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BigScience Biomedical Datasets 151

[ { "id": "549", "type": "title", "text": [ "Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population." ], "offsets": [ [ 0, 154 ] ] }, { "id": "550", "type": "abstract", "text": [ "Evolvement and progression of cardiovascular diseases affecting the venous and arterial system are influenced by a multitude of environmental and hereditary factors. Many of these hereditary factors consist of defined gene polymorphisms, such as single nucleotide polymorphisms (SNPs) or insertion-deletion polymorphisms, which directly or indirectly affect the hemostatic system. The frequencies of individual hemostatic gene polymorphisms in different normal populations are well defined. However, descriptions of patterns of genetic variability of a larger extent of different factors of hereditary hypercoagulability in single populations are scarce. The aim of this study was i) to give a detailed description of the frequencies of factors of hereditary thrombophilia and their combinations in a German population (n = 282) and ii) to compare their distributions with those reported for other regions. Variants of coagulation factors [factor V 1691G>A (factor V Leiden), factor V 4070A>G (factor V HR2 haplotype), factor VII Arg353Gln, factor XIII Val34Leu, beta-fibrinogen -455G>A, prothrombin 20210G>A], coagulation inhibitors [tissue factor pathway inhibitor 536C>T, thrombomodulin 127G>A], fibrinolytic factors [angiotensin converting enzyme intron 16 insertion/deletion, factor VII-activating protease 1601G>A (FSAP Marburg I), plasminogen activator inhibitor 1-675 insertion/deletion (5G/4G), tissue plasminogen activator intron h deletion/insertion], and other factors implicated in influencing susceptibility to thromboembolic diseases [apolipoprotein E2/E3/E4, glycoprotein Ia 807C>T, methylenetetrahydrofolate reductase 677C>T] were included. The distribution of glycoprotein Ia 807C>T deviated significantly from the Hardy-Weinberg equilibrium, and a comparison with previously published data indicates marked region and ethnicity dependent differences in the genotype distributions of some other factors." ], "offsets": [ [ 155, 2076 ] ] } ]

[ { "id": "537", "type": "DNAMutation", "text": [ "1691G>A" ], "offsets": [ [ 1104, 1111 ] ], "normalized": [] }, { "id": "538", "type": "DNAMutation", "text": [ "4070A>G" ], "offsets": [ [ 1140, 1147 ] ], "normalized": [] }, { "id": "539", "type": "ProteinMutation", "text": [ "Arg353Gln" ], "offsets": [ [ 1185, 1194 ] ], "normalized": [] }, { "id": "540", "type": "ProteinMutation", "text": [ "Val34Leu" ], "offsets": [ [ 1208, 1216 ] ], "normalized": [] }, { "id": "541", "type": "DNAMutation", "text": [ "-455G>A" ], "offsets": [ [ 1234, 1241 ] ], "normalized": [] }, { "id": "542", "type": "DNAMutation", "text": [ "20210G>A" ], "offsets": [ [ 1255, 1263 ] ], "normalized": [] }, { "id": "543", "type": "DNAMutation", "text": [ "536C>T" ], "offsets": [ [ 1322, 1328 ] ], "normalized": [] }, { "id": "544", "type": "DNAMutation", "text": [ "127G>A" ], "offsets": [ [ 1345, 1351 ] ], "normalized": [] }, { "id": "545", "type": "DNAMutation", "text": [ "1601G>A" ], "offsets": [ [ 1467, 1474 ] ], "normalized": [] }, { "id": "546", "type": "DNAMutation", "text": [ "807C>T" ], "offsets": [ [ 1746, 1752 ] ], "normalized": [] }, { "id": "547", "type": "DNAMutation", "text": [ "677C>T" ], "offsets": [ [ 1790, 1796 ] ], "normalized": [] }, { "id": "548", "type": "DNAMutation", "text": [ "807C>T" ], "offsets": [ [ 1849, 1855 ] ], "normalized": [] } ]

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[ { "id": "558", "type": "title", "text": [ "Severe prothrombin deficiency caused by prothrombin-Edmonton (R-4Q) combined with a previously undetected deletion." ], "offsets": [ [ 0, 115 ] ] }, { "id": "559", "type": "abstract", "text": [ "BACKGROUND: During infancy, a male patient experienced several life-threatening bleeding episodes. Standard coagulation tests revealed that the patient's plasma prothrombin activity was 8%, while his father's and mother's levels were 74% and 62%, respectively. OBJECTIVES: A molecular genetic approach was used to determine the molecular basis of prothrombin deficiency within the family. PATIENT/METHODS: Prothrombin genomic DNA fragments were amplified by using the polymerase chain reaction (PCR). In addition, liver cDNA fragments were amplified from the patient by using reverse transcription (RT) and PCR. The nucleotide sequences of the DNA fragments were determined. RESULTS: A novel, heterozygous point mutation (g.1755 G > A, named prothrombin-Edmonton) was detected in the patient and his mother, resulting in the mutation of Arg-4 in the prothrombin propeptide to Gln (R-4Q). RT-PCR analysis of the patient's liver sample demonstrated the presence of two mRNA transcripts that differed by the presence or absence of exon 11. Real-time PCR analysis on genomic DNA and cDNA confirmed a deletion (g.10435_10809del) in the paternal allele. CONCLUSIONS: The patient has a maternally-inherited point mutation (R-4Q) and a paternally-inherited deletion. By analogy with the previously reported factor IX San Dimas, the R-4Q mutation probably causes under-carboxylation of prothrombin and poor cleavage of the propeptide in the hepatocyte. The deletion probably results in a polypeptide that lacks 50 amino acids from the protease domain; this is likely to impair folding, secretion, stability and/or activity of the truncated prothrombin. The two mutations combine to give the prothrombin deficiency observed in the patient." ], "offsets": [ [ 116, 1845 ] ] } ]

[ { "id": "552", "type": "ProteinMutation", "text": [ "R-4Q" ], "offsets": [ [ 62, 66 ] ], "normalized": [] }, { "id": "553", "type": "DNAMutation", "text": [ "g.1755 G > A" ], "offsets": [ [ 838, 850 ] ], "normalized": [] }, { "id": "554", "type": "ProteinMutation", "text": [ "R-4Q" ], "offsets": [ [ 997, 1001 ] ], "normalized": [] }, { "id": "555", "type": "DNAMutation", "text": [ "g.10435_10809del" ], "offsets": [ [ 1222, 1238 ] ], "normalized": [] }, { "id": "556", "type": "ProteinMutation", "text": [ "R-4Q" ], "offsets": [ [ 1332, 1336 ] ], "normalized": [] }, { "id": "557", "type": "ProteinMutation", "text": [ "R-4Q" ], "offsets": [ [ 1440, 1444 ] ], "normalized": [] } ]

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[ { "id": "564", "type": "title", "text": [ "A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy." ], "offsets": [ [ 0, 88 ] ] }, { "id": "565", "type": "abstract", "text": [ "PURPOSE: To describe the phenotype and genotype of a family with suspected Sorsby fundus dystrophy (SFD). DESIGN: Case reports and results of deoxyribonucleic acid (DNA) analysis. METHODS: Clinical features were determined by complete ophthalmologic examination or by review of medical records. Mutational analysis of the tissue inhibitor of metalloproteinase (TIMP)3 gene was performed by DNA resequencing. Biochemical properties of the mutant TIMP3 protein were studied, and phylogenetic and molecular modeling analyses of TIMP proteins were performed. RESULTS: Fundi of four affected family members demonstrated active or regressed bilateral choroidal neovascularization, whereas another affected individual displayed severe diffuse pigmentary degeneration associated with nyctalopia characteristic of SFD. Onset of disease occurred in the fifth to seventh decades of life. A heterozygous His158Arg mutation was found in seven affected family members and was absent from an unaffected member and 98 unrelated controls. Bioinformatic analyses indicate that histidine 158 is an evolutionarily conserved residue in most vertebrate TIMP homologs and predict that substitution by arginine disrupts TIMP3 function. The mutant protein appears to be expressed by fibroblasts from an affected family member. Molecular modeling suggests that TIMP3 residue 158 may be part of a protein-protein interaction interface. CONCLUSION: A novel mutation in TIMP3 causes a late-onset form of SFD in this family. His158Arg is the first reported TIMP3 SFD coding sequence mutation that does not create an unpaired cysteine. Further study of this unusual mutation may provide insight into the mechanism of SFD pathogenesis." ], "offsets": [ [ 89, 1792 ] ] } ]

[ { "id": "561", "type": "ProteinMutation", "text": [ "His158Arg" ], "offsets": [ [ 8, 17 ] ], "normalized": [] }, { "id": "562", "type": "ProteinMutation", "text": [ "His158Arg" ], "offsets": [ [ 981, 990 ] ], "normalized": [] }, { "id": "563", "type": "ProteinMutation", "text": [ "His158Arg" ], "offsets": [ [ 1584, 1593 ] ], "normalized": [] } ]

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[ { "id": "571", "type": "title", "text": [ "Analysis of a missense variant of the human N-formyl peptide receptor that is associated with agonist-independent beta-arrestin association and indices of inflammation." ], "offsets": [ [ 0, 168 ] ] }, { "id": "572", "type": "abstract", "text": [ "Formyl-Met-Leu-Phe (fMLP) is a potent chemoattractant molecule released from both bacteria and damaged mitochondria that activates fMLP receptors (FPR) leading to neutrophil chemotaxis, degranulation and superoxide production. A common missense single nucleotide polymorphism in the human FPR1 gene at nucleotide c.32C>T results in the amino-acid substitution, p.I11T, in the FPR1 extracellular amino-terminus. The minor (c.32T) allele frequencies were 0.25, 0.27, 0.25, 0.15 and 0.14 in healthy Caucasian, African, East Indian, Chinese and Native Canadian individuals, respectively. In subjects homozygous for the p.T11 allele, we find elevated serum concentrations of C-reactive protein, increased absolute counts of blood leukocytes and neutrophils, and erythrocyte sedimentation rates. When expressed in HEK 293 and RBL-2H3 cells a substantial proportion of FPR1 p.I11T variant is retained intracellularly and agonist-independent internalization of the FPR1 p.I11T variant, but not the wild-type FPR1, is constitutively associated with beta-arrestin2-GFP in vesicles. Moreover, basal N-acetyl-D-glucosaminidase release is increased in primary neutrophils isolated from subjects either heterozygous or homozygous for the FPR1 p.T11 allele. Taken together, the data suggest an increased receptor activity and phenotypic expression of increased inflammatory indices in subjects with the p.T11 allele." ], "offsets": [ [ 169, 1570 ] ] } ]

[ { "id": "567", "type": "DNAMutation", "text": [ "c.32C>T" ], "offsets": [ [ 482, 489 ] ], "normalized": [] }, { "id": "568", "type": "ProteinMutation", "text": [ "p.I11T" ], "offsets": [ [ 530, 536 ] ], "normalized": [] }, { "id": "569", "type": "ProteinMutation", "text": [ "p.I11T" ], "offsets": [ [ 1036, 1042 ] ], "normalized": [] }, { "id": "570", "type": "ProteinMutation", "text": [ "p.I11T" ], "offsets": [ [ 1131, 1137 ] ], "normalized": [] } ]

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[ { "id": "577", "type": "title", "text": [ "Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients." ], "offsets": [ [ 0, 90 ] ] }, { "id": "578", "type": "abstract", "text": [ "OBJECTIVES: Dystonia is a common movement disorder. The purpose of this study is to examine the relative distribution of the primary dystonia subtypes and identify mutation (s) in the DYT1 gene in Indian patients. MATERIALS AND METHODS: Primary dystonia patients (n = 178) and controls (n = 63), lacking any symptoms of the disease, were recruited for the study from eastern India. The nucleotide variants in the DYT1 gene were identified by carrying out polymerase chain reaction, single stranded conformation polymorphism, and DNA sequencing. RESULTS: Unlike other reports, pain and/or tremor was more common in our sporadic patients than in familial cases. Three reported and two novel changes were identified in this gene. The homozygous genotype (G,G) for a missense variant (c.646G > C; Asp216His) was significantly over-represented in the patients compared with controls (P < 0.05). However, the commonly reported 3 bp deletion (904-906delGAG) was not detected. CONCLUSION: Our results suggest that the DYT1 gene might have a limited role in causation of dystonia in the Indian population." ], "offsets": [ [ 91, 1187 ] ] } ]

[ { "id": "574", "type": "DNAMutation", "text": [ "c.646G > C" ], "offsets": [ [ 872, 882 ] ], "normalized": [] }, { "id": "575", "type": "ProteinMutation", "text": [ "Asp216His" ], "offsets": [ [ 884, 893 ] ], "normalized": [] }, { "id": "576", "type": "DNAMutation", "text": [ "904-906delGAG" ], "offsets": [ [ 1027, 1040 ] ], "normalized": [] } ]

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[ { "id": "582", "type": "title", "text": [ "Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1." ], "offsets": [ [ 0, 85 ] ] }, { "id": "583", "type": "abstract", "text": [ "Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene. We describe 2 families with MEN1 with novel mutations in the MEN1 gene. One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only. The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan. This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before. There was also a prolactinoma. Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands. The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid. The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine. In conclusion, we have identified 2 novel missense mutations in the MEN1 gene." ], "offsets": [ [ 86, 1375 ] ] } ]

[ { "id": "580", "type": "DNAMutation", "text": [ "AAG-->GAG" ], "offsets": [ [ 1035, 1044 ] ], "normalized": [] }, { "id": "581", "type": "DNAMutation", "text": [ "GAC-->TAT" ], "offsets": [ [ 1225, 1234 ] ], "normalized": [] } ]

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[ { "id": "593", "type": "title", "text": [ "Single nucleotide polymorphisms of the HNF4alpha gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial." ], "offsets": [ [ 0, 139 ] ] }, { "id": "594", "type": "abstract", "text": [ "Hepatocyte nuclear factor 4alpha (HNF4alpha) is a transcription factor, which is necessary for normal function of human liver and pancreatic islets. We investigated whether single nucleotide polymorphisms (SNPs) of HNF4A, encoding HNF4alpha, influenced the conversion from impaired glucose tolerance (IGT) to type 2 diabetes mellitus in subjects of the STOP-NIDDM trial. This trial aimed at evaluating the effect of acarbose compared to placebo in the prevention of type 2 diabetes mellitus. Eight SNPs covering the intragenic and alternate P2 promoter regions of HNF4A were genotyped in study samples using the TaqMan Allelic Discrimination Assays. Three SNPs in the P2 promoter region (rs4810424, rs1884614, and rs2144908) were in almost complete association (D'>0.97, r (2)>0.95) and, therefore, only rs4810424 was included in further analyses. Female carriers of the less frequent C allele of rs4810424 had a 1.7-fold elevated risk [95% confidence interval (CI) 1.09-2.66; P=0.020] for the conversion to diabetes compared to women with the common genotype after the adjustment for age, treatment group (placebo or acarbose), smoking, weight at baseline, and weight change. No association was found in men. Haplotype analysis based on three SNPs (rs4810424, rs2071197, and rs3818247) representing the linkage disequilibrium blocks in our study population indicated that the conversion to type 2 diabetes mellitus was dependent on the number of risk alleles in different haplotypes in women. Our results suggest that SNPs of HNF4A and their haplotypes predispose to type 2 diabetes mellitus in female subjects of the STOP-NIDDM study population." ], "offsets": [ [ 140, 1787 ] ] } ]

[ { "id": "585", "type": "SNP", "text": [ "rs4810424" ], "offsets": [ [ 828, 837 ] ], "normalized": [] }, { "id": "586", "type": "SNP", "text": [ "rs1884614" ], "offsets": [ [ 839, 848 ] ], "normalized": [] }, { "id": "587", "type": "SNP", "text": [ "rs2144908" ], "offsets": [ [ 854, 863 ] ], "normalized": [] }, { "id": "588", "type": "SNP", "text": [ "rs4810424" ], "offsets": [ [ 944, 953 ] ], "normalized": [] }, { "id": "589", "type": "SNP", "text": [ "rs4810424" ], "offsets": [ [ 1037, 1046 ] ], "normalized": [] }, { "id": "590", "type": "SNP", "text": [ "rs4810424" ], "offsets": [ [ 1390, 1399 ] ], "normalized": [] }, { "id": "591", "type": "SNP", "text": [ "rs2071197" ], "offsets": [ [ 1401, 1410 ] ], "normalized": [] }, { "id": "592", "type": "SNP", "text": [ "rs3818247" ], "offsets": [ [ 1416, 1425 ] ], "normalized": [] } ]

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[ { "id": "596", "type": "title", "text": [ "Genomic characterization of five deletions in the LDL receptor gene in Danish Familial Hypercholesterolemic subjects." ], "offsets": [ [ 0, 117 ] ] }, { "id": "597", "type": "abstract", "text": [ "BACKGROUND: Familial Hypercholesterolemia is a common autosomal dominantly inherited disease that is most frequently caused by mutations in the gene encoding the receptor for low density lipoproteins (LDLR). Deletions and other major structural rearrangements of the LDLR gene account for approximately 5% of the mutations in many populations. METHODS: Five genomic deletions in the LDLR gene were characterized by amplification of mutated alleles and sequencing to identify genomic breakpoints. A diagnostic assay based on duplex PCR for the exon 7-8 deletion was developed to discriminate between heterozygotes and normals, and bioinformatic analyses were used to identify interspersed repeats flanking the deletions. RESULTS: In one case 15 bp had been inserted at the site of the deleted DNA, and, in all five cases, Alu elements flanked the sites where deletions had occurred. An assay developed to discriminate the wildtype and the deletion allele in a simple duplex PCR detected three FH patients as heterozygotes, and two individuals with normal lipid values were detected as normal homozygotes. CONCLUSION: The identification of the breakpoints should make it possible to develop specific tests for these mutations, and the data provide further evidence for the role of Alu repeats in intragenic deletions." ], "offsets": [ [ 118, 1433 ] ] } ]

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[ { "id": "600", "type": "title", "text": [ "Ectodermal dysplasia-skin fragility syndrome resulting from a new homozygous mutation, 888delC, in the desmosomal protein plakophilin 1." ], "offsets": [ [ 0, 136 ] ] }, { "id": "601", "type": "abstract", "text": [ "We report an unusual case of an inherited disorder of the desmosomal protein plakophilin 1, resulting in ectodermal dysplasia-skin fragility syndrome. The affected 6-year-old boy had red skin at birth and subsequently developed skin fragility, progressive plantar keratoderma, nail dystrophy, and alopecia. Skin biopsy revealed widening of intercellular spaces in the epidermis and a reduced number of small, poorly formed desmosomes. Mutation analysis of the plakophilin 1 gene PKP1 revealed a homozygous deletion of C at nucleotide 888 within exon 5. This mutation differs from the PKP1 gene pathology reported in 8 previously published individuals with this rare genodermatosis. However, all cases show similar clinical features, highlighting the importance of functional plakophilin 1 in maintaining desmosomal adhesion in skin, as well as the role of this protein in aspects of ectodermal development." ], "offsets": [ [ 137, 1043 ] ] } ]

[ { "id": "599", "type": "DNAMutation", "text": [ "888delC" ], "offsets": [ [ 87, 94 ] ], "normalized": [] } ]

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[ { "id": "604", "type": "title", "text": [ "Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis." ], "offsets": [ [ 0, 128 ] ] }, { "id": "605", "type": "abstract", "text": [ "BACKGROUND: Accumulative evidence suggests that low folate intake is associated with increased risk of breast cancer. Polymorphisms in genes involved in folate metabolism may influence DNA methylation, nucleotide synthesis, and thus individual susceptibility to cancer. Thymidylate synthase (TYMS) is a key enzyme that participates in folate metabolism and catalyzes the conversion of dUMP to dTMP in the process of DNA synthesis. Two potentially functional polymorphisms [a 28-bp tandem repeat in the TYMS 5'-untranslated enhanced region (TSER) and a 6-bp deletion/insertion in the TYMS 3'-untranslated region (TS 3'-UTR)] were suggested to be correlated with alteration of thymidylate synthase expression and associated with cancer risk. METHODS: To test the hypothesis that polymorphisms of the TYMS gene are associated with risk of breast cancer, we genotyped these two polymorphisms in a case-control study of 432 incident cases with invasive breast cancer and 473 cancer-free controls in a Chinese population. RESULTS: We found that the distribution of TS3'-UTR (1494del6) genotype frequencies were significantly different between the cases and controls (P = 0.026). Compared with the TS3'-UTR del6/del6 wild-type genotype, a significantly reduced risk was associated with the ins6/ins6 homozygous variant genotype (adjusted OR = 0.58, 95% CI = 0.35-0.97) but not the del6/ins6 genotype (OR = 1.09, 95% CI = 0.82-1.46). Furthermore, breast cancer risks associated with the TS3'-UTR del6/del6 genotype were more evident in older women, postmenopausal subjects, individuals with a younger age at first-live birth and individuals with an older age at menarche. However, there was no evidence for an association between the TSER polymorphism and breast cancer risks. CONCLUSION: These findings suggest that the TS3'-UTR del6 polymorphism may play a role in the etiology of breast cancer. Further larger population-based studies as well as functional evaluation of the variants are warranted to confirm our findings." ], "offsets": [ [ 129, 2146 ] ] } ]

[ { "id": "603", "type": "DNAMutation", "text": [ "1494del6" ], "offsets": [ [ 1198, 1206 ] ], "normalized": [] } ]

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[ { "id": "607", "type": "title", "text": [ "Insertion/deletion polymorphism of angiotensin converting enzyme gene in Kawasaki disease." ], "offsets": [ [ 0, 90 ] ] }, { "id": "608", "type": "abstract", "text": [ "Polymorphism of angiotensin converting enzyme (ACE) gene is reported to be associated with ischemic heart disease, hypertrophic cardiomyopathy, and idiopathic dilated cardiomyopathy. In this study, we investigated the relationship between Kawasaki disease and insertion/deletion polymorphism of ACE gene. Fifty five Kawasaki disease patients and 43 healthy children were enrolled. ACE genotype was evaluated from each of the subjects' DNA fragments through polymerase chain reaction (PCR). Frequencies of ACE genotypes (DD, ID, II) were 12.7%, 60.0%, 27.3% in Kawasaki group, and 41.9%, 30.2%, 27.9% in control group respectively, indicating low rate of DD and high rate of ID genotype among Kawasaki patients (p<0.01). Comparing allelic (I, D) frequencies, I allele was more prevalent in Kawasaki group than in control group (57.3% vs. 43.0%, p<0.05). In Kawasaki group, both genotype and allelic frequencies were not statistically different between those with coronary dilatations and those without. ACE gene I/D polymorphism is thought to be associated with Kawasaki disease but not with the development of coronary dilatations." ], "offsets": [ [ 91, 1222 ] ] } ]

