growth defects and are infertile. Analysis of mitotic chromosomes prepared from the mutant plants revealed abundant dicentric chromosomes and chromosomal fragments. Fluorescence in situ hybridization showed that anaphase bridges are often formed by homologous chromosome arms. The frequency of chromosome fusions was not reduced in mre11 ku70 double mutants, suggesting that plants possess DNA end-joining activities independent of the Ku70/80 and Mre11 complexes. Cytogenetic examination of pollen mother cells revealed massive chromosome fragmentation and the absence of synapsis in the initial stages of meiosis. The fragmentation was substantially suppressed in mre11 spo11-1 double mutants, indicating that Mre11 is required for repair but not for the induction of Spo11-dependent meiotic DNA breaks in Arabidopsis."
],
"offsets": [
[
149,
1455
]
]
}
] |
[] |
[] |
[] |
[] |
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