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[ { "id": "616", "type": "title", "text": [ "Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment." ], "offsets": [ [ 0, 146 ] ] }, { "id": "617", "type": "abstract", "text": [ "PURPOSE: The purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment. PATIENTS AND METHODS: One hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location. RESULTS: Tumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/-6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed. CONCLUSION: Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients." ], "offsets": [ [ 147, 2001 ] ] } ]

[ { "id": "610", "type": "DNAMutation", "text": [ "1494del6" ], "offsets": [ [ 27, 35 ] ], "normalized": [] }, { "id": "611", "type": "DNAMutation", "text": [ "G > C" ], "offsets": [ [ 581, 586 ] ], "normalized": [] }, { "id": "612", "type": "DNAMutation", "text": [ "1494del6" ], "offsets": [ [ 632, 640 ] ], "normalized": [] }, { "id": "613", "type": "DNAMutation", "text": [ "G > C" ], "offsets": [ [ 1214, 1219 ] ], "normalized": [] }, { "id": "614", "type": "DNAMutation", "text": [ "1494del6" ], "offsets": [ [ 1280, 1288 ] ], "normalized": [] }, { "id": "615", "type": "DNAMutation", "text": [ "1494del6" ], "offsets": [ [ 1895, 1903 ] ], "normalized": [] } ]

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[ { "id": "623", "type": "title", "text": [ "Genetic variation in the COX-2 gene and the association with prostate cancer risk." ], "offsets": [ [ 0, 82 ] ] }, { "id": "624", "type": "abstract", "text": [ "COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The prostaglandins produced by COX-2 are involved in inflammation and pain response in different tissues in the body. Accumulating evidence from epidemiologic studies, chemical carcinogen-induced rodent models and clinical trials indicate that COX-2 plays a role in human carcinogenesis and is overexpressed in prostate cancer tissue. We examined whether sequence variants in the COX-2 gene are associated with prostate cancer risk. We analyzed a large population-based case-control study, cancer prostate in Sweden (CAPS) consisting of 1,378 cases and 782 controls. We evaluated 16 single nucleotide polymorphisms (SNPs) spanning the entire COX-2 gene in 94 subjects of the control group. Five SNPs had a minor allele frequency of more than 5% in our study population and these were genotyped in all case patients and control subjects and gene-specific haplotypes were constructed. A statistically significant difference in allele frequency between cases and controls was observed for 2 of the SNPs (+3100 T/G and +8365 C/T), with an odds ratio of 0.78 (95% CI=0.64-0.96) and 0.65 (95% CI=0.45-0.94) respectively. In the haplotype analysis, 1 haplotype carrying the variant allele from both +3100 T/G and +8365 C/T, with a population frequency of 3%, was also significantly associated with decreased risk of prostate cancer (p=0.036, global simulated p-value=0.046). This study supports the hypothesis that inflammation is involved in prostate carcinogenesis and that sequence variation within the COX-2 gene influence the risk of prostate cancer." ], "offsets": [ [ 83, 1710 ] ] } ]

[ { "id": "619", "type": "DNAMutation", "text": [ "+3100 T/G" ], "offsets": [ [ 1163, 1172 ] ], "normalized": [] }, { "id": "620", "type": "DNAMutation", "text": [ "+8365 C/T" ], "offsets": [ [ 1177, 1186 ] ], "normalized": [] }, { "id": "621", "type": "DNAMutation", "text": [ "+3100 T/G" ], "offsets": [ [ 1354, 1363 ] ], "normalized": [] }, { "id": "622", "type": "DNAMutation", "text": [ "+8365 C/T" ], "offsets": [ [ 1368, 1377 ] ], "normalized": [] } ]

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[ { "id": "637", "type": "title", "text": [ "A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes." ], "offsets": [ [ 0, 141 ] ] }, { "id": "638", "type": "abstract", "text": [ "A gain-of-function mutation resulting in the S810L amino acid substitution in the hormone-binding domain of the mineralocorticoid receptor (MR, locus symbol NR3C2) is responsible for early-onset hypertension that is exacerbated in pregnancy. The objective of this study was to test whether other types of missense mutations in the hormone-binding domain could be implicated in hypertension in Japanese. Here, we screened 942 Japanese patients with hypertension for the S810L mutation in exon 6 in the MR. We did not identify the S810L mutation in our hypertensive population, indicating that S810L does not play a major role in the etiology of essential hypertension in Japanese. However, we identified a novel missense mutation, F826Y, in three patients in a heterozygous state, in addition to four single nucleotide polymorphisms, including one synonymous mutation (L809L). The F826Y mutation is present in the MR hormone-binding domain and might affect the ligand affinity. The F826Y mutation was also identified in 13 individuals (5 hypertensives and 8 normotensives) in a Japanese general population (n=3,655). The allele frequency was 0.00178. The frequencies of the F826Y mutation in the hypertensive population (3/942) and in the hypertensive group (5/ 1,480) and the normotensive group (8/2,175) in the general population were not significantly different, suggesting that this mutation does not greatly affect hypertension. Although it is unclear at present whether or not the F826Y mutation makes a substantial contribution to the mineralocorticoid receptor activity, this missense mutation may contribute, to some extent, to clinical phenotypes through its effects on MR." ], "offsets": [ [ 142, 1824 ] ] } ]

[ { "id": "626", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 27, 32 ] ], "normalized": [] }, { "id": "627", "type": "ProteinMutation", "text": [ "S810L" ], "offsets": [ [ 187, 192 ] ], "normalized": [] }, { "id": "628", "type": "ProteinMutation", "text": [ "S810L" ], "offsets": [ [ 611, 616 ] ], "normalized": [] }, { "id": "629", "type": "ProteinMutation", "text": [ "S810L" ], "offsets": [ [ 671, 676 ] ], "normalized": [] }, { "id": "630", "type": "ProteinMutation", "text": [ "S810L" ], "offsets": [ [ 734, 739 ] ], "normalized": [] }, { "id": "631", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 872, 877 ] ], "normalized": [] }, { "id": "632", "type": "ProteinMutation", "text": [ "L809L" ], "offsets": [ [ 1010, 1015 ] ], "normalized": [] }, { "id": "633", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 1022, 1027 ] ], "normalized": [] }, { "id": "634", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 1123, 1128 ] ], "normalized": [] }, { "id": "635", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 1315, 1320 ] ], "normalized": [] }, { "id": "636", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 1628, 1633 ] ], "normalized": [] } ]

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[ { "id": "641", "type": "title", "text": [ "Genetic alterations in primary glioblastomas in Japan." ], "offsets": [ [ 0, 54 ] ] }, { "id": "642", "type": "abstract", "text": [ "Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene." ], "offsets": [ [ 55, 2078 ] ] } ]

[ { "id": "640", "type": "DNAMutation", "text": [ "codon 787 CAG/CAA" ], "offsets": [ [ 1499, 1516 ] ], "normalized": [] } ]

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[ { "id": "644", "type": "title", "text": [ "Evidence for alternative candidate genes near RB1 involved in clonal expansion of in situ urothelial neoplasia." ], "offsets": [ [ 0, 111 ] ] }, { "id": "645", "type": "abstract", "text": [ "In this paper, we present whole-organ histologic and genetic mapping studies using hypervariable DNA markers on chromosome 13 and then integrate the recombination- and single-nucleotide polymorphic sites (SNPs)-based deletion maps with the annotated genome sequence. Using bladders resected from patients with invasive urothelial carcinoma, we studied allelic patterns of 40 microsatellite markers mapping to all regions of chromosome 13 and 79 SNPs located within the 13q14 region containing the RB1 gene. A whole-organ histologic and genetic mapping strategy was used to identify the evolution of allelic losses on chromosome 13 during the progression of bladder neoplasia. Markers mapping to chromosomal regions involved in clonal expansion of preneoplastic intraurothelial lesions were subsequently tested in 25 tumors and 21 voided urine samples of patients with bladder cancer. Four clusters of allelic losses mapping to distinct regions of chromosome 13 were identified. Markers mapping to the 13q14 region that is flanked by D13S263 and D13S276, which contains the RB1 gene, showed allelic losses associated with early clonal expansion of intraurothelial neoplasia. Such losses could be identified in approximately 32% bladder tumor tissue samples and 38% of voided urines from patients with bladder cancer. The integration of distribution patterns of clonal allelic losses revealed by the microsatellite markers with those obtained by genotyping of SNPs disclosed that the loss within an approximately 4-Mb segment centered around RB1 may represent an incipient event in bladder neoplasia. However, the inactivation of RB1 occurred later and was associated with the onset of severe dysplasia/carcinoma in situ. Our studies provide evidence for the presence of critical alternative candidate genes mapping to the 13q14 region that are involved in clonal expansion of neoplasia within the bladder antecedent to the inactivation of the RB1 gene." ], "offsets": [ [ 112, 2063 ] ] } ]

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[ { "id": "647", "type": "title", "text": [ "Allele-specific amplification in cancer revealed by SNP array analysis." ], "offsets": [ [ 0, 71 ] ] }, { "id": "648", "type": "abstract", "text": [ "Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ." ], "offsets": [ [ 72, 1867 ] ] } ]

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[ { "id": "650", "type": "title", "text": [ "Tag/anti-tag liquid-phase primer extension array: a flexible and versatile genotyping platform." ], "offsets": [ [ 0, 95 ] ] }, { "id": "651", "type": "abstract", "text": [ "This study demonstrates an array-based platform to genotype simultaneously single nucleotide polymorphisms (SNPs) and some short insertions/deletions (indels) by the integration of the universal tag/anti-tag (TAT) system, liquid-phase primer extension (LIPEX), and a novel two-color detection strategy on an array format (TATLIPEXA). The TAT system permits a universal chip to be used for many applications, and the LIPEX simplifies the sample preparation but improves the sensitivity significantly. More importantly, all SNPs and some short indels can be interrogated in a single reaction with only two fluorescent ddNTPs. The concept of TATLIPEXA is demonstrated for nine SNPs (eight point mutations and one single-base insertion), and genotypes obtained show a remarkable concordance rate of 100% with both DNA sequencing and restriction fragment length polymorphism. Moreover, TATLIPEXA is able to provide quantitative information on allele frequency in pooled DNA samples, which could serve as a rapid screening tool for SNPs associated with diseases." ], "offsets": [ [ 96, 1152 ] ] } ]

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[ { "id": "653", "type": "title", "text": [ "The promoter of inducible nitric oxide synthase implicated in glaucoma based on genetic analysis and nuclear factor binding." ], "offsets": [ [ 0, 124 ] ] }, { "id": "654", "type": "abstract", "text": [ "PURPOSE: Nitric oxide has many beneficial functions in the human body at the right amounts, but it can also be hazardous if it is produced in amounts more than needed and has therefore been studied in relation to several neurological and non-neurological disorders. In vitro and in vivo studies demonstrate a connection between the inducible form of Nitric Oxide Synthase, iNOS, and the neuropathological disorder glaucoma, one of the major causes of blindness in the world. In this study, we sought to establish the genetic association between iNOS and primary open angle glaucoma, POAG, and to find the functional element(s) connected with the pathogenesis of the disease. METHODS: Two microsatellites, 1 insertion/deletion, and 8 single nucleotide polymorphisms (SNPs) in the regulatory region of iNOS were genotyped in 200 POAG patients and 200 age-matched controls. Also, the CCTTT-microsatellite was examined for its protein-binding capability in an electrophoretic mobility shift assay, EMSA. RESULTS: There was a significant difference in allele distribution of the CCTTT-microsatellite, between patients and controls. (CCTTT)14, which has been reported to have a higher activity in a reporter-construct, was significantly more abundant in POAG patients, while (CCTTT)10 and (CCTTT)13 were less common. In EMSA, the (CCTTT)14 allele exhibited specific binding of nuclear proteins. CONCLUSIONS: These results, together with other studies on this gene and the CCTTT-microsatellite, establish, for the first time, a genetic association of iNOS with POAG and suggest a regulatory function for the microsatellite." ], "offsets": [ [ 125, 1741 ] ] } ]

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[ { "id": "660", "type": "title", "text": [ "Genetic homogeneity for inherited congenital microcoria loci in an Asian Indian pedigree." ], "offsets": [ [ 0, 89 ] ] }, { "id": "661", "type": "abstract", "text": [ "PURPOSE: Congenital microcoria is a rare autosomal dominant developmental disorder of the iris associated with myopia and juvenile open angle glaucoma. Linkage to the chromosomal locus 13q31-q32 has previously been reported in a large French family. In the current study, a three generation Asian Indian family with 15 congenital microcoria (pupils with a diameter <2 mm) affected members was studied for linkage to candidate microsatellite markers at the 13q31-q32 locus. METHODS: Twenty-four members of the family were clinically examined and genomic DNA was extracted. Microsatellite markers at 13q31-q32 were PCR amplified and run on an ABI Prism 310 genetic analyzer and genotyped with the GeneScan analysis. Two point and multipoint linkage analyses were performed using the MLINK and SUPERLINK programs. RESULTS: Peak two point LOD scores of 3.5, 4.7, and 5.3 were found co-incident with consecutive markers D13S154, DCT, and D13S1280. Multipoint analysis revealed a 4 cM region encompassing D13S1300 to D13S1280 where the LOD remains just over 6.0 Thus we confirm localization of the congenital microcoria locus to chromosomal locus 13q31-q32. In addition, eight individuals who had both microcoria and glaucoma were screened for glaucoma genes: myocilin (MYOC), optineurin (OPTN) and CYP1B1. Using direct sequencing a point mutation (144 G>A) resulting in a Q48H substitution in exon 1 of the MYOC gene was observed in five of the eight glaucoma patients, but not in unaffected family members and 100 unrelated controls. CONCLUSIONS: We have confirmed the localization of the congenital microcoria locus (MCOR) to 13q31-q32 in a large Asian Indian family and conclude that current information suggests this is a single locus disorder and genetically homogeneous. When combined with the initial linkage paper our haplotype and linkage data map the MCOR locus to a 6-7 cM region between D13S265 and D13S1280. The DCT locus, a member of the tyrosinase family involved in pigmentation, maps within this region. Data presented here supports the hypothesis that congenital microcoria is a potential risk factor for glaucoma, although this observation is complicated by the partial segregation of MYOC Q48H (1q24.3-q25.2), a mutation known to be associated with glaucoma in India. Fine mapping and candidate gene analysis continues with the hope that characterizing the micocoria gene will lead to a better understanding of microcoria and glaucoma causation. The relationship between microcoria, glaucoma, and the MYOC Q48H mutation in this family is discussed." ], "offsets": [ [ 90, 2653 ] ] } ]

[ { "id": "656", "type": "DNAMutation", "text": [ "144 G>A" ], "offsets": [ [ 1433, 1440 ] ], "normalized": [] }, { "id": "657", "type": "ProteinMutation", "text": [ "Q48H" ], "offsets": [ [ 1457, 1461 ] ], "normalized": [] }, { "id": "658", "type": "ProteinMutation", "text": [ "Q48H" ], "offsets": [ [ 2294, 2298 ] ], "normalized": [] }, { "id": "659", "type": "ProteinMutation", "text": [ "Q48H" ], "offsets": [ [ 2611, 2615 ] ], "normalized": [] } ]

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[ { "id": "670", "type": "title", "text": [ "Segregation of a M404V mutation of the p62/sequestosome 1 (p62/SQSTM1) gene with polyostotic Paget's disease of bone in an Italian family." ], "offsets": [ [ 0, 138 ] ] }, { "id": "671", "type": "abstract", "text": [ "Mutations of the p62/Sequestosome 1 gene (p62/SQSTM1) account for both sporadic and familial forms of Paget's disease of bone (PDB). We originally described a methionine-->valine substitution at codon 404 (M404V) of exon 8, in the ubiquitin protein-binding domain of p62/SQSTM1 gene in an Italian PDB patient. The collection of data from the patient's pedigree provided evidence for a familial form of PDB. Extension of the genetic analysis to other relatives in this family demonstrated segregation of the M404V mutation with the polyostotic PDB phenotype and provided the identification of six asymptomatic gene carriers. DNA for mutational analysis of the exon 8 coding sequence was obtained from 22 subjects, 4 PDB patients and 18 clinically unaffected members. Of the five clinically ascertained affected members of the family, four possessed the M404V mutation and exhibited the polyostotic form of PDB, except one patient with a single X-ray-assessed skeletal localization and one with a polyostotic disease who had died several years before the DNA analysis. By both reconstitution and mutational analysis of the pedigree, six unaffected subjects were shown to bear the M404V mutation, representing potential asymptomatic gene carriers whose circulating levels of alkaline phosphatase were recently assessed as still within the normal range. Taken together, these results support a genotype-phenotype correlation between the M404V mutation in the p62/SQSTM1 gene and a polyostotic form of PDB in this family. The high penetrance of the PDB trait in this family together with the study of the asymptomatic gene carriers will allow us to confirm the proposed genotype-phenotype correlation and to evaluate the potential use of mutational analysis of the p62/SQSTM1 gene in the early detection of relatives at risk for PDB." ], "offsets": [ [ 139, 1967 ] ] } ]

[ { "id": "663", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 17, 22 ] ], "normalized": [] }, { "id": "664", "type": "ProteinMutation", "text": [ "methionine-->valine substitution at codon 404" ], "offsets": [ [ 298, 343 ] ], "normalized": [] }, { "id": "665", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 345, 350 ] ], "normalized": [] }, { "id": "666", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 646, 651 ] ], "normalized": [] }, { "id": "667", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 991, 996 ] ], "normalized": [] }, { "id": "668", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 1317, 1322 ] ], "normalized": [] }, { "id": "669", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 1572, 1577 ] ], "normalized": [] } ]

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[ { "id": "676", "type": "title", "text": [ "HPRTSardinia: a new point mutation causing HPRT deficiency without Lesch-Nyhan disease." ], "offsets": [ [ 0, 87 ] ] }, { "id": "677", "type": "abstract", "text": [ "Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency always causing hyperuricemia presents various degrees of neurological manifestations, the most severe which is Lesch-Nyhan syndrome. The HPRT gene is situated in the region Xq26-q27.2 and consists of 9 exons. At least 300 different mutations at different sites in the HPRT coding region from exon 1 to exon 9 have been identified. A new mutation in the HPRT gene has been determined in one patient with complete deficiency of erythrocyte activity, with hyperuricemia and gout but without Lesch-Nyhan disease. Analysis of cultured fibroblasts revealed minimal residual HPRT activity mainly when guanine was the substrate. Genomic DNA sequencing demonstrated patient's mother heterozygosity for the mutation and no mutation in her brother. The mutation consists in a C-->T transversion at cDNA base 463 (C463T) in exon 6, resulting in proline to serine substitution at codon 155 (P155S). This mutation had not been reported previously and has been designated HPRT(Sardinia). The mutation identified in this patient allows some expression of functional enzyme in nucleated cells such as fibroblasts, indicating that such cell type may add further information to conventional blood analysis. A multicentre survey gathering patients with variant neurological forms could contribute to understand the pathophysiology of the neurobehavioral symptoms of HPRT deficiency." ], "offsets": [ [ 88, 1515 ] ] } ]

[ { "id": "673", "type": "DNAMutation", "text": [ "C-->T transversion at cDNA base 463" ], "offsets": [ [ 918, 953 ] ], "normalized": [] }, { "id": "674", "type": "DNAMutation", "text": [ "C463T" ], "offsets": [ [ 955, 960 ] ], "normalized": [] }, { "id": "675", "type": "ProteinMutation", "text": [ "P155S" ], "offsets": [ [ 1031, 1036 ] ], "normalized": [] } ]

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[ { "id": "689", "type": "title", "text": [ "Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians." ], "offsets": [ [ 0, 102 ] ] }, { "id": "690", "type": "abstract", "text": [ "AIMS/HYPOTHESIS: Uncoupling protein-2 (UCP2) is thought to play a role in insulin secretion and the development of obesity. In this study, we investigated the effects of genetic variation in UCP2 on type 2 diabetes and obesity, as well as on metabolic phenotypes related to these diseases, in Pima Indians. METHODS: The coding and untranslated regions of UCP2, and approximately 1 kb of the 5' upstream region, were sequenced in DNA samples taken from 83 extremely obese Pima Indians who were not first-degree relatives. RESULTS: Five variants were identified: (1) a -866G/A in the 5' upstream region; (2) a G/A in exon 2; (3) a C/T resulting in an Ala55Val substitution in exon 4; and (4, 5) two insertion/deletions (ins/del; 45-bp and 3-bp) in the 3' untranslated region. Among the 83 subjects whose DNA was sequenced, the -866G/A was in complete genotypic concordance with the Ala55Val and the 3-bp ins/del polymorphism. The G/A polymorphism in exon 2 was extremely rare. To capture the common variation in this gene for association analyses, the -866G/A variant (as a representative of Ala55Val and the 3-bp ins/del polymorphism) and the 45-bp ins/del were also genotyped for 864 full-blooded Pima Indians. Neither of these variants was associated with type 2 diabetes or body mass index. However, in a subgroup of 185 subjects who had undergone detailed metabolic measurements, these variants were associated with 24-h energy expenditure as measured in a human metabolic chamber (p=0.007 for the 45-bp ins/del and p=0.03 for the -866G/A after adjusting for age, sex, family membership, fat-free mass and fat mass). CONCLUSIONS/INTERPRETATION: Our data indicate that variation in UCP2 may play a role in energy metabolism, but this gene does not contribute significantly to the aetiology of type 2 diabetes and/or obesity in Pima Indians." ], "offsets": [ [ 103, 1945 ] ] } ]

[ { "id": "679", "type": "DNAMutation", "text": [ "-866G/A" ], "offsets": [ [ 670, 677 ] ], "normalized": [] }, { "id": "680", "type": "DNAMutation", "text": [ "G/A" ], "offsets": [ [ 711, 714 ] ], "normalized": [] }, { "id": "681", "type": "DNAMutation", "text": [ "C/T" ], "offsets": [ [ 732, 735 ] ], "normalized": [] }, { "id": "682", "type": "ProteinMutation", "text": [ "Ala55Val" ], "offsets": [ [ 752, 760 ] ], "normalized": [] }, { "id": "683", "type": "DNAMutation", "text": [ "-866G/A" ], "offsets": [ [ 928, 935 ] ], "normalized": [] }, { "id": "684", "type": "ProteinMutation", "text": [ "Ala55Val" ], "offsets": [ [ 983, 991 ] ], "normalized": [] }, { "id": "685", "type": "DNAMutation", "text": [ "G/A" ], "offsets": [ [ 1031, 1034 ] ], "normalized": [] }, { "id": "686", "type": "DNAMutation", "text": [ "-866G/A" ], "offsets": [ [ 1153, 1160 ] ], "normalized": [] }, { "id": "687", "type": "ProteinMutation", "text": [ "Ala55Val" ], "offsets": [ [ 1193, 1201 ] ], "normalized": [] }, { "id": "688", "type": "DNAMutation", "text": [ "-866G/A" ], "offsets": [ [ 1637, 1644 ] ], "normalized": [] } ]

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[ { "id": "692", "type": "title", "text": [ "Association of atopy and eczema with polymorphisms in T-cell immunoglobulin domain and mucin domain-IL-2-inducible T-cell kinase gene cluster in chromosome 5 q 33." ], "offsets": [ [ 0, 163 ] ] }, { "id": "693", "type": "abstract", "text": [ "BACKGROUND: The T-cell immunoglobulin domain and mucin domain (TIM) gene family and the gene for IL-2-inducible T-cell kinase (ITK), located in chromosome 5 q 33 and potentially involved in the T-cell proliferation and differentiation, are good candidate genes for allergic diseases. OBJECTIVE: We assessed the role of polymorphisms in the TIM family genes and ITK in atopy, eczema, and asthma. METHODS: Twenty-one polymorphisms in the TIM-ITK gene cluster were genotyped in 564 children enrolled in the Tucson Children's Respiratory Study. Skin prick tests to common allergens were performed at age 6.1 years (n=508), age 10.8 years (n=539), and age 16.6 years (n=424). Asthma and eczema were assessed by questionnaire at these 3 points. Averaged relative risks were estimated. RESULTS: One 15-bp insertion/deletion in exon 4 of TIM 1 was significantly related to atopy and eczema (relative risk associated with carrying at least 1 rare allele=1.24 [1.07--1.45], P=.005; and 1.43 [1.01--2.01], P=.004, respectively). The 3 tested single nucleotide polymorphisms (SNPs) in TIM 3 were significantly related to atopy and eczema. One of them, at position +4259 calculated from the translation start site, predicts a putative change in the amino acid sequence of the protein, and was the most strongly related to atopy (relative risk=1.28 [1.12--1.47]; P=.0003). SNPs in the 5' genomic region in ITK, which show moderate linkage disequilibrium with those in TIM 3, had an independent effect on atopy. None of the polymorphisms studied was related to asthma. CONCLUSION: Our findings support a potential role for SNPs in TIM 1, TIM 3, and ITK, independent of each other, in allergic diseases." ], "offsets": [ [ 164, 1851 ] ] } ]

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[ { "id": "703", "type": "title", "text": [ "Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies." ], "offsets": [ [ 0, 136 ] ] }, { "id": "704", "type": "abstract", "text": [ "Nijmegen breakage syndrome (NBS) is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition, in particular to lymphoma and leukemia. Recently, significantly higher frequencies of heterozygous carriers of the Slavic founder NBS1 mutation, 657del5, were found in Russian children with sporadic lymphoid malignancies, and in Polish adults with non-Hodgkin lymphoma (NHL). In addition, the substitution 643C>T (R215W) has also been found in excess among children with acute lymphoblastic leukemia (ALL). In an attempt to asses the contribution of both mutations to the development of sporadic lymphoid malignancies, we analyzed DNA samples from a large group of Polish pediatric patients. The NBS1 mutation 657del5 on one allele was found in 3 of 270 patients with ALL and 2 of 212 children and adolescents with NHL; no carrier was found among 63 patients with Hodgkin lymphoma (HL). No carriers of the variant R215W were detected in any studied group. The relative frequency of the 657del5 mutation was calculated from a total of 6,984 controls matched by place of patient residence, of whom 42 were found to be carriers (frequency = 0.006). In the analyzed population with malignancies, an increased odds ratio for the occurrence of mutation 657del5 was found in comparison with the control Polish population (OR range 1.48-1.85, 95% confidence interval 1.18-2.65). This finding indicates that the frequency of the mutation carriers was indeed increased in patients with ALL and NHL (p < 0.05). Nonetheless, NBS1 gene heterozygosity is not a major risk factor for lymphoid malignancies in childhood and adolescence." ], "offsets": [ [ 137, 1802 ] ] } ]

[ { "id": "695", "type": "DNAMutation", "text": [ "657del5" ], "offsets": [ [ 30, 37 ] ], "normalized": [] }, { "id": "696", "type": "DNAMutation", "text": [ "657del5" ], "offsets": [ [ 427, 434 ] ], "normalized": [] }, { "id": "697", "type": "DNAMutation", "text": [ "643C>T" ], "offsets": [ [ 588, 594 ] ], "normalized": [] }, { "id": "698", "type": "ProteinMutation", "text": [ "R215W" ], "offsets": [ [ 596, 601 ] ], "normalized": [] }, { "id": "699", "type": "DNAMutation", "text": [ "657del5" ], "offsets": [ [ 892, 899 ] ], "normalized": [] }, { "id": "700", "type": "ProteinMutation", "text": [ "R215W" ], "offsets": [ [ 1096, 1101 ] ], "normalized": [] }, { "id": "701", "type": "DNAMutation", "text": [ "657del5" ], "offsets": [ [ 1168, 1175 ] ], "normalized": [] }, { "id": "702", "type": "DNAMutation", "text": [ "657del5" ], "offsets": [ [ 1429, 1436 ] ], "normalized": [] } ]

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[ { "id": "706", "type": "title", "text": [ "Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy." ], "offsets": [ [ 0, 83 ] ] }, { "id": "707", "type": "abstract", "text": [ "In this study, we characterized five Ullrich scleroatonic muscular dystrophy patients (two Italians, one Belgian, and two Turks) with a clinical phenotype showing different degrees of severity, all carrying mutations localized in COL6A1. We sequenced the three entire COL6 complementary DNA. Three of five patients have recessive mutations: two patients (P1and P3) have homozygous single-nucleotide deletions, one in exon 9 and one in exon 22; one patient (P2) has a homozygous single-nucleotide substitution leading to a premature termination codon in exon 31. The nonsense mutation of P2 also causes a partial skipping of exon 31 with the formation of a premature termination codon in exon 32 in 15% of the total COL6A1 messenger RNA. The remaining two patients carry a heterozygous glycine substitution in exons 9 and 10 inside the triple-helix region; both are dominant mutations because the missense mutations are absent in the DNA of their respective parents. As for the three homozygous recessive mutations, the apparently healthy consanguineous parents all carry a heterozygous mutated allele. Here, for the first time, we report a genotype-phenotype correlation demonstrating that heterozygous glycine substitutions in the triple-helix domain of COL6A1 are dominant and responsible for a milder Ullrich scleroatonic muscular dystrophy phenotype, and that recessive mutations in COL6A1 correlate with more severe clinical and biochemical Ullrich scleroatonic muscular dystrophy phenotypes." ], "offsets": [ [ 84, 1581 ] ] } ]

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[ { "id": "713", "type": "title", "text": [ "A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference." ], "offsets": [ [ 0, 119 ] ] }, { "id": "714", "type": "abstract", "text": [ "The PERIOD2 (PER2) gene is a key component of the molecular mechanism that generates circadian rhythms in mammals. A missense mutation in the human PER2 gene has previously been linked to advanced sleep phase syndrome (ASPS). We have investigated three other single-nucleotide polymorphisms in the hPER2 gene, one downstream of the transcription start site (C-1228T), one in exon 2 in the 5'-untranslated region (5'-UTR) (C111G), and one missense mutation (G3853A) causing a glycine to glutamine substitution in the predicted protein. Subjects selected from a group of 484 volunteers for extreme morning or evening preference, or intermediate diurnal preference were genotyped with regard to the three polymorphisms (n=35 for each group). Whereas allele frequencies for the other two polymorphisms did not differ significantly between any of the groups, the 111G allele frequency was significantly higher in subjects with extreme morning preference (0.14) than in subjects with extreme evening preference (0.03) (Fisher's exact test, two-sided P value=0.031, odds ratio=5.67). No significant difference in 111G allele frequency was observed between either of these groups and subjects with intermediate diurnal preference. Computer prediction indicated that the C111G polymorphism, which occurs 12 bases upstream from the translation start codon, might alter the secondary structure of the transcript. The PER2 111G allele associates with morning preference and is a potential candidate allele for ASPS." ], "offsets": [ [ 120, 1623 ] ] } ]

[ { "id": "709", "type": "DNAMutation", "text": [ "C-1228T" ], "offsets": [ [ 478, 485 ] ], "normalized": [] }, { "id": "710", "type": "DNAMutation", "text": [ "C111G" ], "offsets": [ [ 542, 547 ] ], "normalized": [] }, { "id": "711", "type": "DNAMutation", "text": [ "G3853A" ], "offsets": [ [ 577, 583 ] ], "normalized": [] }, { "id": "712", "type": "DNAMutation", "text": [ "C111G" ], "offsets": [ [ 1382, 1387 ] ], "normalized": [] } ]

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[ { "id": "720", "type": "title", "text": [ "Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G." ], "offsets": [ [ 0, 89 ] ] }, { "id": "721", "type": "abstract", "text": [ "As a primary target for opioid drugs and peptides, the mu opioid receptor (OPRM1) plays a key role in pain perception and addiction. Genetic variants of OPRM1 have been implicated in predisposition to drug addiction, in particular the single nucleotide polymorphism A118G, leading to an N40D substitution, with an allele frequency of 10-32%, and uncertain functions. We have measured allele-specific mRNA expression of OPRM1 in human autopsy brain tissues, using A118G as a marker. In 8 heterozygous samples measured, the A118 mRNA allele was 1.5-2.5-fold more abundant than the G118 allele. Transfection into Chinese hamster ovary cells of a cDNA representing only the coding region of OPRM1, carrying adenosine, guanosine, cytidine, and thymidine in position 118, resulted in 1.5-fold lower mRNA levels only for OPRM1-G118, and more than 10-fold lower OPRM1 protein levels, measured by Western blotting and receptor binding assay. After transfection and inhibition of transcription with actinomycin D, analysis of mRNA turnover failed to reveal differences in mRNA stability between A118 and G118 alleles, indicating a defect in transcription or mRNA maturation. These results indicate that OPRM1-G118 is a functional variant with deleterious effects on both mRNA and protein yield. Clarifying the functional relevance of polymorphisms associated with susceptibility to a complex disorder such as drug addiction provides a foundation for clinical association studies." ], "offsets": [ [ 90, 1559 ] ] } ]

[ { "id": "716", "type": "DNAMutation", "text": [ "A118G" ], "offsets": [ [ 83, 88 ] ], "normalized": [] }, { "id": "717", "type": "DNAMutation", "text": [ "A118G" ], "offsets": [ [ 356, 361 ] ], "normalized": [] }, { "id": "718", "type": "ProteinMutation", "text": [ "N40D" ], "offsets": [ [ 377, 381 ] ], "normalized": [] }, { "id": "719", "type": "DNAMutation", "text": [ "A118G" ], "offsets": [ [ 553, 558 ] ], "normalized": [] } ]

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[ { "id": "725", "type": "title", "text": [ "Identification of a novel WFS1 mutation (AFF344-345ins) in Japanese patients with Wolfram syndrome." ], "offsets": [ [ 0, 99 ] ] }, { "id": "726", "type": "abstract", "text": [ "Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS." ], "offsets": [ [ 100, 909 ] ] } ]

[ { "id": "723", "type": "ProteinMutation", "text": [ "AFF344-345ins" ], "offsets": [ [ 41, 54 ] ], "normalized": [] }, { "id": "724", "type": "ProteinMutation", "text": [ "AFF344-345ins" ], "offsets": [ [ 649, 662 ] ], "normalized": [] } ]

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[ { "id": "728", "type": "title", "text": [ "Loss of heterozygosity and transcriptome analyses of a 1.2 Mb candidate ovarian cancer tumor suppressor locus region at 17q25.1-q25.2." ], "offsets": [ [ 0, 134 ] ] }, { "id": "729", "type": "abstract", "text": [ "Loss of heterozygosity (LOH) analysis was performed in epithelial ovarian cancers (EOC) to further characterize a previously identified candidate tumor suppressor gene (TSG) region encompassing D17S801 at chromosomal region 17q25.1. LOH of at least one informative marker was observed for 100 (71%) of 140 malignant EOC samples in an analysis of 6 polymorphic markers (cen-D17S1839-D17S785-D17S1817-D17S801-D17S751-D17S722-tel). The combined LOH analysis revealed a 453 kilobase (Kb) minimal region of deletion (MRD) bounded by D17S1817 and D17S751. Human and mouse genome assemblies were used to resolve marker inconsistencies in the D17S1839-D17S722 interval and identify candidates. The region contains 32 known and strongly predicted genes, 9 of which overlap the MRD. The reference genomic sequences share nearly identical gene structures and the organization of the region is highly collinear. Although, the region does not show any large internal duplications, a 1.5 Kb inverted duplicated sequence of 87% nucleotide identity was observed in a 13 Kb region surrounding D17S801. Transcriptome analysis by Affymetrix GeneChip and reverse transcription (RT)-polymerase chain reaction (PCR) methods of 3 well characterized EOC cell lines and primary cultures of normal ovarian surface epithelial (NOSE) cells was performed with 32 candidates spanning D17S1839-D17S722 interval. RT-PCR analysis of 8 known or strongly predicted genes residing in the MRD in 10 EOC samples, that exhibited LOH of the MRD, identified FLJ22341 as a strong candidate TSG. The proximal repeat sequence of D17S801 occurs 8 Kb upstream of the putative promoter region of FLJ22341. RT-PCR analysis of the EOC samples and cell lines identified DKFZP434P0316 that maps proximal to the MRD, as a candidate. While Affymetrix technology was useful for initially eliminating less promising candidates, subsequent RT-PCR analysis of well-characterized EOC samples was essential to prioritize TSG candidates for further study." ], "offsets": [ [ 135, 2130 ] ] } ]

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[ { "id": "731", "type": "title", "text": [ "Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6." ], "offsets": [ [ 0, 113 ] ] }, { "id": "732", "type": "abstract", "text": [ "Williams-Beuren syndrome (WBS) is a neurodevelopmental microdeletion disorder that usually occurs sporadically due to its location within a highly repetitive genomic region that is unstable and prone to unequal cross-over during meiosis. The consequential loss of chromosomal material includes approximately 1.5 Mb of DNA at 7q11.23. Whilst cases of dominant inheritance have been described in the literature, there have been few reports of molecular confirmation and none have carried out detailed genotyping. We describe a Bulgarian father and son with WBS detected by fluorescent in situ hybridisation (with an elastin gene probe) and loss of heterozygosity mapping using microsatellite markers located in the critical region. These individuals appear to have a common WBS heterozygous deletion, confirming the expected dominant transmission and adding to the few familial cases reported. The deletion includes the gene FKBP6 which has recently been shown to play a role in homologous chromosome pairing in meiosis and male fertility in mouse models. Homozygous Fkbp6 -/- male mice are infertile and our data suggests that haploinsufficiency for FKBP6 does not appear to preclude male fertility in WBS, although male infertility involving this gene has the potential to follow the mouse model as a human autosomal recessive condition." ], "offsets": [ [ 114, 1451 ] ] } ]

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[ { "id": "737", "type": "title", "text": [ "Hb zoeterwoude [beta23(B5)Val-->Ala)]: a new beta-globin variant found in association with erythrocytosis." ], "offsets": [ [ 0, 106 ] ] }, { "id": "738", "type": "abstract", "text": [ "We describe the characterization of a new hemoglobin (Hb) variant found in a 77-year-old Dutch woman, suspected of hypoxia-mediated erythrocytosis. The typical blood parameters (Hb 17.3 g/dL; PCV 0.525 L/L; RBC 5.82 x 10(12)/L) could not be explained by any of the pathological or physiological conditions causing erythrocytosis. The patient was preventively phlebotomized because of intermittent claudication and erythrocytosis. At the hematological and biochemical levels, no anemia or hemolysis were present and no abnormal Hb fractions were detectable on alkaline electrophoresis or high performance liquid chromatography (HPLC). Molecular analysis revealed intact alpha-globin genes and a heterozygosity for a GTT-->GCT transition at codon 23 of the beta-globin gene, causing a Val-->Ala amino acid substitution. The P50 measured in full blood indicated that this mutant has an elevated oxygen affinity. This is the fourth single nucleotide substitution at codon 23 of the beta gene and the second associated with erythrocytosis. Because the family was not available for investigation no information was obtained as to whether the mutation represents a de novo event or was inherited, and might be a more common cause of erythrocytosis in Dutch patients. Considering the relatively high frequency of beta-thalassemia (thal) in the large allochthonous population in The Netherlands, combinations of Hb Zoeterwoude and beta-thal traits may lead to hemizygosity, with severe hypoxia and erythrocytosis from a few months after birth." ], "offsets": [ [ 107, 1641 ] ] } ]

[ { "id": "734", "type": "ProteinMutation", "text": [ "Val-->Ala" ], "offsets": [ [ 26, 35 ] ], "normalized": [] }, { "id": "735", "type": "DNAMutation", "text": [ "GTT-->GCT transition at codon 23" ], "offsets": [ [ 822, 854 ] ], "normalized": [] }, { "id": "736", "type": "ProteinMutation", "text": [ "Val-->Ala" ], "offsets": [ [ 890, 899 ] ], "normalized": [] } ]

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[ { "id": "740", "type": "title", "text": [ "[Angiotensin converting enzyme gene polymorphisms and coronary risk in a Portuguese population]." ], "offsets": [ [ 0, 96 ] ] }, { "id": "741", "type": "abstract", "text": [ "BACKGROUND: A family history of coronary heart disease (CHD) is a strong risk marker for the disease, independently of classical risk factors. It could be decoded by recognizing the polymorphisms associated with increased risk. Renin-angiotensin system genes are candidate genes in CHD and the deletion allele of the angiotensin converting enzyme (ACE) has been reported as deleterious. However, there is disagreement as to the role of the insertion/deletion polymorphism of the ACE gene in coronary risk. AIM: To evaluate whether ACE gene polymorphisms constitute a CHD risk factor. METHODS: We conducted a population-based case-control study of 301 subjects with a history of myocardial infarction or angiographic evidence of coronary heart disease and 510 age- and gender-matched controls, without CHD, living in a region with high CHD mortality rates. Blood samples were taken, DNA extracted and genotypes determined by the polymerase chain reaction (PCR). Amplification products were identified by agarose gel electrophoresis. STATISTICAL ANALYSIS: The Data were evaluated by SPSS for Windows, using the Student's t test, the chi-square test, odds ratios and 95% confidence intervals. RESULTS: The prevalence of the DD, ID and II genotype was 41.2%, 46.3%, 12.5% in the cases and 28.1%, 55.2% and 16.7% in the control group. The frequency of the DD genotype was significantly higher in the cases than in the controls (41.2% vs. 28.1%, odds ratio 1.79, 95% CI 1.31 to 2.4, p < 0.0001). By contrast, the ID and II genotypes' prevalence was higher in the control group (55.2% vs. 46.3%, p = 0.002 and 16.7 vs. 12.5%, p = NS, respectively) compared to the case group. CONCLUSIONS: This study clearly shows that the ACE DD polymorphism is strongly linked to CHD, and if our data are confirmed in a larger population sample, more aggressive vascular prevention could be justified in patients carrying the DD genotype." ], "offsets": [ [ 97, 2013 ] ] } ]

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[ { "id": "747", "type": "title", "text": [ "DNA repair gene polymorphisms in relation to chromosome aberration frequencies in retired radiation workers." ], "offsets": [ [ 0, 108 ] ] }, { "id": "748", "type": "abstract", "text": [ "Polymorphic variation in DNA repair genes was examined in a group of retired workers from the British Nuclear Fuels plc facility at Sellafield in relation to previously determined translocation frequencies in peripheral blood lymphocytes. Variation at seven polymorphisms in four genes involved in the base excision repair (XRCC1 R194W, R399Q and a [AC]n microsatellite in the 3' UTR) and double strand break repair (XRCC3 T241M and a [AC]n microsatellite in intron 3 of XRCC3, XRCC4 I134T, and a GACTAn microsatellite located 120 kb 5' of XRCC5) pathways was determined for 291 retired radiation workers who had received cumulative occupational external radiation doses of between 0 and 1873 mSv. When the interaction between radiation dose and each DNA repair gene polymorphism was examined in relation to translocation frequency there was no evidence for any of the polymorphisms studied influencing the response to occupational exposure. A positive interaction observed between genotype (individuals with at least one allele > or =20 repeat units) at a microsatellite locus in the XRCC3 gene and smoking status should be interpreted cautiously because interactions were investigated for seven polymorphisms and two exposures. Nonetheless, further research is warranted to examine whether this DNA repair gene variant might be associated with a sub-optimal repair response to smoking-induced DNA damage and hence an increased frequency of translocations." ], "offsets": [ [ 109, 1566 ] ] } ]

[ { "id": "743", "type": "ProteinMutation", "text": [ "R194W" ], "offsets": [ [ 439, 444 ] ], "normalized": [] }, { "id": "744", "type": "ProteinMutation", "text": [ "R399Q" ], "offsets": [ [ 446, 451 ] ], "normalized": [] }, { "id": "745", "type": "ProteinMutation", "text": [ "T241M" ], "offsets": [ [ 532, 537 ] ], "normalized": [] }, { "id": "746", "type": "ProteinMutation", "text": [ "I134T" ], "offsets": [ [ 593, 598 ] ], "normalized": [] } ]

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[ { "id": "751", "type": "title", "text": [ "Primary malignant lymphoma of the brain: frequent abnormalities and inactivation of p14 tumor suppressor gene." ], "offsets": [ [ 0, 110 ] ] }, { "id": "752", "type": "abstract", "text": [ "Ten primary central nervous system lymphomas (PCNSL, brain lymphomas) were examined for p14 gene exon 1beta deletion, mutation and methylation by Southern blot analysis, nucleotide analysis of polymerase chain reaction clones and Southern blot-based methylation assay. In Southern blot analysis, from the signal densities of the hybridized bands and their similarities to those of exons 2 and 3 in our previous quantitative study, we found that exon 1beta was homozygously deleted in four cases, hemizygously deleted in five cases and not deleted in one case. Thus, the same deletion patterns covered the entire p14 gene for all cases except for one case, which suggested the hemizygous deletion of exons 1beta and 2 and homozygous deletion of exon 3. In addition, although exon 1beta mutation is rare in various tumors, we detected a missense mutation (L50R) in one case with a hemizygous deletion. Methylation of the 5'CpG island of the p14 gene was not suggested for any case without homozygous deletion. Our observation of frequent p14 gene abnormalities (90%) and inactivation (40-60%) was in striking contrast to the same pathological subtype of systemic lymphoma in which p14 gene abnormalities and inactivation were infrequent, suggesting a difference in carcinogenesis between PCNSL and systemic lymphoma." ], "offsets": [ [ 111, 1425 ] ] } ]

[ { "id": "750", "type": "ProteinMutation", "text": [ "L50R" ], "offsets": [ [ 965, 969 ] ], "normalized": [] } ]

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[ { "id": "756", "type": "title", "text": [ "Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome." ], "offsets": [ [ 0, 167 ] ] }, { "id": "757", "type": "abstract", "text": [ "Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder due to quantitative or qualitative abnormalities in the platelet glycoprotein (GP) Ib/IX/V complex, the major von Willebrand factor receptor. The complex comprises four subunits, each encoded by a separate gene. Several mutations have been described for each of the subunits, except for GPV, as a cause of BSS. We describe here the genetic basis of the disorder in a child with BSS. Flow-cytometric analysis of the patient's platelets showed a markedly reduced surface expression of all three glycoproteins of the GPIb/IX/V complex. DNA sequencing analysis showed the patient to be a compound heterozygote for two mutations in the GPIX gene, a novel nine-nucleotide deletion starting at position 1952 of the gene that changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline) and a previously reported point mutation that changes the codon asparagine (AAC) for serine (AGC) at residue 45. Her mother was heterozygous for the Asn45Ser mutation, and her father, for the nine-nucleotide deletion. Our findings suggest that the additive effects of both mutations in the GPIX gene are responsible for the BSS phenotype of the patient." ], "offsets": [ [ 168, 1419 ] ] } ]

[ { "id": "754", "type": "ProteinMutation", "text": [ "Asn45Ser" ], "offsets": [ [ 69, 77 ] ], "normalized": [] }, { "id": "755", "type": "ProteinMutation", "text": [ "Asn45Ser" ], "offsets": [ [ 1215, 1223 ] ], "normalized": [] } ]

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[ { "id": "759", "type": "title", "text": [ "Leydig cell hypoplasia due to inactivation of luteinizing hormone receptor by a novel homozygous nonsense truncation mutation in the seventh transmembrane domain." ], "offsets": [ [ 0, 162 ] ] }, { "id": "760", "type": "abstract", "text": [ "Inactivating mutations in the LH receptor are the predominant cause for male pseudohermaphroditism in subjects with Leydig cell hypoplasia (LCH). The severity of the mutations, correlates with residual receptor activities. Here, we detail the clinical presentation of one subject with complete male pseudohermaphroditism and LCH. We identify within the proband and her similarly afflicted sibling a homozygous T to G transversion at nucleotide 1836 in exon 11 of the LH/CGR gene. This causes conversion of a tyrosine codon into a stop codon at codon 612 in the seventh transmembrane domain, resulting in a truncated receptor that lacks a cytoplasmic tail. In vitro, in contrast to cells expressing a normal LHR, cells transfected with the mutant cDNA exhibit neither surface binding of radiolabeled hCG nor cAMP generation. In vitro expression under the control of the LHR signal peptide of either a wild type or mutant LHR-GFP fusion protein shows no differences in receptor cellular localization. In conclusion, the in vitro studies suggest that residues in the seventh transmembrane domain and cytoplasmic tail are important for receptor binding and activation without playing a major role in receptor cellular trafficking." ], "offsets": [ [ 163, 1389 ] ] } ]

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[ { "id": "764", "type": "title", "text": [ "Polymorphic forms of prostate specific antigen and their interaction with androgen receptor trinucleotide repeats in prostate cancer." ], "offsets": [ [ 0, 133 ] ] }, { "id": "765", "type": "abstract", "text": [ "BACKGROUND: Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed to be associated with PC risk. The effect on PC risks from PSA polymorphisms alone and synergistically with the AR gene was examined in this report. METHODS: One hundred PC patients and an age matched cohort of 79 benign prostate hyperplasia and 67 population controls were entered in this study. DNA was extracted from blood and PSA/ARE promoter region amplified by PCR. PCR products were cut with Nhe 1 restriction enzyme to distinguish G/A alleles. AR/CAG and GGC repeat length was detected by automated fluorescence from PCR products. RESULTS: We found a significantly higher PSA/GG distribution in PC (30%) than either benign prostatic hyperplasia (BPH) (18%) or population controls (16%) (P = 0.025). Furthermore the GG distribution within cases was even greater in younger men (< 65 years; 42%; P = 0.012). Additionally, when PSA genotype was cross classified with CAG repeat, significantly more cases than both BPH and population controls were observed to have a short (< 22) CAG/GG genotype (P = 0.006). CONCLUSIONS: Our results indicate that the PSA/ARE GG genotype confers an increased risk of PC especially among younger men. Moreover, we confirm previous results that a short glutamine repeat in conjunction with GG genotype significantly increases the risk of malignant disease." ], "offsets": [ [ 134, 1788 ] ] } ]

[ { "id": "762", "type": "DNAMutation", "text": [ "G/A" ], "offsets": [ [ 294, 297 ] ], "normalized": [] }, { "id": "763", "type": "DNAMutation", "text": [ "G/A" ], "offsets": [ [ 935, 938 ] ], "normalized": [] } ]

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[ { "id": "767", "type": "title", "text": [ "Genetic linkage of snowflake vitreoretinal degeneration to chromosome 2q36." ], "offsets": [ [ 0, 75 ] ] }, { "id": "768", "type": "abstract", "text": [ "PURPOSE: To identify the chromosomal location of the gene causing snowflake vitreoretinal degeneration (SVD), an autosomal dominant retinal degeneration characterized by small yellow-white dots in the retina, fibrillar anomaly of the vitreous humor, and retinal detachment. METHODS: Clinical data were collected on 31 family members by history and examination. Thirteen family members underwent prospective examination. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two-point and multipoint linkage analysis was performed (FASTLINK version of the MLINK program and the VITESSE algorithm, both available at http://linkage.rockefeller.edu/soft/list.html). Direct DNA sequencing of amplified genomic DNA and mRNA was performed for candidate gene analysis. RESULTS: The SVD locus was linked to markers in a region of chromosome 2q36 defined by D2S2158 and D2S2202, based on meiotic breakpoint mapping of affected individuals. A maximum two-point lod score of 5.5 was obtained with marker D2S172 at theta; = 0 within this region. Direct DNA sequencing of all 52 exons of the COL4A3 gene revealed no potentially pathogenic coding sequence variation or evidence for deletion. CONCLUSIONS: The genetic locus for SVD lies in a 9 Mb region flanked by D2S2158 and D2S2202. Localization of SVD to a genomic region distinct from both Wagner disease and the Stickler syndromes indicates that SVD is a distinct genetic entity. The absence of coding sequence variation in the only collagen gene within the disease-region, suggests a novel pathogenesis for vitreoretinal degeneration. Snowflake vitreoretinal degeneration should be considered in the differential diagnosis of families with fibrillar anomaly of the vitreous." ], "offsets": [ [ 76, 1832 ] ] } ]

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[ { "id": "770", "type": "title", "text": [ "Polymorphisms in the MMP1 and MMP3 promoter and non-small cell lung carcinoma in North China." ], "offsets": [ [ 0, 93 ] ] }, { "id": "771", "type": "abstract", "text": [ "Matrix metalloproteinases (MMPs) are proteolytic enzymes that regulate various cell behaviors in cancer biology, via their basic function of degradation of proteins. Genetic variations in several MMP promoters may influence transcription and expression of MMPs. The aim of this study is to assess the effects of the two single nucleotide polymorphisms (SNPs), the guanine insertion polymorphism in the MMP1 promoter and the adenosine insertion polymorphism in the MMP3 promoter, on risk of the development and lymphatic metastasis of non-small cell lung carcinoma (NSCLC). The MMP1 and MMP3 SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 243 NSCLC patients and 350 control subjects in North China. The overall genotype and allelotype distribution of both the variants in cancer patients and controls was not significantly different (all P values are above 0.05). However, stratification analysis showed that smoking individuals with the MMP3 5A allele had a >1.5-fold increased risk to develop NSCLC, compared with those harboring the 6A homozygous [the age and gender adjusted odds ratio (OR) = 1.68, 95% confidence interval (CI) = 1.04-2.70]. In addition, the frequency of the MMP3 5A homozygote in NSCLC patients with lymphatic metastasis was significantly higher than that in lymph node negative ones (5.7 versus 0%, P = 0.04). Moreover, the MMP 1G/5A haplotype significantly increased the risk of lymphatic metastasis (OR = 3.36, 95% CI = 1.42-7.94), compared with the 2G/6A haplotype. The present result suggested that the MMP3 promoter polymorphism may modify susceptibility to NSCLC, and the MMP 1G/5A haplotype may predicate the risk of lymphatic metastasis of this tumor." ], "offsets": [ [ 94, 1841 ] ] } ]

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[ { "id": "773", "type": "title", "text": [ "Lack of evidence for mutations or deletions in the CDKN2A/p16 and CDKN2B/p15 genes of Brazilian neuroblastoma patients." ], "offsets": [ [ 0, 119 ] ] }, { "id": "774", "type": "abstract", "text": [ "Neuroblastoma, the most common extracranial tumor in childhood, has a wide spectrum of clinical and biological features. The loss of heterozygosity within the 9p21 region has been reported as a prognostic factor. Two tumor suppressor genes located in this region, the CDKN2B/p15 and CDKN2A/p16 (cyclin-dependent kinase inhibitors 2B and 2A, respectively) genes, play a critical role in cell cycle progression and are considered to be targets for tumor inactivation. We analyzed CDKN2B/p15 and CDKN2A/p16 gene alterations in 11 patients, who ranged in age from 4 months to 13 years (male/female ratio was 1.2:1). The most frequent stage of the tumor was stage IV (50%), followed by stages II and III (20%) and stage I (10%). The samples were submitted to the multiplex PCR technique for homozygous deletion analysis and to single-strand conformation polymorphism and nucleotide sequencing for mutation analysis. All exons of both genes were analyzed, but no deletion was detected. One sample exhibited shift mobility specific for exon 2 in the CDKN2B/p15 gene, not confirmed by DNA sequencing. Homozygous deletions and mutations are not involved in the inactivation mechanism of the CDKN2B/p15 and CDKN2A/p16 genes in neuroblastoma; however, these two abnormalities do not exclude other inactivation pathways. Recent evidence has shown that the expression of these genes is altered in this disease. Therefore, other mechanisms of inactivation, such as methylation of promoter region and unproperly function of proteins, may be considered in order to estimate the real contribution of these genes to neuroblastoma genesis or disease progression." ], "offsets": [ [ 120, 1763 ] ] } ]

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[ { "id": "776", "type": "title", "text": [ "Fabry disease female proband with clinical manifestations similar to hypertrophic cardiomyopathy." ], "offsets": [ [ 0, 97 ] ] }, { "id": "777", "type": "abstract", "text": [ "Fabry's disease is an X-linked inborn error of glycosphingolipid catabolism, resulting from a deficiency in alpha-galactosidase A (alpha-Gal A). A 56-year-old Japanese woman was at first suspected of having hypertrophic cardiomyopathy. The patient and her son had alpha-Gal A activity in leukocytes that was remarkably below the limit of controls. DNA analysis of the alpha-Gal A gene revealed a novel missense mutation at codon 19 in exon 1, resulting in leucine-to-proline substitution. As a result she was confirmed as a classic Fabry heterozygote. Recent advances in enzyme replacement therapy can reverse the storage of glycosphingolipids in Fabry's disease. Thus, in patients with cardiac hypertrophy, it is important to differentiate Fabry's disease from other causes of hypertrophy. Therefore, it is necessary to measure alpha-Gal A activity in all suspected cases and to analyze genetic abnormalities in heterozygotes." ], "offsets": [ [ 98, 1025 ] ] } ]

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[ { "id": "784", "type": "title", "text": [ "Genetic variation in apolipoprotein D and Alzheimer's disease." ], "offsets": [ [ 0, 62 ] ] }, { "id": "785", "type": "abstract", "text": [ "Apolipoprotein D (apoD) is a lipoprotein-associated glycoprotein, structurally unrelated to apoE, that transports small hydrophobic ligands including cholesterol and sterols. Levels are increased in the hippocampus and CSF of Alzheimer's disease (AD) patients. We tested whether variation in the APOD gene affects AD risk. Four single nucleotide polymorphisms (SNPs) were investigated (in map order): exon 2, 15T-->C encodes an amino acid substitution Phe-->Ser at codon 15; intron 2, -352G-->A; intron 3, +45C-->T; intron 4, +718C-->T, determined by SNaPshot assay. SNP frequencies for 394 eastern Finnish AD patients were compared with those found for 470 control subjects, dividing subjects also into early-onset AD (EOAD; < or = 65 years) and late-onset AD (LOAD; >65 years) groups. The -352G allele was associated with a significant 3-fold increase in the risk of EOAD (OR: 2.7; 95% CI: 1.1-6.5). The -352G containing haplotypes were more common for EOAD cases (TGCC: 0.48 vs 0.41; TGCT: 0.08 vs 0.01 (p = 0.002). In the Grade-of-membership analysis, APOD genotype frequencies at each SNP site and disease status were used to construct two latent groups: the affected group carried -352 as GG or GA and +45 CC, was often women and enriched in APOE epsilon4. Each method suggested that the -352G allele frequency is higher for EOAD in the eastern Finnish population." ], "offsets": [ [ 63, 1433 ] ] } ]

[ { "id": "779", "type": "DNAMutation", "text": [ "15T-->C" ], "offsets": [ [ 472, 479 ] ], "normalized": [] }, { "id": "780", "type": "ProteinMutation", "text": [ "Phe-->Ser at codon 15" ], "offsets": [ [ 515, 536 ] ], "normalized": [] }, { "id": "781", "type": "DNAMutation", "text": [ "intron 2, -352G-->A" ], "offsets": [ [ 538, 557 ] ], "normalized": [] }, { "id": "782", "type": "DNAMutation", "text": [ "intron 3, +45C-->T" ], "offsets": [ [ 559, 577 ] ], "normalized": [] }, { "id": "783", "type": "DNAMutation", "text": [ "intron 4, +718C-->T" ], "offsets": [ [ 579, 598 ] ], "normalized": [] } ]

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[ { "id": "794", "type": "title", "text": [ "Genetic analyses and expression studies identified a novel mutation (W486C) as a molecular basis of congenital coagulation factor XII deficiency." ], "offsets": [ [ 0, 145 ] ] }, { "id": "795", "type": "abstract", "text": [ "We analyzed the factor XII (FXII) gene of a patient with congenital FXII deficiency and identified a novel amino acid substitution (W486C) in the catalytic domain. The proband was an asymptomatic 49-year-old Japanese female with abnormal coagulation test, discovered by chance. The FXII activity and antigen level were both under 10%, suggesting a cross-reacting material-negative FXII deficiency. Sequence analysis of the proband's FXII gene revealed a homozygous nucleotide substitution G --> C in exon 12, resulting in the amino acid substitution W486C in the catalytic domain. We constructed the mutant FXII cDNA in an expression plasmid vector and transfected it into Chinese hamster ovary cells. The recombinant wild-type FXII antigen was detected in the culture medium by immunoprecipitation assay, but the mutant FXII (W486C) was not observed. On the other hand, both the wild-type FXII and W486C cell lysates contained FXII antigen and FXII mRNA, as estimated by western blotting and quantitative reverse transcriptase-polymerase chain reaction. These findings suggest that the W486C substitution of FXII impairs intracellular processing of the protein and/or transport system." ], "offsets": [ [ 146, 1332 ] ] } ]

[ { "id": "787", "type": "ProteinMutation", "text": [ "W486C" ], "offsets": [ [ 69, 74 ] ], "normalized": [] }, { "id": "788", "type": "ProteinMutation", "text": [ "W486C" ], "offsets": [ [ 278, 283 ] ], "normalized": [] }, { "id": "789", "type": "DNAMutation", "text": [ "G --> C" ], "offsets": [ [ 635, 642 ] ], "normalized": [] }, { "id": "790", "type": "ProteinMutation", "text": [ "W486C" ], "offsets": [ [ 696, 701 ] ], "normalized": [] }, { "id": "791", "type": "ProteinMutation", "text": [ "W486C" ], "offsets": [ [ 973, 978 ] ], "normalized": [] }, { "id": "792", "type": "ProteinMutation", "text": [ "W486C" ], "offsets": [ [ 1045, 1050 ] ], "normalized": [] }, { "id": "793", "type": "ProteinMutation", "text": [ "W486C" ], "offsets": [ [ 1233, 1238 ] ], "normalized": [] } ]

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[ { "id": "799", "type": "title", "text": [ "Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity." ], "offsets": [ [ 0, 116 ] ] }, { "id": "800", "type": "abstract", "text": [ "BACKGROUND: Primary vesicoureteral reflux (VUR) is a hereditary disorder characterized by the retrograde flow of urine into the ureters and kidneys. It affects about 1% of the young children and is thus one of the most common hereditary diseases. Its associated nephropathy is an important cause of end-stage renal failure in children and adults. Recent studies indicate that genetic ablation of mouse uroplakin (UP) III gene, which encodes a 47 kD urothelial-specific integral membrane protein forming urothelial plaques, causes VUR and hydronephrosis. METHODS: To begin to determine whether mutations in UP genes might play a role in human VUR, we genotyped all four UP genes in 76 patients with radiologically proven primary VUR by polymerase chain reaction (PCR) amplification and sequencing of all their exons plus 50 to 150 bp of flanking intronic sequences. RESULTS: Eighteen single nucleotide polymorphisms (SNPs) were identified, seven of which were missense, with no truncation or frame shift mutations. Since healthy relatives of the VUR probands are not reliable negative controls for VUR, we used a population of 90 race-matched, healthy individuals, unrelated to the VUR patients, as controls to perform an association study. Most of the SNPs were not found to be significantly associated with VUR. However, SNP1 of UP Ia gene affecting a C to T conversion and an Ala7Val change, and SNP7 of UP III affecting a C to G conversion and a Pro154Ala change, were marginally associated with VUR (both P= 0.08). Studies of additional cases yielded a second set of data that, in combination with the first set, confirmed a weak association of UP III SNP7 in VUR (P= 0.036 adjusted for both subsets of cases vs. controls). CONCLUSION: Such a weak association and the lack of families with simple dominant Mendelian inheritance suggest that missense changes of uroplakin genes cannot play a dominant role in causing VUR in humans, although they may be weak risk factors contributing to a complex polygenic disease. The fact that no truncation or frame shift mutations have been found in any of the VUR patients, coupled with our recent finding that some breeding pairs of UP III knockout mice yield litters that show not only VUR, but also severe hydronephrosis and neonatal death, raises the possibility that major uroplakin mutations could be embryonically or postnatally lethal in humans." ], "offsets": [ [ 117, 2512 ] ] } ]

[ { "id": "797", "type": "ProteinMutation", "text": [ "Ala7Val" ], "offsets": [ [ 1495, 1502 ] ], "normalized": [] }, { "id": "798", "type": "ProteinMutation", "text": [ "Pro154Ala" ], "offsets": [ [ 1566, 1575 ] ], "normalized": [] } ]

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[ { "id": "810", "type": "title", "text": [ "Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin-1 gene." ], "offsets": [ [ 0, 88 ] ] }, { "id": "811", "type": "abstract", "text": [ "Endothelin-1 (ET-1) is a potent vasoconstrictor and shows various pharmacological responses. Two single nucleotide polymorphisms in the ET-1 gene (EDN1) have been reported to be associated with blood pressure (BP). One is the Lys198Asn polymorphism, which showed a positive association with BP in overweight people. Another is the 3A/4A polymorphism (-134delA) located in the 5'-untranslated region. In this study, we investigated the expression of the Lys198Asn polymorphism in ET-1 in vitro, as well as the association between either of the two polymorphisms and the plasma ET-1 level. We expressed both the major (Lys-type) and minor type (Asn-type) preproET-1 in three different cell lines, and measured the levels of ET-1 and big ET-1 in the culture supernatant. There was no significant difference in the levels of ET-1 or big ET-1 between the Asn-type and Lys-type transfectant. In the association study, the plasma levels of ET-1 in 54 hypertensive patients having an amino acid substitution from Lys to Asn at position 198 were not different from those of hypertensives without the substitution. However, we found a significant difference in ET-1 levels between individuals with the 3A/3A and 3A/4A genotypes. Our transient expression study indicates that the Lys198Asn polymorphism may not directly affect ET-1 and big ET-1 production. Another variant in the EDN1 gene in linkage disequilibrium with the Lys198Asn polymorphism may be responsible for the association with BP, or the interaction between the EDN1 Lys198Asn polymorphism and other factors such as obesity may be involved in the mechanisms elevating BP in vivo." ], "offsets": [ [ 89, 1722 ] ] } ]

[ { "id": "802", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 18, 27 ] ], "normalized": [] }, { "id": "803", "type": "DNAMutation", "text": [ "-134delA" ], "offsets": [ [ 32, 40 ] ], "normalized": [] }, { "id": "804", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 315, 324 ] ], "normalized": [] }, { "id": "805", "type": "DNAMutation", "text": [ "-134delA" ], "offsets": [ [ 440, 448 ] ], "normalized": [] }, { "id": "806", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 542, 551 ] ], "normalized": [] }, { "id": "807", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 1358, 1367 ] ], "normalized": [] }, { "id": "808", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 1503, 1512 ] ], "normalized": [] }, { "id": "809", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 1610, 1619 ] ], "normalized": [] } ]

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[ { "id": "813", "type": "title", "text": [ "Altered replication timing of the HIRA/Tuple1 locus in the DiGeorge and Velocardiofacial syndromes." ], "offsets": [ [ 0, 99 ] ] }, { "id": "814", "type": "abstract", "text": [ "DiGeorge and Velocardiofacial syndromes (DGS/VCFS) are endowed by a similar complex phenotype including cardiovascular, craniofacial, and thymic malformations, and are associated with heterozygous deletions of 22q11 chromosomal band. The Typically Deleted Region in the 22q11.21 subband (here called TDR22) is very gene-dense, and the extent of the deletion has been defined precisely in several studies. However, to date there is no evidence for a mechanism of haploinsufficiency that can fully explain the DGS/VCFS phenotype. In this study, we show that the candidate gene HIRA/Tuple1 mapping on the non-deleted TDR22, in DGS/VCFS subjects presents a delayed replication timing. Moreover, we observed an increase in the cell ratio showing the HIRA/Tuple1 locus localised toward the nuclear periphery. It is known that replication timing and nuclear location are generally correlated to the transcription activity of the relative DNA region. We propose that the alteration in the replication/nuclear location pattern of the non-deleted TDR22 indicates an altered gene regulation hence an altered transcritpion in DGS/VCFS." ], "offsets": [ [ 100, 1223 ] ] } ]

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[ { "id": "817", "type": "title", "text": [ "Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene." ], "offsets": [ [ 0, 109 ] ] }, { "id": "818", "type": "abstract", "text": [ "Desmin-related myopathies (DRMs) are a heterogeneous group of muscle disorders, morphologically defined by intrasarcoplasmic aggregates of desmin. Mutations in the desmin and the alpha-B crystallin genes account for approximately one third of the DRM cases. The genetic basis of the other forms remain unknown, including the early-onset, recessive form with Mallory body-like inclusions (MB-DRMs), first described in five related German patients. Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of classical multiminicore disease. The finding of Mallory body-like inclusions in two cases of genetically documented SEPN-RM led us to suspect a relationship between MB-DRM and SEPN1. In the original MB-DRM German family, we demonstrated a linkage of the disease to the SEPN1 locus (1p36), and subsequently a homozygous SEPN1 deletion (del 92 nucleotide -19/+73) in the affected patients. A comparative reevaluation showed that MB-DRM and SEPN-RM share identical clinical features. Therefore, we propose that MB-DRM should be categorized as SEPN-RM. These findings substantiate the molecular heterogeneity of DRM, expand the morphological spectrum of SEPN-RM, and implicate a necessary reassessment of the nosological boundaries in early-onset myopathies." ], "offsets": [ [ 110, 1562 ] ] } ]

[ { "id": "816", "type": "DNAMutation", "text": [ "del 92 nucleotide -19/+73" ], "offsets": [ [ 1143, 1168 ] ], "normalized": [] } ]

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[ { "id": "823", "type": "title", "text": [ "CRYBA3/A1 gene mutation associated with suture-sparing autosomal dominant congenital nuclear cataract: a novel phenotype." ], "offsets": [ [ 0, 121 ] ] }, { "id": "824", "type": "abstract", "text": [ "PURPOSE: To identify the genetic defect leading to the congenital nuclear cataract affecting a large five-generation Swiss family. METHODS: Family history and clinical data were recorded. The phenotype was documented by both slit lamp and Scheimpflug photography. One cortical lens was evaluated by electron microscopy after cataract extraction. Lenticular phenotyping and genotyping were performed independently with short tandem repeat polymorphism. Linkage analysis was performed, and candidate genes were PCR amplified and screened for mutations on both strands using direct sequencing. RESULTS: Affected individuals had a congenital nuclear lactescent cataract in both eyes. Linkage was observed on chromosome 17 for DNA marker D17S1857 (lod score: 3.44 at theta = 0). Direct sequencing of CRYBA3/A1, which maps to the vicinity, revealed an in-frame 3-bp deletion in exon 4 (279delGAG). This mutation involved a deletion of glycine-91, cosegregated in all affected individuals, and was not observed in unaffected individuals or in 250 normal control subjects from the same ethnic background. Electron microscopy showed that cortical lens fiber morphology was normal. CONCLUSIONS: The DeltaG91 mutation in CRYBA3/A1 is associated with an autosomal dominant congenital nuclear lactescent cataract. A splice mutation (IVS3+1G/A) in this gene has been reported in a zonular cataract with sutural opacities. These results indicate phenotypic heterogeneity related to mutations in this gene." ], "offsets": [ [ 122, 1612 ] ] } ]

[ { "id": "820", "type": "DNAMutation", "text": [ "279delGAG" ], "offsets": [ [ 1002, 1011 ] ], "normalized": [] }, { "id": "821", "type": "ProteinMutation", "text": [ "DeltaG91" ], "offsets": [ [ 1311, 1319 ] ], "normalized": [] }, { "id": "822", "type": "DNAMutation", "text": [ "IVS3+1G/A" ], "offsets": [ [ 1442, 1451 ] ], "normalized": [] } ]

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[ { "id": "830", "type": "title", "text": [ "A first Taiwanese Chinese family of type 2B von Willebrand disease with R1306W mutation." ], "offsets": [ [ 0, 88 ] ] }, { "id": "831", "type": "abstract", "text": [ "Clinical, laboratory and genetic defect of a Taiwanese family with type 2B von Willebrand disease (VWD) were studied. The proband was a 55-year-old woman who gave birth to two daughters and one son aged 30, 29 and 27, respectively. All had abnormal mucocutaneous bleedings since their childhood. In proband, PT, PTT and platelet count were normal; template bleeding time was 14 min; VIII:C was 51%, von Willebrand factor antigen (VWF:Ag), 42% and von Willerand factor ristocetin-cofactor (VWF:RCo, 15%); ristocetin-induced platelet aggregation (RIPA) at 0.3 and 0.6 mg/ml of ristocetin was 16% and 68%, respectively. The enhanced response to ristocetin was identified to be in plasma, not in platelet itself, by mixing studies. Analysis of von Willebrand factor (VWF) multimer of plasma but not of platelets showed absence of high-molecular weight (HMW) multimer. All three children had similar laboratory findings. Exon 28 of VWF gene was amplified using polymerase chain reaction (PCR) and sequenced. The proband and three children were all found to be heterozygous for C to T transition at nucleotide 3916 resulting in Arg 1306 Trp (R1306W) substitution. This mutation in the glycoprotein Ib (GPIb)-binding site has been found to increase the affinity of plasma VWF for platelets, and thus cause loss of HMW multimers and often thrombocytopenia. In conclusion, a first report of type 2B VWD in a Taiwanese Chinese family who show R1306W mutation in VWF gene was described." ], "offsets": [ [ 89, 1564 ] ] } ]

[ { "id": "826", "type": "ProteinMutation", "text": [ "R1306W" ], "offsets": [ [ 72, 78 ] ], "normalized": [] }, { "id": "827", "type": "ProteinMutation", "text": [ "Arg 1306 Trp" ], "offsets": [ [ 1211, 1223 ] ], "normalized": [] }, { "id": "828", "type": "ProteinMutation", "text": [ "R1306W" ], "offsets": [ [ 1225, 1231 ] ], "normalized": [] }, { "id": "829", "type": "ProteinMutation", "text": [ "R1306W" ], "offsets": [ [ 1522, 1528 ] ], "normalized": [] } ]

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[ { "id": "835", "type": "title", "text": [ "Comparison of sequential cytomegalovirus isolates in a patient with lymphoma and failing antiviral therapy." ], "offsets": [ [ 0, 107 ] ] }, { "id": "836", "type": "abstract", "text": [ "BACKGROUND: Long-term anti-cytomegalovirus (CMV) treatments in immunocompromised patients are hampered by resistance to antiviral drugs. Longitudinal changes in the resistance genotype may depend on changes in selective pressure and the complexity of CMV isolates. OBJECTIVE: To evaluate longitudinal changes in the CMV resistance genotype and phenotype along with strain-specific variability in a patient with non-Hodgkin's lymphoma in whom successive anti-CMV treatments failed. STUDY DESIGN: The resistance phenotype and genotype of seven CMV isolates collected from one patient during a 2-year follow-up period were retrospectively analysed. In parallel, we used glycoprotein B (gB) genotyping, and a- and UL10-13-sequence analysis to study CMV interstrain variability. RESULTS: The patient was infected by at least three CMV strains plus variants of the parental strains. Resistance to ganciclovir, cidofovir and foscarnet was successively detected during the follow-up period. UL97 protein kinase changes responsible for resistance to ganciclovir were initially detected at residues 591 and 592, and then at position 594. Decreased sensitivity to foscarnet coincided with the appearance of amino acid substitution N495K in DNA polymerase, whereas cross-resistance to ganciclovir and cidofovir was due to the L501I substitution. CONCLUSIONS: The CMV isolates obtained from our patient were complex mixtures of strains. Changes in resistance genotypes depended on resistance selective pressure and were not linked to interstrain variation." ], "offsets": [ [ 108, 1651 ] ] } ]

[ { "id": "833", "type": "ProteinMutation", "text": [ "N495K" ], "offsets": [ [ 1328, 1333 ] ], "normalized": [] }, { "id": "834", "type": "ProteinMutation", "text": [ "L501I" ], "offsets": [ [ 1422, 1427 ] ], "normalized": [] } ]

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[ { "id": "849", "type": "title", "text": [ "Molecular analysis of acute intermittent porphyria: mutation screening in 20 patients in Germany reveals 11 novel mutations." ], "offsets": [ [ 0, 124 ] ] }, { "id": "850", "type": "abstract", "text": [ "Acute intermittent porphyria (AIP) is a very rare autosomal dominant disorder with low penetrance. Mutations in the gene of the porphobilinogen deaminase (PBG-D), also called hydroxymethylbilane synthase (HMBS), cause a partial deficiency of this enzyme of the heme biosynthetic pathway. Overstimulation of heme biosynthesis causes clinical symptoms. Because of the variability of the symptoms, diagnosis is often delayed. Using two approaches for genetic analysis, first in a stepwise manner, then sequencing extensive parts of the gene, the screening of the DNA of 20 unrelated individuals revealed 20 different mutations, 11 of which had not been reported previously. The novel mutations affected intron 1 (33 + 2 T-->C), exon 5 (181 G-->C), intron 6 (267-61 del 8 bp), intron 7 (345-1 G-->C), intron 9 (498 + 15 G-->T and 499-13 Delta-14 bp indel TGA), intron 13 (825 + 1 G-->C and 825 + 2 T-->C), exon 15 (962 G-A, 1067 del A and 1067-1068 ins 5 bp). The other nine mutations detected affected intron 14, exons 6, 7, 8, 9, 10 (3x) and 12. In the majority of AIP patients, the genotype does not predict phenotypic expression. Since the sudden manifestation of the disease maybe prevented by early diagnosis, identification of AIP gene carriers is the best preventive measure. This was performed in five families, revealing 10 additional AIP gene carriers." ], "offsets": [ [ 125, 1484 ] ] } ]

[ { "id": "838", "type": "DNAMutation", "text": [ "33 + 2 T-->C" ], "offsets": [ [ 835, 847 ] ], "normalized": [] }, { "id": "839", "type": "DNAMutation", "text": [ "181 G-->C" ], "offsets": [ [ 858, 867 ] ], "normalized": [] }, { "id": "840", "type": "DNAMutation", "text": [ "267-61 del 8 bp" ], "offsets": [ [ 880, 895 ] ], "normalized": [] }, { "id": "841", "type": "DNAMutation", "text": [ "345-1 G-->C" ], "offsets": [ [ 908, 919 ] ], "normalized": [] }, { "id": "842", "type": "DNAMutation", "text": [ "498 + 15 G-->T" ], "offsets": [ [ 932, 946 ] ], "normalized": [] }, { "id": "843", "type": "DNAMutation", "text": [ "499-13 Delta-14 bp indel TGA" ], "offsets": [ [ 951, 979 ] ], "normalized": [] }, { "id": "844", "type": "DNAMutation", "text": [ "825 + 1 G-->C" ], "offsets": [ [ 993, 1006 ] ], "normalized": [] }, { "id": "845", "type": "DNAMutation", "text": [ "825 + 2 T-->C" ], "offsets": [ [ 1011, 1024 ] ], "normalized": [] }, { "id": "846", "type": "DNAMutation", "text": [ "962 G-A" ], "offsets": [ [ 1036, 1043 ] ], "normalized": [] }, { "id": "847", "type": "DNAMutation", "text": [ "1067 del A" ], "offsets": [ [ 1045, 1055 ] ], "normalized": [] }, { "id": "848", "type": "DNAMutation", "text": [ "1067-1068 ins 5 bp" ], "offsets": [ [ 1060, 1078 ] ], "normalized": [] } ]

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[ { "id": "853", "type": "title", "text": [ "Identification of the Kna/Knb polymorphism and a method for Knops genotyping." ], "offsets": [ [ 0, 77 ] ] }, { "id": "854", "type": "abstract", "text": [ "BACKGROUND: DNA mutations resulting in the McCoy and Swain-Langley polymorphisms have been identified on complement receptor 1 (CR1)-a ligand for rosetting of Plasmodium falciparum-infected RBCs. The molecular identification of the Kna/Knb polymorphism was sought to develop a genotyping method for use in the study of the Knops blood group and malaria. STUDY DESIGN AND METHODS: CR1 deletion constructs were used in inhibition studies of anti-Kna. PCR amplification of Exon 29 was followed by DNA sequencing. A PCR-RFLP was developed with NdeI, BsmI, and MfeI for the detection of Kna/Knb, McCa/McCb, and Sl1/Sl2, respectively. Knops phenotypes were determined with standard serologic techniques. RESULTS: A total of 310 Malian persons were phenotyped for Kna with 200 (64%) Kn(a+) and 110 (36%) Kn(a-). Many of the Kn(a-) exhibited the Knops-null phenotype, that is, Helgeson. The Kna/b DNA polymorphism was identified as a V1561M mutation with allele frequencies of Kna (V1561) 0.9 and Knb (M1561) 0.1. CONCLUSION: The high frequency (18%) of Knb in West African persons suggests that it is not solely a Caucasian trait. Furthermore, because of the high incidence of heterozygosity as well as amorphs, accurate Knops typing of donors of African descent is best accomplished by a combination of molecular and serologic techniques." ], "offsets": [ [ 78, 1410 ] ] } ]

[ { "id": "852", "type": "ProteinMutation", "text": [ "V1561M" ], "offsets": [ [ 1004, 1010 ] ], "normalized": [] } ]

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[ { "id": "861", "type": "title", "text": [ "Two novel severe mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) cause familial and/or hereditary pancreatitis." ], "offsets": [ [ 0, 133 ] ] }, { "id": "862", "type": "abstract", "text": [ "Mutations in the serine protease inhibitor Kazal type 1 gene (SPINK1) encoding pancreatic secretory trypsin inhibitor (PSTI) have recently been found to be associated with chronic pancreatitis. Nevertheless, knowledge of severe mutations is particularly scarce, both in terms of number and in the extent of clinical information. The aim of this study was to expand the known spectrum of such mutations. 46 unrelated families, each including at least two pancreatitis patients and carrying neither cationic trypsinogen (PRSS1) mutations nor the frequent SPINK1 N34S mutation, participated in this study. The four exons and their flanking sequences of the SPINK1 gene were screened by denaturing high performance liquid chromatography analysis (DHPLC); and mutations were identified by direct sequencing. A heterozygous microdeletion mutation (c.27delC), which occurs within a symmetric element, was identified in two families. In one family, c.27delC showed segregation with the disease across two generations, with a penetrance of up to 75%. But in the other family, however, the same mutation manifested as a low-penetrance susceptibility factor. In addition, a novel heterozygous splicing mutation, c.87+1G>A (G>A substitution at nucleotide +1 of intron 2) was found in one family with familial pancreatitis. Our results also helped to resolve the sharply differing views about PSTI's role in pancreatitis." ], "offsets": [ [ 134, 1542 ] ] } ]

[ { "id": "856", "type": "ProteinMutation", "text": [ "N34S" ], "offsets": [ [ 694, 698 ] ], "normalized": [] }, { "id": "857", "type": "DNAMutation", "text": [ "c.27delC" ], "offsets": [ [ 976, 984 ] ], "normalized": [] }, { "id": "858", "type": "DNAMutation", "text": [ "c.27delC" ], "offsets": [ [ 1075, 1083 ] ], "normalized": [] }, { "id": "859", "type": "DNAMutation", "text": [ "c.87+1G>A" ], "offsets": [ [ 1335, 1344 ] ], "normalized": [] }, { "id": "860", "type": "DNAMutation", "text": [ "G>A substitution at nucleotide +1 of intron 2" ], "offsets": [ [ 1346, 1391 ] ], "normalized": [] } ]

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[ { "id": "864", "type": "title", "text": [ "A novel two nucleotide deletion in the apolipoprotein A-I gene, apoA-I Shinbashi, associated with high density lipoprotein deficiency, corneal opacities, planar xanthomas, and premature coronary artery disease." ], "offsets": [ [ 0, 210 ] ] }, { "id": "865", "type": "abstract", "text": [ "Familial HDL deficiency (FHD) is a rare autosomal dominant lipoprotein disorder. We describe a novel genetic variant of the apolipoprotein A-I (apoA-I) gene resulting in FHD. The proband is a 51-year-old woman who was hospitalized due to severe heart failure. Her plasma HDL-cholesterol (C) and apoA-I concentrations were 0.08mmol/l and 1mg/dl, respectively. She exhibited corneal opacities and planar xanthomas on eyelids and elbows. Coronary angiography demonstrated extensive obstructions in two major vessels. Genomic DNA sequencing of the patient's apoA-I gene revealed a homozygosity for a GC deletion between 5 GC repeats in exon 4, creating a frameshift and a stop codon at residue 178. We designated this mutation as apoA-I Shinbashi. The proband's father, son, and daughter were found to be heterozygous for this mutation and their HDL-C and apoA-I levels were about half of normal levels, demonstrating a gene dosage effect. The father underwent coronary bypass surgery at age of 70 years. Lecithin-cholesterol acyltransferase (LCAT) activity was decreased by 63% in the homozygote and 31% in heterozygotes, respectively. This new case of apoA-I deficiency, apoA-I Shinbashi, is the first case involving a single gene defect of the apoA-I gene to develop all the characteristics for apoA-I deficiency, including premature coronary heart disease." ], "offsets": [ [ 211, 1567 ] ] } ]

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[ { "id": "869", "type": "title", "text": [ "Gonadal mosaicism in severe Pallister-Hall syndrome." ], "offsets": [ [ 0, 52 ] ] }, { "id": "870", "type": "abstract", "text": [ "Pallister-Hall syndrome (PHS, MIM #146510) is characterized by central and postaxial polydactyly, hypothalamic hamartoma (HH), bifid epiglottis, imperforate anus, renal abnormalities, and pulmonary segmentation anomalies. It is inherited in an autosomal dominant pattern. Here, we describe a family with two affected children manifesting severe PHS with mental retardation, behavioral problems, and intractable seizures. Both parents are healthy, with normal intelligence, and have no malformations on physical, laryngoscopic, and cranial MRI exam. The atypical presentation of these children and the absence of parental manifestations suggested an autosomal recessive mode of inheritance or gonadal mosaicism. Sequencing of GLI3 revealed a two nucleotide deletion in exon 15 (c.3385_3386delTT) predicting a frameshift and premature stop at codon 1129 (p.F1129X) in the children while both parents have wild type alleles. Genotyping with GLI3 intragenic markers revealed that both children inherited the abnormal allele from their mother thus supporting gonadal mosaicism as the underlying mechanism of inheritance (paternity was confirmed). This is the first reported case of gonadal mosaicism in PHS. The severe CNS manifestations of these children are reminiscent of children with non-syndromic HH who often have progressive mental retardation with behavioral problems and intractable seizures. We conclude that the phenotypic spectrum of PHS can include severe CNS manifestations and that recurrence risks for PHS should include a proviso for gonadal mosaicism, though the frequency cannot be calculated from a single case report. Published 2003 Wiley-Liss, Inc." ], "offsets": [ [ 53, 1719 ] ] } ]

[ { "id": "867", "type": "DNAMutation", "text": [ "c.3385_3386delTT" ], "offsets": [ [ 830, 846 ] ], "normalized": [] }, { "id": "868", "type": "ProteinMutation", "text": [ "p.F1129X" ], "offsets": [ [ 906, 914 ] ], "normalized": [] } ]

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[ { "id": "872", "type": "title", "text": [ "High-resolution deletion mapping of 15q13.2-q21.1 in transitional cell carcinoma of the bladder." ], "offsets": [ [ 0, 96 ] ] }, { "id": "873", "type": "abstract", "text": [ "Deletions found in several types of human tumor, including carcinomas of the colorectum, breast, and lung, suggest the presence of a potential tumor suppressor gene(s) on chromosome 15. Common regions of deletion in these tumors are at 15q15 and 15q21. Here, we have analyzed loss of heterozygosity (LOH) on chromosome 15 to ascertain its potential involvement in the development and progression of transitional cell carcinoma (TCC) of the bladder. A panel of 26 polymorphic markers, spanning 15q12-15q22, were used to map regions of LOH in 51 TCCs. LOH was found for at least one marker in the region 15q14-15q15.3 in 20 of 51 (39%) tumors. Deletion mapping defined two minimum regions of deletion: a distal region between the markers D15S514 and D15S537 at 15q15.1-15q15.3 (estimated as 3 Mb) and a more proximal region between the markers D15S971 and D15S1042 at 15q14 (estimated as 1.1 Mb). Analysis of a panel of 33 bladder tumor cell lines revealed regions of contiguous homozygosity for markers in 15q15, indicating likely LOH. Fluorescence in situ hybridization analysis demonstrated that mitotic recombination is the predicted mechanism of LOH in two of these. These regions of LOH on 15q may contain tumor suppressor genes the loss or inactivation of which is associated with TCC development. The DNA repair gene RAD51 at 15q15.1 represents a candidate 15q tumor suppressor gene. Expression analysis of rad51 protein in tumor cell lines revealed variable levels of expression but no significant loss of expression in cell lines with likely 15q LOH." ], "offsets": [ [ 97, 1655 ] ] } ]

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[ { "id": "875", "type": "title", "text": [ "Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in both the myophosphorylase and deoxyguanosine kinase genes." ], "offsets": [ [ 0, 139 ] ] }, { "id": "876", "type": "abstract", "text": [ "OBJECTIVES: To document 2 apparently incongruous clinical disorders occurring in the same infant: congenital myopathy with myophosphorylase deficiency (McArdle disease) and mitochondrial hepatopathy with liver failure and mitochondrial DNA depletion. METHODS: An infant girl born to consanguineous Moroccan parents had severe congenital hypotonia and hepatomegaly, developed liver failure, and died at 5 months of age. We studied muscle and liver biopsy specimens histochemically and biochemically, and we sequenced the whole coding regions of the deoxyguanosine kinase (dGK) and myophosphorylase (PYGM) genes. RESULTS: Muscle biopsy specimens showed subsarcolemmal glycogen accumulation and negative histochemical reaction for phosphorylase. Liver biopsy specimens showed micronodular cirrhosis and massive mitochondrial proliferation. Biochemical analysis showed phosphorylase deficiency in muscle and cytochrome c oxidase deficiency in liver. We identified a novel homozygous missense G-to-A mutation at codon 456 in exon 11 of PYGM, as well as a homozygous 4-base pair GATT duplication (nucleotides 763-766) in exon 6 of dGK, which produces a frame shift and a premature TGA stop codon at nucleotides 766 to 768, resulting in a truncated 255-amino acid protein. Both mutations were absent in 100 healthy individuals. CONCLUSIONS: Our data further expand the genetic heterogeneity in patients with McArdle disease; confirm the strong relationship between mitochondrial DNA depletion syndrome, liver involvement, and dGK mutations; and suggest that genetic \"double trouble\" should be considered in patients with unusual severe phenotypes." ], "offsets": [ [ 140, 1780 ] ] } ]

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[ { "id": "878", "type": "title", "text": [ "Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk." ], "offsets": [ [ 0, 79 ] ] }, { "id": "879", "type": "abstract", "text": [ "Microsomal epoxide hydrolase (mEH) plays a dual role in the detoxification and activation of tobacco procarcinogens. Two polymorphisms affecting enzyme activity have been described in the exons 3 and 4 of the mEH gene, which result in the substitution of amino acids histidine to tyrosine at residue 113, and arginine to histidine at residue 139, respectively. We performed a hospital-based case-control study consisting of 277 newly diagnosed lung cancer patients and 496 control subjects to investigate a possible association between these two polymorphisms and lung cancer risk. The polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism and TaqMan assay using DNA from peripheral white blood cells. Logistic regression was performed to calculate odds ratios (ORs), confidence limits (CL) and to control for possible confounders. The exon 3 polymorphism of the mEH gene was associated with a significantly decreased risk of lung cancer. The adjusted OR, calculated relative to subjects with the Tyr113/Tyr113 wild type, for the His113/His113 genotype was 0.38 (95% CL 0.20-0.75). An analysis according to histological subtypes revealed a statistically significant association for adenocarcinomas; the adjusted OR for the His113/His113 genotype was 0.40 (95% CL 0.17-0.94). In contrast, no relationship between the exon 4 polymorphism and lung cancer risk was found. The adjusted OR, calculated relative to the His139/His139 wild type, was for the Arg139/Arg139 genotype 1.83 (0.76-4.44). Our results support the hypothesis that genetically reduced mEH activity may be protective against lung cancer." ], "offsets": [ [ 80, 1727 ] ] } ]

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[ { "id": "886", "type": "title", "text": [ "Detection of PHKA2 gene mutation in four Japanese patients with hepatic phosphorylase kinase deficiency." ], "offsets": [ [ 0, 104 ] ] }, { "id": "887", "type": "abstract", "text": [ "We analyzed the PHKA2 gene in four Japanese families with hepatic phosphorylase kinase (PhK) deficiency. Mutational analysis of PHKA2 cDNA was performed by reverse-transcribed polymerase chain reaction (RT-PCR) and direct sequencing, and each mutation was confirmed on the genomic DNA. In boys with low erythrocyte PhK activity (i.e., x-linked liver glycogenosis [XLG] type I), deletion of exon 2 (splice site mutation of 79-1 G > T) or nonsense mutation of Q1169X or R497X was identified. However, missense mutation of R295C was identified in one boy with normal erythrocyte PhK activity (i.e., XLG type II). This mutation was not found in 100 control alleles, and was considered responsible for presentation of the XLG type II phenotype. Excluding Q1169X, all mutations detected in this study represented novel mutations. All mothers were found to be heterozygous carriers of the mutations. Gene analysis was confirmed to represent a useful procedure for diagnosing XLG type II, for which liver biopsy had previously been required to detect hepatic PhK deficiency." ], "offsets": [ [ 105, 1171 ] ] } ]

[ { "id": "881", "type": "DNAMutation", "text": [ "79-1 G > T" ], "offsets": [ [ 527, 537 ] ], "normalized": [] }, { "id": "882", "type": "ProteinMutation", "text": [ "Q1169X" ], "offsets": [ [ 563, 569 ] ], "normalized": [] }, { "id": "883", "type": "ProteinMutation", "text": [ "R497X" ], "offsets": [ [ 573, 578 ] ], "normalized": [] }, { "id": "884", "type": "ProteinMutation", "text": [ "R295C" ], "offsets": [ [ 625, 630 ] ], "normalized": [] }, { "id": "885", "type": "ProteinMutation", "text": [ "Q1169X" ], "offsets": [ [ 855, 861 ] ], "normalized": [] } ]

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[ { "id": "896", "type": "title", "text": [ "Mutation analysis of SLC7A9 in cystinuria patients in Sweden." ], "offsets": [ [ 0, 61 ] ] }, { "id": "897", "type": "abstract", "text": [ "Cystinuria is an autosomal recessive disorder characterized by increased urinary excretion of cystine and dibasic amino acids, which cause recurrent stone formation in affected individuals. Three subtypes of cystinuria have been described (type I, II, and III): type I is caused by mutations in the SLC3A1 gene, whereas nontype I (II and III) has been associated with SLC7A9 mutations. Of the 53 patients reported in our previous work, patients that showed SLC7A9 mutations in single-strand conformation polymorphism (SSCP) screening and/or either lacked or showed heterozygosity for SLC3A1 mutations were included in the present study. The entire coding region and the exon/intron boundaries of the SLC7A9 gene were analyzed by means of both SSCP and DNA sequencing in 16 patients, all but one of which were clinically diagnosed as homozygous cystinurics. Three novel SLC7A9 mutations were identified in the patient group: two missense mutations (P261L and V330M), and one single base-pair deletion (1009 delA). We also detected the previously reported A182T and nine novel polymorphisms in the patients. Mutations V330M and 1009delA occurred on different alleles in one individual, and we suggest that these mutations cause cystinuria in this patient. One patient that was homozygously mutated in the SLC3A1 gene carried the third novel mutation (P261L). We conclude that SLC3A1 is still the major disease gene among Swedish cystinuria patients, with only a minor contribution of SLC7A9 mutations as the genetic basis of cystinuria. The absence of SLC3A1 and SLC7A9 mutations in a substantial proportion of the patients implies that mutations in parts of the genes that were not analyzed may be present, as well as large deletions that escape detection by the methods used. However, our results raise the question of whether other, as yet unknown genes, may also be involved in cystinuria." ], "offsets": [ [ 62, 1953 ] ] } ]

[ { "id": "889", "type": "ProteinMutation", "text": [ "P261L" ], "offsets": [ [ 1010, 1015 ] ], "normalized": [] }, { "id": "890", "type": "ProteinMutation", "text": [ "V330M" ], "offsets": [ [ 1020, 1025 ] ], "normalized": [] }, { "id": "891", "type": "DNAMutation", "text": [ "1009 delA" ], "offsets": [ [ 1063, 1072 ] ], "normalized": [] }, { "id": "892", "type": "ProteinMutation", "text": [ "A182T" ], "offsets": [ [ 1116, 1121 ] ], "normalized": [] }, { "id": "893", "type": "ProteinMutation", "text": [ "V330M" ], "offsets": [ [ 1178, 1183 ] ], "normalized": [] }, { "id": "894", "type": "DNAMutation", "text": [ "1009delA" ], "offsets": [ [ 1188, 1196 ] ], "normalized": [] }, { "id": "895", "type": "ProteinMutation", "text": [ "P261L" ], "offsets": [ [ 1411, 1416 ] ], "normalized": [] } ]

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[ { "id": "902", "type": "title", "text": [ "A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village." ], "offsets": [ [ 0, 138 ] ] }, { "id": "903", "type": "abstract", "text": [ "In 1982, one of us reported a cluster of eight individuals affected by spondylocostal dysostosis (SD, MIM 277300) in four nuclear families indigenous to a village from eastern Switzerland. We tested the hypothesis that the molecular basis for this cluster was segregation of a single mutation in the DLL3 gene, recently linked to SD. Marker haplotypes around the DLL3 locus contradicted this hypothesis as three different haplotypes were seen in affected individuals, but sequence analysis showed that three unreported DLL3 mutations were segregating: a duplication of 17 bp in exon 8 (c.1285-1301dup), a single-nucleotide deletion in exon 5 (c.615delC), and a R238X nonsense mutation in exon 6. Contrary to our initial assumption of a single allele segregating in this small community, three different pathogenic alleles were observed, with a putative founder mutation occurring at the homozygous state but also compounding with, and thus revealing, two other independent mutations. As all three mutations predict truncation of the DLL3 protein and loss of the membrane-attaching domain, the results confirm that autosomal recessive spondylocostal dysostosis represents the null phenotype of DLL3, with remarkable phenotypic consistency across families." ], "offsets": [ [ 139, 1393 ] ] } ]

[ { "id": "899", "type": "DNAMutation", "text": [ "c.1285-1301dup" ], "offsets": [ [ 725, 739 ] ], "normalized": [] }, { "id": "900", "type": "DNAMutation", "text": [ "c.615delC" ], "offsets": [ [ 782, 791 ] ], "normalized": [] }, { "id": "901", "type": "ProteinMutation", "text": [ "R238X" ], "offsets": [ [ 800, 805 ] ], "normalized": [] } ]

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[ { "id": "910", "type": "title", "text": [ "A \"null allele\" mutation is responsible for erythropoietic protoporphyria in an Israeli patient who underwent liver transplantation: relationships among biochemical, clinical, and genetic parameters." ], "offsets": [ [ 0, 199 ] ] }, { "id": "911", "type": "abstract", "text": [ "Mutations in the human ferrochelatase gene (FECH) are the primary cause of the inborn disorder erythropoietic protoporphyria (EPP). While the majority of the EPP patients exhibit only photosensitivity, a small percentage of patients (approximately 2%) develop liver complications in addition to the cutaneous symptoms. In this study, the FECH gene of an Israeli EPP patient who suffered from EPP-related liver complications was sequenced. A splicing defect IVS10+1, g-->t, which is known to cause the deletion of exon 10, was identified in the index patient as well as in his symptomatic older sister and his asymptomatic mother. Like the other 12 known FECH mutations associated with liver complications, IVS10+1, g-->t is a \"null-allele\" mutation. Although the two siblings with overt EPP share an identical genotype with respect to both the mutation on one FECH allele and three intragenic single nucleotide polymorphisms, -251G, IVS1-23T, and IVS3-48C on the other allele, the sister of the index patient has so far shown no signs of liver involvement, suggesting that additional factors might account for the liver disease in EPP." ], "offsets": [ [ 200, 1335 ] ] } ]

[ { "id": "905", "type": "DNAMutation", "text": [ "IVS10+1, g-->t" ], "offsets": [ [ 657, 671 ] ], "normalized": [] }, { "id": "906", "type": "DNAMutation", "text": [ "IVS10+1, g-->t" ], "offsets": [ [ 906, 920 ] ], "normalized": [] }, { "id": "907", "type": "DNAMutation", "text": [ "-251G" ], "offsets": [ [ 1126, 1131 ] ], "normalized": [] }, { "id": "908", "type": "DNAMutation", "text": [ "IVS1-23T" ], "offsets": [ [ 1133, 1141 ] ], "normalized": [] }, { "id": "909", "type": "DNAMutation", "text": [ "IVS3-48C" ], "offsets": [ [ 1147, 1155 ] ], "normalized": [] } ]

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[ { "id": "914", "type": "title", "text": [ "A novel compound heterozygous mutation in the CYP17 (P450 17alpha-hydroxylase) gene leading to 17alpha-hydroxylase/17,20-lyase deficiency." ], "offsets": [ [ 0, 138 ] ] }, { "id": "915", "type": "abstract", "text": [ "Mutations in the CYP17 gene impair steroid biosynthesis in the adrenals and gonads and often cause 17alpha-hydroxylase/17,20-lyase deficiency, leading to amenorrhea, sexual infantilism, and hypokalemic low aldosterone hypertension. Several CYP17 mutations resulting in 17alpha-hydroxylase/17,20-lyase deficiency have been reported previously. In the present study, we found a novel CYP17 mutation from the molecular analysis of a Korean patient with primary amenorrhea with a 46,XX karyotype, and hypokalemic hypertension. We sequenced all 8 exons of the CYP17 gene that were amplified from patient's genomic DNA using polymerase chain reaction (PCR) and found a compound heterozygous mutation in the CYP17 structural gene; a 1-base deletion and a 1-base transversion (TAC-->AA) at codon 329, leading to the production of a truncated protein (1-417 amino acids), and a 3-base deletion (TCC, either 350-351 or 351-352 codon) in the other allele. Restriction enzyme digestion analysis of patient's and parental DNA showed that the 1-base deletion and the 3-base deletion are inherited from mother and father, respectively. Here we conclude that these novel compound heterozygous mutations might account for the patient's clinical manifestations of 17alpha-hydroxylase/17,20-lyase deficiency." ], "offsets": [ [ 139, 1428 ] ] } ]

[ { "id": "913", "type": "DNAMutation", "text": [ "(TAC-->AA) at codon 329" ], "offsets": [ [ 907, 930 ] ], "normalized": [] } ]

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[ { "id": "918", "type": "title", "text": [ "Haplotypes extending across ACE are associated with Alzheimer's disease." ], "offsets": [ [ 0, 72 ] ] }, { "id": "919", "type": "abstract", "text": [ "Numerous genes have been implicated in Alzheimer's disease (AD), but, with the exception of a demonstrated association with the epsilon 4 allele of APOE, findings have not been consistently replicated across populations. One of the most widely studied is the gene for angiotensin I converting enzyme (ACE ). A meta-analysis of published data on a common Alu indel polymorphism in ACE was performed which indicated highly significant association of the insertion allele with AD (OR 1.30; 95% CI 1.19 - 1.41; P=4 x 10(-8)). To further explore the influence of ACE on AD, several single-nucleotide polymorphisms (SNPs) were genotyped in five independent populations represented by over 3100 individuals. Analyses based upon single markers and haplotypes revealed strong evidence of association in case-control models and also in a model examining the influence of variation in ACE upon cerebrospinal fluid levels of amyloid beta42 peptide (Abeta42). The most significant evidence for association with AD was found for an SNP, A-262T, located in the ACE promoter (OR 1.64; 95% CI 1.33 -1.94; P=2 x 10(-5)). Estimates of population attributable risk for the common allele of this SNP suggest that it, or an allele in tight linkage disequilibrium (LD) with it, may contribute to as much as 35% of AD in the general population. Results support a model whereby decreased ACE activity may influence AD susceptibility by a mechanism involving beta-amyloid metabolism." ], "offsets": [ [ 73, 1530 ] ] } ]

[ { "id": "917", "type": "DNAMutation", "text": [ "A-262T" ], "offsets": [ [ 1096, 1102 ] ], "normalized": [] } ]

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[ { "id": "924", "type": "title", "text": [ "Identification of new polymorphisms in the CACNA1S gene." ], "offsets": [ [ 0, 56 ] ] }, { "id": "925", "type": "abstract", "text": [ "We identified four novel polymorphisms in the CACNA1S gene that encodes the alpha1-subunit of the dihydropyridine receptor. Mutations in this gene are associated with two genetic diseases: malignant hyperthermia and hypokalemic periodic paralysis. The nucleotide substitutions c2403T --> C and c5398T --> C did not result in amino acid replacement, the nucleotide substitution c4475C --> A caused the replacement of the Ala1492 with an Asp residue and an A insertion was identified in intron 36. By using methods based on digestion with restriction enzymes we calculated the frequencies of these novel polymorphisms, as well as heterozygosity, in normal subjects from southern Italy." ], "offsets": [ [ 57, 740 ] ] } ]

[ { "id": "921", "type": "DNAMutation", "text": [ "c2403T --> C" ], "offsets": [ [ 334, 346 ] ], "normalized": [] }, { "id": "922", "type": "DNAMutation", "text": [ "c5398T --> C" ], "offsets": [ [ 351, 363 ] ], "normalized": [] }, { "id": "923", "type": "DNAMutation", "text": [ "c4475C --> A" ], "offsets": [ [ 434, 446 ] ], "normalized": [] } ]

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[ { "id": "931", "type": "title", "text": [ "Association of an IL-1A 3'UTR polymorphism with end-stage renal disease and IL-1 alpha expression." ], "offsets": [ [ 0, 98 ] ] }, { "id": "932", "type": "abstract", "text": [ "BACKGROUND: We evaluated polymorphisms in the interleukin-1 alpha 3'-untranslated region (IL-1A 3'[UTR]) for association with type 2 diabetes-associated (DM) and nondiabetic-associated (non-DM) end-stage renal disease (ESRD) in two ethnic groups. METHODS: IL-1A 3'UTR polymorphisms were identified by alignment of overlapping human expressed sequence tags (ESTs). Sequence ambiguities were experimentally confirmed and variants genotyped to test for association with ESRD in 75 unrelated Caucasians with DM ESRD, 95 unrelated Caucasian controls and, in a parallel study, 92 unrelated African Americans with type 2 DM ESRD, 95 unrelated African Americans with non-DM ESRD, and 86 unrelated African American controls. IL-1A 3' UTR genotype and lipopolysaccharide (LPS)-stimulated IL-1 alpha protein levels were measured in healthy Caucasians (N = 112) and African Americans (N = 101) to evaluate association between genotype and protein level. RESULTS: A polymorphism in the 3' UTR of the human IL-1A gene was associated with ESRD and IL-1 alpha protein expression. The polymorphism consists of two single nucleotide polymorphisms (SNPs) and an insertion/deletion generating four different haplotypes: TN7TTCAA, AN7TTCAA, TN7TTCAG and an allele deleted for four internal bases, TN7(delTTCA)A. The 4 bp deletion allele, TN7(delTTCA)A, was significantly less common among Caucasian DM ESRD and African American non-DM ESRD patients (recessive model; P = 0.0364 and P = 0.0293, respectively). In vitro, this polymorphism is associated with the amount of IL-1 alpha protein synthesized in LPS-stimulated lymphocytes from healthy subjects (P = 0.0013, additive model), with the TN7(delTTCA)A haplotype associated with higher levels of stimulated IL-1 alpha. CONCLUSION: The association of the TN7(delTTCA)A haplotype with higher levels of IL-1 alpha expression and reduced risk for ESRD is consistent with involvement of cytokines in risk for developing nephropathy." ], "offsets": [ [ 99, 2058 ] ] } ]

[ { "id": "927", "type": "DNAMutation", "text": [ "delTTCA" ], "offsets": [ [ 1379, 1386 ] ], "normalized": [] }, { "id": "928", "type": "DNAMutation", "text": [ "delTTCA" ], "offsets": [ [ 1420, 1427 ] ], "normalized": [] }, { "id": "929", "type": "DNAMutation", "text": [ "delTTCA" ], "offsets": [ [ 1774, 1781 ] ], "normalized": [] }, { "id": "930", "type": "DNAMutation", "text": [ "delTTCA" ], "offsets": [ [ 1889, 1896 ] ], "normalized": [] } ]

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[ { "id": "939", "type": "title", "text": [ "The association between GJB2 mutation and GJB6 gene in non syndromic hearing loss school children." ], "offsets": [ [ 0, 98 ] ] }, { "id": "940", "type": "abstract", "text": [ "Recently, molecular testing for GJB2 mutations has become the standard of care for the diagnosis of patients with non syndromic hearing impairment of unknown cause. The aims of this study are to determine the association between GJB2 mutation and GJB6 and to report the variation of mutations in deaf students who have heterozygous GJB2. This retrospective study was conducted at Universiti Kebangsaan Malaysia Medical Center (UKMMC). Data was collected from previous files and records from Tissue Engineering and Human Genetic Research Group Laboratory. Approval from Ethical Committee was obtained prior to the study. A total of 138 students have been screened in previous studies in UKMMC for the presence of GJB2 mutations as a cause for hearing loss. Thirty four of the 138 subjects have GJB2 mutations; 2 showed homozygous mutations whereas another 32 were heterozygous for GJB2 gene mutation. Only 31 DNA samples of students presented with sensorineural hearing loss with heterozygous mutation in GJB2 gene were included in this study. The sequencing results obtained were analyzed. The degree of hearing loss of those students with association between GJB2 mutation and GJB6 mutation will be discussed. Five out of 31 subjects (16.2%) have mutations in their GJB6 gene, suggesting a digenic inheritance of GJB2/GJB6 mutation. In total, four novel mutations were identified; E137D (n=1), R32Q (n=1), E101K (n=1) and Y156H (n=1) and one mutation deletion; 366delT (n=1). All students with association GJB2 mutation and GJB6 showed severe to profound hearing loss in both ears. Interestingly this study not detected the large deletion of 342 kb in GJB6 gene suggesting that the mutation is very rare in this region compared to certain parts of the world." ], "offsets": [ [ 99, 1858 ] ] } ]

[ { "id": "934", "type": "ProteinMutation", "text": [ "E137D" ], "offsets": [ [ 1481, 1486 ] ], "normalized": [] }, { "id": "935", "type": "ProteinMutation", "text": [ "R32Q" ], "offsets": [ [ 1494, 1498 ] ], "normalized": [] }, { "id": "936", "type": "ProteinMutation", "text": [ "E101K" ], "offsets": [ [ 1506, 1511 ] ], "normalized": [] }, { "id": "937", "type": "ProteinMutation", "text": [ "Y156H" ], "offsets": [ [ 1522, 1527 ] ], "normalized": [] }, { "id": "938", "type": "DNAMutation", "text": [ "366delT" ], "offsets": [ [ 1561, 1568 ] ], "normalized": [] } ]

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[ { "id": "942", "type": "title", "text": [ "Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells." ], "offsets": [ [ 0, 84 ] ] }, { "id": "943", "type": "abstract", "text": [ "Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells." ], "offsets": [ [ 85, 1773 ] ] } ]

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[ { "id": "950", "type": "title", "text": [ "PTCH1 gene mutations in exon 17 and loss of heterozygosity on D9S180 microsatellite in sporadic and inherited human basal cell carcinomas." ], "offsets": [ [ 0, 138 ] ] }, { "id": "951", "type": "abstract", "text": [ "BACKGROUND: Basal cell carcinomas (BCCs) are the most frequent human cancer that results from malignant transformation of basal cells in the epidermis. Gorlin syndrome is a rare inherited autosomal dominant disease that predisposes with multiple BCCs and other birth defects. Both sporadic and inherited BCCs are associated with mutations in the tumor suppressor gene PTCH1, but there is still uncertainty on the role of its homolog PTCH2. OBJECTIVES: To search for mutations and genomic instability in sporadic and inherited BCCs. METHODS: DNA obtained from leukocytes and tumor cells was amplified by polymerase chain reaction regarding five exons of PTCH1 and PTCH2 and neighboring microsatellites. Exons were sequenced and compared with the GenBank database. RESULTS: Only D9S180, of six microsatellites, showed loss of heterozygosity in three BCCs (two sporadic and one inherited). One sporadic BCC presented the mutation g.2885G>C in exon 17 of PTCH1, which predicts the substitution p.R962T in an external domain of the protein. In addition, the leukocytes and tumor cells of one patient with Gorlin syndrome showed the mutation g.2839T>G in the same exon and gene, which predicts a p.E947stop and truncated protein. All control and tumor samples presented IVS9 + 217T in intron 9 of PTCH1. CONCLUSION: Mutations found in the PTCH1 gene and neighboring repetitive sequences may have contributed to the development of the studied BCCs." ], "offsets": [ [ 139, 1580 ] ] } ]

[ { "id": "945", "type": "DNAMutation", "text": [ "g.2885G>C" ], "offsets": [ [ 1066, 1075 ] ], "normalized": [] }, { "id": "946", "type": "ProteinMutation", "text": [ "p.R962T" ], "offsets": [ [ 1129, 1136 ] ], "normalized": [] }, { "id": "947", "type": "DNAMutation", "text": [ "g.2839T>G" ], "offsets": [ [ 1275, 1284 ] ], "normalized": [] }, { "id": "948", "type": "ProteinMutation", "text": [ "p.E947stop" ], "offsets": [ [ 1329, 1339 ] ], "normalized": [] }, { "id": "949", "type": "DNAMutation", "text": [ "IVS9 + 217T" ], "offsets": [ [ 1403, 1414 ] ], "normalized": [] } ]

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[ { "id": "955", "type": "title", "text": [ "Chasing the ubiquitous RET proto-oncogene in South African MEN2 families--implications for the surgeon." ], "offsets": [ [ 0, 103 ] ] }, { "id": "956", "type": "abstract", "text": [ "The RET proto-oncogene (REarranged during Transfection; RET) plays an important role in the causation of many thyroid tumours. Germline RET proto-oncogene missense mutations have been clearly linked to medullary thyroid carcinoma (MTC) and the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2A, MEN2B). METHODS: We investigated a cohort of MEN2-related patients referred to Tygerberg Hospital, W Cape (2003-2009). The study cohort was divided into three groups based on pathology (viz. MEN/MTC, phaeochromocytoma, and a miscellaneous group of MEN pathologies). Families with identified high-risk factors were recalled. Serum calcitonin levels were monitored where indicated. DNA was extracted from whole blood by standard techniques and polymerase chain reaction (PCR) products screened for RET gene variations by heteroduplex single-strand duplication techniques (heteroduplex single-strand conformation polymorphism analysis) being validated with automated sequencing techniques showing conformational variants in acrylamide gel. RESULTS: We screened 40 persons, male/female ratio 1:1.5. Three ethnic groups were represented (white (12), black (11) and mixed race (17)). Nine were index MTC cases, 5 phaeochromocytoma, 3 Hirschsprung's disease-MEN associations and 2 miscellaneous (1 neuroblastoma, 1 intestinal neuronal dysplasia), while 1 fell into the MEN2B category. The remaining 19 were unaffected relatives screened for carrier status, among whom afamilial recurrence was observed in 7. On genetic testing, an RET point mutation at the high-risk 634 cysteine allele was identified in 11 cases. A further cysteine radical mutation at the 620 position was related to MEN2 in 3 families plus 1 other family referred from elsewhere. Other less-recognised gene variations were detected throughout the RET gene in 70% of cases and included the 691 position on codon 11 (11 cases); the 432 position (4 cases, 1 homozygous) intronic mutations on exon 4 (1 case); and an IVS19-37G/C and a D1017N variation in exon 19 in 2 MEN families. Fifteen MTC patients have had thyroidectomies, of which 2 were prophylactic (C-cell hyperplasia; early occult MTC). A further 3 are awaiting prophylactic surgery. CONCLUSION: RET gene mutation carries a risk of MEN2 and MTC in all ethnic groups in South Africa. Prophylactic surgery may prevent MTC, so genetic screening is important to identify and treat high-risk patients." ], "offsets": [ [ 104, 2534 ] ] } ]

[ { "id": "953", "type": "DNAMutation", "text": [ "IVS19-37G/C" ], "offsets": [ [ 2094, 2105 ] ], "normalized": [] }, { "id": "954", "type": "ProteinMutation", "text": [ "D1017N" ], "offsets": [ [ 2112, 2118 ] ], "normalized": [] } ]

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[ { "id": "960", "type": "title", "text": [ "Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD." ], "offsets": [ [ 0, 108 ] ] }, { "id": "961", "type": "abstract", "text": [ "Homozygous or compound heterozygous mutations in renin (REN) cause renal tubular dysgenesis, which is characterized by death in utero due to kidney failure and pulmonary hypoplasia. The phenotype resembles the fetopathy caused by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker intake during pregnancy. Recently, heterozygous REN mutations were shown to result in early-onset hyperuricemia, anemia, and chronic kidney disease (CKD). To date, only 3 different heterozygous REN mutations have been published. We report mutation analysis of the REN gene in 39 kindreds with hyperuricemia and CKD who previously tested negative for mutations in the UMOD (uromodulin) and HNF1B (hepatocyte nuclear factor 1b) genes. We identified one kindred with a novel thymidine to cytosine mutation at position 28 in the REN complementary DNA, corresponding to a tryptophan to arginine substitution at amino acid 10, which is found within the signal sequence (c.28T>C; p.W10R). On this basis, we conclude that REN mutations are rare events in patients with CKD. Within the kindred, we found affected individuals over 4 generations who carried the novel REN mutation and were characterized by significant anemia, hyperuricemia, and CKD. Anemia was severe and disproportional to the degree of decreased kidney function. Because all heterozygous REN mutations that have been described are localized in the signal sequence, screening of the REN gene for patients with CKD with hyperuricemia and anemia may best be focused on sequencing of exon 1, which encodes the signal peptide." ], "offsets": [ [ 109, 1691 ] ] } ]

[ { "id": "958", "type": "DNAMutation", "text": [ "c.28T>C" ], "offsets": [ [ 1075, 1082 ] ], "normalized": [] }, { "id": "959", "type": "ProteinMutation", "text": [ "p.W10R" ], "offsets": [ [ 1084, 1090 ] ], "normalized": [] } ]

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[ { "id": "963", "type": "title", "text": [ "Detection of possible restriction sites for type II restriction enzymes in DNA sequences." ], "offsets": [ [ 0, 89 ] ] }, { "id": "964", "type": "abstract", "text": [ "In order to make a step forward in the knowledge of the mechanism operating in complex polygenic disorders such as diabetes and obesity, this paper proposes a new algorithm (PRSD -possible restriction site detection) and its implementation in Applied Genetics software. This software can be used for in silico detection of potential (hidden) recognition sites for endonucleases and for nucleotide repeats identification. The recognition sites for endonucleases may result from hidden sequences through deletion or insertion of a specific number of nucleotides. Tests were conducted on DNA sequences downloaded from NCBI servers using specific recognition sites for common type II restriction enzymes introduced in the software database (n = 126). Each possible recognition site indicated by the PRSD algorithm implemented in Applied Genetics was checked and confirmed by NEBcutter V2.0 and Webcutter 2.0 software. In the sequence NG_008724.1 (which includes 63632 nucleotides) we found a high number of potential restriction sites for ECO R1 that may be produced by deletion (n = 43 sites) or insertion (n = 591 sites) of one nucleotide. The second module of Applied Genetics has been designed to find simple repeats sizes with a real future in understanding the role of SNPs (Single Nucleotide Polymorphisms) in the pathogenesis of the complex metabolic disorders. We have tested the presence of simple repetitive sequences in five DNA sequence. The software indicated exact position of each repeats detected in the tested sequences. Future development of Applied Genetics can provide an alternative for powerful tools used to search for restriction sites or repetitive sequences or to improve genotyping methods." ], "offsets": [ [ 90, 1804 ] ] } ]

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[ { "id": "966", "type": "title", "text": [ "Carboxy-terminal sequence variation of LMP1 gene in Epstein-Barr-virus-associated mononucleosis and tumors from Serbian patients." ], "offsets": [ [ 0, 129 ] ] }, { "id": "967", "type": "abstract", "text": [ "Seven strains of Epstein-Barr virus (EBV) are defined based on C-terminal sequence variations of the latent membrane protein 1 (LMP1). Some strains, especially those with a 30-bp deletion, are thought to be related to tumorigenic activity and geographical localization. The aims of the study were to determine the prevalence of different LMP1 strains and to investigate sequence variation in the C-terminal region of LMP1 in Serbian isolates. This study included 53 EBV-DNA-positive plasma and tissue block samples from patients with mononucleosis syndrome, renal transplantation, and tumors, mostly nasopharyngeal carcinoma. The sequence of the 506-bp fragment of LMP1 C terminus was used for phylogenetic analyses and identification of LMP1 strains, deletions, and mutations. The majority of isolates were non-deleted (66%), and the rest had 30-bp, rare 69-bp, or yet unknown 27-bp deletions, which were not related to malignant or non-malignant isolate origin. However, the majority of 69-bp deletion isolates were derived from patients with nasopharyngeal carcinoma. Less than five 33-bp repeats were found in the majority of non-deleted isolates (68.6%), whereas most 69-bp deletion isolates (75%) had five or six repeats. Serbian isolates were assigned to four LMP1 strains: B95-8 (32.1%), China 1 (24.5%), North Carolina (NC; 18.9%), and Mediterranean (Med; 24.5%). In NC isolates, three new mutations unique for this strain were identified. EBV EBNA2 genotypes 1 and 2 were both found, with dominance of genotype 1 (90.7%). This study demonstrated noticeable geographical-associated characteristics in the LMP1 C terminus of investigated isolates." ], "offsets": [ [ 130, 1787 ] ] } ]

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[ { "id": "970", "type": "title", "text": [ "Roles of G1359A polymorphism of the cannabinoid receptor gene (CNR1) on weight loss and adipocytokines after a hypocaloric diet." ], "offsets": [ [ 0, 128 ] ] }, { "id": "971", "type": "abstract", "text": [ "BACKGROUND: A intragenic biallelic polymorphism (1359 G/A) of the CB1 gene resulting in the substitution of the G to A at nucleotide position 1359 in codon 435 (Thr), was reported as a common polymorphism in Caucasian populations. Intervention studies with this polymorphism have not been realized. OBJECTIVE: We decided to investigate the role of the polymorphism (G1359A) of CB1 receptor gene on adipocytokines response and weight loss secondary to a lifestyle modification (Mediterranean hypocaloric diet and exercise) in obese patients. DESIGN: A population of 94 patients with obesity was analyzed. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for the combined G1359A and A1359A as a group and wild type G1359G as second group, with a dominant model. Results: Forty seven patients (50%) had the genotype G1359G (wild type group) and 47 (50%) patients G1359A (41 patients, 43.6%) or A1359A (6 patients, 6.4%) (mutant type group) had the genotype. In wild and mutant type groups, weight, body mass index, fat mass, waist circumference and systolic blood pressure decreased. In mutant type group, resistin (4.15 1.7 ng/ml vs. 3.90 2.1 ng/ml: P < 0.05), leptin (78.4 69 ng/ml vs 66.2 32 ng/ml: P < 0.05) and IL-6 (1.40 1.9 pg/ml vs 0.81 1.5 pg/ml: P < 0.05) levels decreased after dietary treatment. CONCLUSION: The novel finding of this study is the association of the mutant allele (A1359) with a decrease of resistin, leptin and interleukin-6 secondary to weight loss." ], "offsets": [ [ 129, 1771 ] ] } ]

[ { "id": "969", "type": "DNAMutation", "text": [ "1359 G/A" ], "offsets": [ [ 178, 186 ] ], "normalized": [] } ]

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[ { "id": "975", "type": "title", "text": [ "Large contiguous gene deletions in Sj gren-Larsson syndrome." ], "offsets": [ [ 0, 61 ] ] }, { "id": "976", "type": "abstract", "text": [ "Sj gren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis." ], "offsets": [ [ 62, 1535 ] ] } ]

[ { "id": "973", "type": "DNAMutation", "text": [ "c.407C>T" ], "offsets": [ [ 1186, 1194 ] ], "normalized": [] }, { "id": "974", "type": "ProteinMutation", "text": [ "P136L" ], "offsets": [ [ 1196, 1201 ] ], "normalized": [] } ]

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[ { "id": "984", "type": "title", "text": [ "OPA1 mutations in Japanese patients suspected to have autosomal dominant optic atrophy." ], "offsets": [ [ 0, 87 ] ] }, { "id": "985", "type": "abstract", "text": [ "PURPOSE: To report three types of heterozygous mutations in the OPA1 gene in five patients from three families with autosomal dominant optic atrophy (ADOA, MIM#165500). METHODS: DNA was extracted from the leukocytes of the peripheral blood. For mtDNA, mutations were examined at positions 11778, 3460 and 14484. For the OPA1 gene, the exons were amplified by PCR and mutations were detected by restriction enzymes or the dye terminator method. RESULTS: We detected three types of OPA1 mutation but no mtDNA mutations. In the OPA1 gene, heterozygous frameshift mutations from codon 903 due to a four-base pair deletion in exon 27 were detected in three patients from one family (c.2708_2711delTTAG, p.V903GfsX905). A heterozygous mutation due to a three-base pair deletion in exon 17, leading to a one-amino acid deletion (c.1618_1620delACT, p.T540del), and a heterozygous mutation due to a one-base substitution in exon 11, leading to a stop codon (c.1084G>T, p.E362X), were detected in sporadic cases. CONCLUSION: OPA1 mutations existed in three Japanese families with ADOA. After a detailed clinical assessment of the proband, the screening of the OPA1 gene may be helpful for precise diagnosis of ADOA, provided the relevant information of the family members is limited." ], "offsets": [ [ 88, 1361 ] ] } ]

[ { "id": "978", "type": "DNAMutation", "text": [ "c.2708_2711delTTAG" ], "offsets": [ [ 766, 784 ] ], "normalized": [] }, { "id": "979", "type": "ProteinMutation", "text": [ "p.V903GfsX905" ], "offsets": [ [ 786, 799 ] ], "normalized": [] }, { "id": "980", "type": "DNAMutation", "text": [ "c.1618_1620delACT" ], "offsets": [ [ 910, 927 ] ], "normalized": [] }, { "id": "981", "type": "ProteinMutation", "text": [ "p.T540del" ], "offsets": [ [ 929, 938 ] ], "normalized": [] }, { "id": "982", "type": "DNAMutation", "text": [ "c.1084G>T" ], "offsets": [ [ 1037, 1046 ] ], "normalized": [] }, { "id": "983", "type": "ProteinMutation", "text": [ "p.E362X" ], "offsets": [ [ 1048, 1055 ] ], "normalized": [] } ]

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[ { "id": "989", "type": "title", "text": [ "Interleukin-17F gene polymorphism in patients with chronic immune thrombocytopenia." ], "offsets": [ [ 0, 83 ] ] }, { "id": "990", "type": "abstract", "text": [ "INTRODUCTION: IL-17F is a novel inflammatory cytokine and plays an important role in some autoimmune diseases. We investigated the association between chronic ITP and the frequency of the single-nucleotide polymorphism rs763780 (7488T/C), which causes a His-to-Arg substitution at amino acid 161. PATIENTS AND METHODS: We examined 102 patients (men/women, 40/62; median age, 42) diagnosed with chronic ITP and 188 healthy controls (men/women, 78/110; median age, 38). Genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: Compared with the control group, patients with chronic ITP had a significantly lower frequency of the IL-17F 7488CC genotype (0% vs. 4.8%, P<0.05). The number of IL-17F 7488C alleles among the patients with chronic ITP was also significantly lower than in the control group (8.7% vs. 15.2% OR=0.48, 95%CI=0.27-0.84, P=0.016). Furthermore, patients with the IL-17F 7488TT genotype showed a severe thrombocytopenic state (platelet count<10 10(9) /L) at diagnosis than those with the IL-17F 7488TC genotype (20.9% vs. 0%, P=0.04). CONCLUSION: These findings suggest that the IL-17F 7488 T allele is significantly associated with the development of chronic ITP, suggesting a role for IL-17F in the pathogenesis of chronic ITP." ], "offsets": [ [ 84, 1405 ] ] } ]

[ { "id": "987", "type": "SNP", "text": [ "rs763780" ], "offsets": [ [ 303, 311 ] ], "normalized": [] }, { "id": "988", "type": "DNAMutation", "text": [ "7488T/C" ], "offsets": [ [ 313, 320 ] ], "normalized": [] } ]

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[ { "id": "992", "type": "title", "text": [ "Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome." ], "offsets": [ [ 0, 107 ] ] }, { "id": "993", "type": "abstract", "text": [ "Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a \"second hit,\" that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome." ], "offsets": [ [ 108, 1967 ] ] } ]

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[ { "id": "1022", "type": "title", "text": [ "The TREX1 exonuclease R114H mutation in Aicardi-Gouti res syndrome and lupus reveals dimeric structure requirements for DNA degradation activity." ], "offsets": [ [ 0, 146 ] ] }, { "id": "1023", "type": "abstract", "text": [ "Mutations in the TREX1 gene cause Aicardi-Gouti res syndrome (AGS) and are linked to the autoimmune disease systemic lupus erythematosus. The TREX1 protein is a dimeric 3' DNA exonuclease that degrades DNA to prevent inappropriate immune activation. One of the most common TREX1 mutations, R114H, causes AGS as a homozygous and compound heterozygous mutation and is found as a heterozygous mutation in systemic lupus erythematosus. The TREX1 proteins containing R114H and the insertion mutations aspartate at position 201 (D201ins) and alanine at position 124 (A124ins), found in compound heterozygous AGS with R114H, were prepared and the DNA degradation activities were tested. The homodimer TREX1(R114H/R114H) exhibits a 23-fold reduced single-stranded DNA (ssDNA) exonuclease activity relative to TREX1(WT). The TREX1(D201ins/D201ins) and TREX1(A124ins/A124ins) exhibit more than 10,000-fold reduced ssDNA degradation activities. However, the TREX1(R114H/D201ins) and TREX1(R114H/A124ins) compound heterodimers exhibit activities 10-fold greater than the TREX1(R114H/R114H) homodimer during ssDNA and double-stranded DNA (dsDNA) degradation. These higher levels of activities measured in the TREX1(R114H/D201ins) and TREX1(R114H/A124ins) compound heterodimers are attributed to Arg-114 residues of TREX1(D201ins) and TREX1(A124ins) positioned at the dimer interface contributing to the active sites of the opposing TREX1(R114H) protomer. This interpretation is further supported by exonuclease activities measured for TREX1 enzymes containing R114A and R114K mutations. These biochemical data provide direct evidence for TREX1 residues in one protomer contributing to DNA degradation catalyzed in the opposing protomer and help to explain the dimeric TREX1 structure required for full catalytic competency." ], "offsets": [ [ 147, 1958 ] ] } ]

[ { "id": "995", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 22, 27 ] ], "normalized": [] }, { "id": "996", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 438, 443 ] ], "normalized": [] }, { "id": "997", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 610, 615 ] ], "normalized": [] }, { "id": "998", "type": "ProteinMutation", "text": [ "D201ins" ], "offsets": [ [ 671, 678 ] ], "normalized": [] }, { "id": "999", "type": "ProteinMutation", "text": [ "A124ins" ], "offsets": [ [ 709, 716 ] ], "normalized": [] }, { "id": "1000", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 759, 764 ] ], "normalized": [] }, { "id": "1001", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 848, 853 ] ], "normalized": [] }, { "id": "1002", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 854, 859 ] ], "normalized": [] }, { "id": "1003", "type": "ProteinMutation", "text": [ "D201ins" ], "offsets": [ [ 970, 977 ] ], "normalized": [] }, { "id": "1004", "type": "ProteinMutation", "text": [ "D201ins" ], "offsets": [ [ 978, 985 ] ], "normalized": [] }, { "id": "1005", "type": "ProteinMutation", "text": [ "A124ins" ], "offsets": [ [ 997, 1004 ] ], "normalized": [] }, { "id": "1006", "type": "ProteinMutation", "text": [ "A124ins" ], "offsets": [ [ 1005, 1012 ] ], "normalized": [] }, { "id": "1007", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1101, 1106 ] ], "normalized": [] }, { "id": "1008", "type": "ProteinMutation", "text": [ "D201ins" ], "offsets": [ [ 1107, 1114 ] ], "normalized": [] }, { "id": "1009", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1126, 1131 ] ], "normalized": [] }, { "id": "1010", "type": "ProteinMutation", "text": [ "A124ins" ], "offsets": [ [ 1132, 1139 ] ], "normalized": [] }, { "id": "1011", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1213, 1218 ] ], "normalized": [] }, { "id": "1012", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1219, 1224 ] ], "normalized": [] }, { "id": "1013", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1350, 1355 ] ], "normalized": [] }, { "id": "1014", "type": "ProteinMutation", "text": [ "D201ins" ], "offsets": [ [ 1356, 1363 ] ], "normalized": [] }, { "id": "1015", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1375, 1380 ] ], "normalized": [] }, { "id": "1016", "type": "ProteinMutation", "text": [ "A124ins" ], "offsets": [ [ 1381, 1388 ] ], "normalized": [] }, { "id": "1017", "type": "ProteinMutation", "text": [ "D201ins" ], "offsets": [ [ 1456, 1463 ] ], "normalized": [] }, { "id": "1018", "type": "ProteinMutation", "text": [ "A124ins" ], "offsets": [ [ 1475, 1482 ] ], "normalized": [] }, { "id": "1019", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1573, 1578 ] ], "normalized": [] }, { "id": "1020", "type": "ProteinMutation", "text": [ "R114A" ], "offsets": [ [ 1695, 1700 ] ], "normalized": [] }, { "id": "1021", "type": "ProteinMutation", "text": [ "R114K" ], "offsets": [ [ 1705, 1710 ] ], "normalized": [] } ]

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[ { "id": "1030", "type": "title", "text": [ "Genetic polymorphism of the glutathione-S-transferase P1 gene (GSTP1) and susceptibility to prostate cancer in the Kashmiri population." ], "offsets": [ [ 0, 135 ] ] }, { "id": "1031", "type": "abstract", "text": [ "Glutathione-S-transferase P1 (GSTP1) is a critical enzyme of the phase II detoxification pathway. One of the common functional polymorphisms of GSTP1 is A > G at nucleotide 313, which results in an amino acid substitution (Ile105Val) at the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. To investigate the GSTP1 Ile105Val genotype frequency in prostate cancer cases in the Kashmiri population, we designed a case-control study, in which 50 prostate cancer cases and 45 benign prostate hyperplasia cases were studied for GSTP1 Ile105Val polymorphism, compared to 80 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of GSTP1 Ile105Val in our ethnic Kashmir population, i.e., Ile/Ile, Ile/Val and Val/Val, to be 52.4, 33.3 and 14.3% among prostate cancer cases, 48.5, 37.5 and 14% among benign prostate hyperplasia cases and 73.8, 21.3 and 5% in the control population, respectively. There was a significant association between the GSTP1 Ile/Val genotype and the advanced age group among the cases. We conclude that GSTP1 Ile/Val polymorphism is involved in the risk of prostate cancer development in our population." ], "offsets": [ [ 136, 1361 ] ] } ]

[ { "id": "1025", "type": "DNAMutation", "text": [ "A > G at nucleotide 313" ], "offsets": [ [ 289, 312 ] ], "normalized": [] }, { "id": "1026", "type": "ProteinMutation", "text": [ "Ile105Val" ], "offsets": [ [ 359, 368 ] ], "normalized": [] }, { "id": "1027", "type": "ProteinMutation", "text": [ "Ile105Val" ], "offsets": [ [ 475, 484 ] ], "normalized": [] }, { "id": "1028", "type": "ProteinMutation", "text": [ "Ile105Val" ], "offsets": [ [ 689, 698 ] ], "normalized": [] }, { "id": "1029", "type": "ProteinMutation", "text": [ "Ile105Val" ], "offsets": [ [ 871, 880 ] ], "normalized": [] } ]

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[ { "id": "1035", "type": "title", "text": [ "Identification of LIPH gene mutation in a consanguineous family segregating the woolly hair/hypotrichosis phenotype." ], "offsets": [ [ 0, 116 ] ] }, { "id": "1036", "type": "abstract", "text": [ "OBJECTIVE: To identify the disease causing gene in a four generation consanguineous family in which eleven family members were suffering from Woolly hair/hypotrichosis phenotype. METHODS: Linkage analysis was carried out to identify the disease-causing gene in this family. Genomic DNA of all the available family members was genotyped for the microsatellite markers for all the known woolly hair/hypotrichosis loci.Automated DNA sequencing of the candidate gene was performed to identify the disease-causing mutation. RESULTS: By using homozygosity linkage analysis we have mapped the family on chromosome 3q27.3 with a two point LOD score of 4.04, Mutation screening of the LIPH gene revealed a homozygous c.659_660delTA deletion mutation segregating with the disease phenotype. CONCLUSION: The results indicate that the c.659_660delTA mutation in the LIPH gene cause autosomal recessive WH/hypotrichosis phenotype in this family. This mutation has been reported in several Pakistani and Guyanese families suggesting a founder mutation in the LIPH gene in Indo-Pak sub-continent." ], "offsets": [ [ 117, 1198 ] ] } ]

[ { "id": "1033", "type": "DNAMutation", "text": [ "c.659_660delTA" ], "offsets": [ [ 825, 839 ] ], "normalized": [] }, { "id": "1034", "type": "DNAMutation", "text": [ "c.659_660delTA" ], "offsets": [ [ 940, 954 ] ], "normalized": [] } ]

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[ { "id": "1039", "type": "title", "text": [ "Familial glucocorticoid receptor haploinsufficiency by non-sense mediated mRNA decay, adrenal hyperplasia and apparent mineralocorticoid excess." ], "offsets": [ [ 0, 144 ] ] }, { "id": "1040", "type": "abstract", "text": [ "Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11b-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension." ], "offsets": [ [ 145, 2464 ] ] } ]

[ { "id": "1038", "type": "ProteinMutation", "text": [ "p.R469[R,X]" ], "offsets": [ [ 687, 698 ] ], "normalized": [] } ]

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[ { "id": "1042", "type": "title", "text": [ "cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control." ], "offsets": [ [ 0, 118 ] ] }, { "id": "1043", "type": "abstract", "text": [ "BACKGROUND: HCN channels activate the pacemaker current I(f), which is thought to contribute significantly to generation and regulation of heart rhythm. HCN4 represents the dominant isotype in the sinoatrial node and binding of cAMP was suggested to be necessary for autonomic heart rate regulation. METHODS AND RESULTS: In a candidate gene approach, a heterozygous insertion of 13 nucleotides in exon 6 of the HCN4 gene leading to a truncated cyclic nucleotide-binding domain was identified in a 45-year-old woman with sinus bradycardia. Biophysical properties determined by whole-cell patch-clamp recording of HEK293 cells demonstrated that mutant subunits (HCN4-695X) were insensitive to cAMP. Heteromeric channels composed of wild-type and mutant subunits failed to respond to cAMP-like homomeric mutant channels, indicating a dominant-negative suppression of cAMP-induced channel activation by mutant subunits. Pedigree analysis identified 7 additional living carriers showing similar clinical phenotypes, that is, sinus node dysfunction with mean resting heart rate of 45.9 4.6 bpm (n=8) compared with 66.5 9.1 bpm of unaffected relatives (n=6; P<0.01). Clinical evaluation revealed no ischemic or structural heart disease in any family member. Importantly, mutant carriers exhibited normal heart rate variance and full ability to accelerate heart rate under physical activity or pharmacological stimulation. Moreover, mutant carriers displayed distinctive sinus arrhythmias and premature beats linked to adrenergic stress. CONCLUSIONS: In humans, cAMP responsiveness of I(f) determines basal heart rate but is not critical for maximum heart rate, heart rate variability, or chronotropic competence. Furthermore, cAMP-activated I(f) may stabilize heart rhythm during chronotropic response." ], "offsets": [ [ 119, 1916 ] ] } ]

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[ { "id": "1046", "type": "title", "text": [ "A novel homozygous splice site mutation in COL7A1 in a Chinese patient with severe recessive dystrophic epidermolysis bullosa and squamous cell carcinoma." ], "offsets": [ [ 0, 154 ] ] }, { "id": "1047", "type": "abstract", "text": [ "BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering skin disorder caused by mutations in COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils in the dermo-epidermal junction. The development of cutaneous squamous cell carcinoma (SCC) is one of the most serious complications of this disease. We report herein a Chinese patient with the severe generalized subtype of RDEB (RDEB-sev gen) complicated by SCC. METHODS: Skin biopsies were examined for histology, basement membrane ultrastructure, and type VII collagen expression. Genomic DNA was extracted from the peripheral blood samples and subjected to polymerase chain reaction amplification and direct automated DNA sequencing. RESULTS: Histopathological examination of the patient's skin revealed an undetectable expression of type VII collagen polypeptides in the basement membrane zone. Mutation analysis identified a novel splice site mutation in intron 64 (IVS64+5g->a) of COL7A1 gene, which resulted in an in-frame deletion of exon 64 in both alleles. CONCLUSIONS: This report contributes to the expanding database of COL7A1 mutations and emphasizes the need to elucidate the underlying genetic mechanisms associated with the increased incidence of SCC in RDEB patients." ], "offsets": [ [ 155, 1448 ] ] } ]

[ { "id": "1045", "type": "DNAMutation", "text": [ "IVS64+5g->a" ], "offsets": [ [ 1134, 1145 ] ], "normalized": [] } ]

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[ { "id": "1055", "type": "title", "text": [ "Molecular diagnosis of 46,XY DSD and identification of a novel 8 nucleotide deletion in exon 1 of the SRD5A2 gene." ], "offsets": [ [ 0, 114 ] ] }, { "id": "1056", "type": "abstract", "text": [ "Phenotypic presentation of 46,XY DSD depends on the underlying defects. Defect in androgen action on the target tissues or production of active metabolite share common morphological features. Molecular study may help differentiating these abnormalities with precision. Mutational analysis of androgen receptor (AR) and SRD5A2 genes was performed in 29 patients with 46,XY DSD, by PCR-SSCP. The amplicons that showed an aberrant migration in SSCP were subjected to sequencing. Interestingly, six patients from 4 unrelated families (a pair of sibs, uncle/nephew and other two isolated) were identified with mutations in SRD5A2 gene. In five patients p.R246Q missense mutation was detected, of which four were homozygous and one was compound heterozygous: g.80_87delT CGCGAAG (p.A27fsX132) and p.R246Q. Another patient with isolated micropenis harbored a heterozygous p.G196S missense mutation. No AR gene mutation was detected. In conclusion, our study suggests that p.R246Q mutation is common amongst patients with SRD5A2 gene defect from the Northern states of India. Also, it records a novel deletion in exon 1 of SRD5A2 gene in a patient with severe hypospadias." ], "offsets": [ [ 115, 1279 ] ] } ]

[ { "id": "1049", "type": "ProteinMutation", "text": [ "p.R246Q" ], "offsets": [ [ 763, 770 ] ], "normalized": [] }, { "id": "1050", "type": "DNAMutation", "text": [ "g.80_87delT CGCGAAG" ], "offsets": [ [ 868, 887 ] ], "normalized": [] }, { "id": "1051", "type": "ProteinMutation", "text": [ "p.A27fsX132" ], "offsets": [ [ 889, 900 ] ], "normalized": [] }, { "id": "1052", "type": "ProteinMutation", "text": [ "p.R246Q" ], "offsets": [ [ 906, 913 ] ], "normalized": [] }, { "id": "1053", "type": "ProteinMutation", "text": [ "p.G196S" ], "offsets": [ [ 980, 987 ] ], "normalized": [] }, { "id": "1054", "type": "ProteinMutation", "text": [ "p.R246Q" ], "offsets": [ [ 1080, 1087 ] ], "normalized": [] } ]

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[ { "id": "1066", "type": "title", "text": [ "A novel mutation screening system for Ehlers-Danlos Syndrome, vascular type by high-resolution melting curve analysis in combination with small amplicon genotyping using genomic DNA." ], "offsets": [ [ 0, 182 ] ] }, { "id": "1067", "type": "abstract", "text": [ "Ehlers-Danlos syndrome, vascular type (vEDS) (MIM #130050) is an autosomal dominant disorder caused by type III procollagen gene (COL3A1) mutations. Most COL3A1 mutations are detected by using total RNA from patient-derived fibroblasts, which requires an invasive skin biopsy. High-resolution melting curve analysis (hrMCA) has recently been developed as a post-PCR mutation scanning method which enables simple, rapid, cost-effective, and highly sensitive mutation screening of large genes. We established a hrMCA method to screen for COL3A1 mutations using genomic DNA. PCR primers pairs for COL3A1 (52 amplicons) were designed to cover all coding regions of the 52 exons, including the splicing sites. We used 15 DNA samples (8 validation samples and 7 samples of clinically suspected vEDS patients) in this study. The eight known COL3A1 mutations in validation samples were all successfully detected by the hrMCA. In addition, we identified five novel COL3A1 mutations, including one deletion (c.2187delA) and one nonsense mutation (c.2992C>T) that could not be determined by the conventional total RNA method. Furthermore, we established a small amplicon genotyping (SAG) method for detecting three high frequency coding-region SNPs (rs1800255:G>A, rs1801184:T>C, and rs2271683:A>G) in COL3A1 to differentiate mutations before sequencing. The use of hrMCA in combination with SAG from genomic DNA enables rapid detection of COL3A1 mutations with high efficiency and specificity. A better understanding of the genotype-phenotype correlation in COL3A1 using this method will lead to improve in diagnosis and treatment." ], "offsets": [ [ 183, 1804 ] ] } ]

[ { "id": "1058", "type": "DNAMutation", "text": [ "c.2187delA" ], "offsets": [ [ 1181, 1191 ] ], "normalized": [] }, { "id": "1059", "type": "DNAMutation", "text": [ "c.2992C>T" ], "offsets": [ [ 1220, 1229 ] ], "normalized": [] }, { "id": "1060", "type": "SNP", "text": [ "rs1800255" ], "offsets": [ [ 1422, 1431 ] ], "normalized": [] }, { "id": "1061", "type": "DNAMutation", "text": [ "G>A" ], "offsets": [ [ 1432, 1435 ] ], "normalized": [] }, { "id": "1062", "type": "SNP", "text": [ "rs1801184" ], "offsets": [ [ 1437, 1446 ] ], "normalized": [] }, { "id": "1063", "type": "DNAMutation", "text": [ "T>C" ], "offsets": [ [ 1447, 1450 ] ], "normalized": [] }, { "id": "1064", "type": "SNP", "text": [ "rs2271683" ], "offsets": [ [ 1456, 1465 ] ], "normalized": [] }, { "id": "1065", "type": "DNAMutation", "text": [ "A>G" ], "offsets": [ [ 1466, 1469 ] ], "normalized": [] } ]

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[ { "id": "1071", "type": "title", "text": [ "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta." ], "offsets": [ [ 0, 103 ] ] }, { "id": "1072", "type": "abstract", "text": [ "Osteogenesis imperfecta, or \"brittle bone disease,\" is a type I collagen-related condition associated with osteoporosis and increased risk of bone fractures. Using a combination of homozygosity mapping and candidate gene approach, we have identified a homozygous single base pair deletion (c.1052delA) in SP7/Osterix (OSX) in an Egyptian child with recessive osteogenesis imperfecta. The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera. OSX encodes a transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus, which, in mice, has been shown to be essential for bone formation. The frameshift caused by the c.1052delA deletion removes the last 81 amino acids of the protein, including the third zinc-finger motif. This finding adds another locus to the spectrum of genes associated with osteogenesis imperfecta and reveals that SP7/OSX also plays a key role in human bone development." ], "offsets": [ [ 104, 1124 ] ] } ]

[ { "id": "1069", "type": "DNAMutation", "text": [ "c.1052delA" ], "offsets": [ [ 394, 404 ] ], "normalized": [] }, { "id": "1070", "type": "DNAMutation", "text": [ "c.1052delA" ], "offsets": [ [ 847, 857 ] ], "normalized": [] } ]

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[ { "id": "1077", "type": "title", "text": [ "A Taiwanese boy with congenital generalized lipodystrophy caused by homozygous Ile262fs mutation in the BSCL2 gene." ], "offsets": [ [ 0, 115 ] ] }, { "id": "1078", "type": "abstract", "text": [ "Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease that is characterized by a near-complete absence of adipose tissue from birth or early infancy. Mutations in the BSCL2 gene are known to result in CGL2, a more severe phenotype than CGL1, with earlier onset, more extensive fat loss and biochemical changes, more severe intellectual impairment, and more severe cardiomyopathy. We report a 3-month-old Taiwanese boy with initial presentation of a lack of subcutaneous fat, prominent musculature, generalized eruptive xanthomas, and extreme hypertriglyceridemia. Absence of mechanical adipose tissue in the orbits and scalp was revealed by head magnetic resonance imaging. Hepatomegaly was noticed, and histological examination of a liver biopsy specimen suggested severe hepatic steatosis and periportal necrosis. However, echocardiography indicated no sign of cardiomyopathy and he showed no distinct intellectual impairment that interfered with daily life. About 1 year later, abdominal computed tomography revealed enlargement of kidneys. He had a homozygous insertion of a nucleotide, 783insG (Ile262fs mutation), in exon 7 of the BSCL2 gene. We reviewed the genotype of CGL cases from Japan, India, China and Taiwan, and found that BSCL2 is a major causative gene for CGL in Asian." ], "offsets": [ [ 116, 1431 ] ] } ]

[ { "id": "1074", "type": "ProteinMutation", "text": [ "Ile262fs" ], "offsets": [ [ 79, 87 ] ], "normalized": [] }, { "id": "1075", "type": "DNAMutation", "text": [ "783insG" ], "offsets": [ [ 1234, 1241 ] ], "normalized": [] }, { "id": "1076", "type": "ProteinMutation", "text": [ "Ile262fs" ], "offsets": [ [ 1243, 1251 ] ], "normalized": [] } ]

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[ { "id": "1080", "type": "title", "text": [ "8q24 allelic imbalance and MYC gene copy number in primary prostate cancer." ], "offsets": [ [ 0, 75 ] ] }, { "id": "1081", "type": "abstract", "text": [ "Four independent regions within 8q24 near the MYC gene are associated with risk for prostate cancer (Pca). Here, we investigated allelic imbalance (AI) at 8q24 risk variants and MYC gene DNA copy number (CN) in 27 primary Pcas. Heterozygotes were observed in 24 of 27 patients at one or more 8q24 markers and 27% of the loci exhibited AI in tumor DNA. The 8q24 risk alleles were preferentially favored in the tumors. Increased MYC gene CN was observed in 33% of tumors, and the co-existence of increased MYC gene CN with AI at risk loci was observed in 86% (P<0.004 exact binomial test) of the informative tumors. No AI was observed in tumors, which did not reveal increased MYC gene CN. Higher Gleason score was associated with tumors exhibiting AI (P=0.04) and also with increased MYC gene CN (P=0.02). Our results suggest that AI at 8q24 and increased MYC gene CN may both be related to high Gleason score in Pca. Our findings also suggest that these two somatic alterations may be due to the same preferential chromosomal duplication event during prostate tumorigenesis." ], "offsets": [ [ 76, 1150 ] ] } ]

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[ { "id": "1083", "type": "title", "text": [ "Lack of p16 gene mutations in gastric cancers in Kashmir." ], "offsets": [ [ 0, 57 ] ] }, { "id": "1084", "type": "abstract", "text": [ "BACKGROUND AND AIM: The focus of the study was to investigate the frequencies of homozygous deletions and mutations of p16 gene in gastric carcinomas in the Kashmiri population. METHODS: A total of 84 gastric carcinoma patients were screened by the single strand conformation polymorphism (SSCP) technique and later by DNA sequencing to detect mutations of the p16 gene. Also PCR was applied further to further detect any homozygous deletions. RESULTS: SSCP and DNA sequencing performed encompassing all the three exons of p16 gene could not detect any mutations in any ofl 84 cases. Though we could observe mobility shifts in SSCP of two samples, subsequent DNA sequencing did not show any mutation. Further PCR could not detect any homozygous deletion in P16 in any case. CONCLUSION: Though Kashmir is a high incidence area of gastric carcinomas, p16gene mutations /or deletions do not appear to be involved." ], "offsets": [ [ 58, 968 ] ] } ]

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[ { "id": "1086", "type": "title", "text": [ "Clinical and genetic characterization of manifesting carriers of DMD mutations." ], "offsets": [ [ 0, 79 ] ] }, { "id": "1087", "type": "abstract", "text": [ "Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in 15 manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X-chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47 years. Seven had no family history and eight had male relatives with Duchenne muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X-chromosome inactivation pattern was skewed toward non-random in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes." ], "offsets": [ [ 80, 1773 ] ] } ]

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[ { "id": "1091", "type": "title", "text": [ "Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors." ], "offsets": [ [ 0, 167 ] ] }, { "id": "1092", "type": "abstract", "text": [ "AIMS: EGFR mutations now guide the clinical use of EGFR-targeted therapy in lung cancer. However, standard EGFR mutation analysis requires a minimum amount of tumor tissue, which may not be available in certain situations. In this study, we combined a mass spectrometry genotyping assay (Sequenom) with a mutant-enriched PCR (ME-PCR) to detect EGFR mutations in free plasma DNA from patients with lung cancer. METHOD: DNAs were extracted from 31 plasma samples from 31 patients and analyzed by both methods for EGFR Exon 19 deletion and EGFR L858R mutation. Results in plasma DNA samples were compared with EGFR mutation status obtained in tumor DNA (18/31 EGFR mutant). The relationship of EGFR mutation status in tumor and/or plasma samples to overall survival was assessed. RESULTS: The EGFR mutation status in plasma DNA was identical to the primary tumor in 61% of patients (19/31). By mass spectrometry genotyping, the plasma samples contained mutant DNA corresponding to 5/14 EGFR Exon 19 deletions and 3/4 EGFR L858R mutations previously diagnosed in the matched tumors. Two samples were positive in plasma DNA but negative in primary tumor tissue. Results were similar for samples studied by ME-PCR. For patients treated with erlotinib, overall survival was correlated with the presence of EGFR mutation in plasma and/or tumor tissue (p=0.002), with the two patients positive only in plasma DNA showing responses and favorable outcomes. CONCLUSION: The detection of EGFR mutations in plasma DNA samples by mass spectrometry genotyping and ME-PCR is feasible. A positive EGFR result in plasma DNA has a high predictive value for tumor EGFR status and for favorable clinical course on EGFR-targeted therapy and could therefore be useful in guiding clinical decisions in patients with insufficient or unavailable tumor specimens." ], "offsets": [ [ 168, 2003 ] ] } ]

[ { "id": "1089", "type": "ProteinMutation", "text": [ "L858R" ], "offsets": [ [ 710, 715 ] ], "normalized": [] }, { "id": "1090", "type": "ProteinMutation", "text": [ "L858R" ], "offsets": [ [ 1187, 1192 ] ], "normalized": [] } ]

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[ { "id": "1094", "type": "title", "text": [ "Recombinant phenotyping of cytomegalovirus sequence variants detected after 200 or 100 days of valganciclovir prophylaxis." ], "offsets": [ [ 0, 122 ] ] }, { "id": "1095", "type": "abstract", "text": [ "BACKGROUND: In a phase III controlled trial IMproved Protection Against Cytomegalovirus in Transplantation (IMPACT) comparing 200 with 100 days of valganciclovir prophylaxis in 318 cytomegalovirus D+/R- kidney transplant recipients, an equal number of patients (n=3 per arm) had known ganciclovir resistance mutations detected during viral breakthrough. In addition, many other viral sequence variants were observed that were of unknown significance for ganciclovir resistance. Recombinant phenotyping was performed to determine whether the previously uncharacterized genotypic changes affected ganciclovir susceptibility, especially in those receiving the longer duration of prophylaxis. METHODS: Sequences encoding individual amino acid substitutions in the UL97 kinase or UL54 DNA polymerase gene were transferred by recombination into a cloned cytomegalovirus laboratory strain, followed by reporter-based yield reduction phenotypic assay of the resulting virus for ganciclovir susceptibility. RESULTS: Twenty-six uncharacterized amino acid substitutions were detected, 2 in UL97 and 24 in UL54. All 10 substitutions in the 200-day arm and 9 of 17 substitutions in the 100-day arm (prioritized based on location and conservation) were selected for phenotyping; one substitution was detected in both subsets. Results were generated for nine of ten 200-day and eight of nine 100-day substitutions, with no substitution demonstrating a significant reduction in ganciclovir susceptibility. The two remaining amino acid substitutions, both in UL54, were not evaluated because of poor viral viability. CONCLUSION: Phenotypic evaluation of previously uncharacterized viral genotypes in the 200-day valganciclovir prophylaxis group showed no evidence of an increased incidence of genotypic ganciclovir resistance when compared with those in the 100-day prophylaxis group." ], "offsets": [ [ 123, 1990 ] ] } ]

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[ { "id": "1098", "type": "title", "text": [ "Monoallelic thyroid peroxidase gene mutation in a patient with congenital hypothyroidism with total iodide organification defect." ], "offsets": [ [ 0, 129 ] ] }, { "id": "1099", "type": "abstract", "text": [ "The aim of this study was to identify the genetic defect of a patient with dyshormonogenetic congenital hypothyroidisms (CH) with total iodide organification defect (TIOD). A male child diagnosed with CH during neonatal screening. Laboratory tests confirmed the permanent and severe CH with TIOD (99% perchlorate release). The coding sequence of TPO, DUOX2, and DUOXA2 genes and 2957 base pairs (bp) of the TPO promoter were sequenced. Molecular analysis of patient's DNA identified the heterozygous duplication GGCC (c.1186_1187insGGCC) in exon 8 of the TPO gene. No additional mutation was detected either in the TPO gene, TPO promoter, DUOX2 or DUOXA2 genes. We have described a patient with a clear TIOD causing severe goitrous CH due to a monoallelic TPO mutation. A plausible explanation for the association between an autosomal recessive disorder with a single TPO-mutated allele is the presence of monoallelic TPO expression." ], "offsets": [ [ 130, 1063 ] ] } ]

[ { "id": "1097", "type": "DNAMutation", "text": [ "c.1186_1187insGGCC" ], "offsets": [ [ 648, 666 ] ], "normalized": [] } ]

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[ { "id": "1104", "type": "title", "text": [ "The M235T polymorphism of the angiotensinogen gene in South Indian patients of hypertrophic cardiomyopathy." ], "offsets": [ [ 0, 107 ] ] }, { "id": "1105", "type": "abstract", "text": [ "INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a complex disorder and genetically transmitted cardiac disease with a diverse clinical course. The objective of the present study was to examine the association of the T704C polymorphism of exon 2 of the angiotensinogen (AGT) gene with HCM in a South Indian population from Andhra Pradesh. Subjects and methods. One-hundred and fifty HCM (90 sporadic hypertrophic cardiomyopathy [SHCM] and 60 familial hypertrophic cardiomyopathy [FHCM]) patients and 165 age- and sex-matched normal healthy controls without known hypertension and left ventricular hypertrophy were included in the study. DNA was isolated from peripheral leukocytes and the region of interest in the AGT gene bearing a missense mutation methionine to threonine substitution at codon 235 (M235T) of exon 2, was amplified by polymerase chain reaction (PCR). The PCR products were subjected to restriction digestion with the enzyme SfaNI. RESULTS: Significant differences were detected in genotypic distribution (p = 0.04) as well as the allelic frequency (p = 0.003) between the SHCM patients and controls. The polymorphism did not show any association with FHCM. CONCLUSION: Our results suggest that the T allele of the AGT gene is significantly associated with SHCM in a South Indian population from Andhra Pradesh. However, we did not find significant association of this polymorphism with FHCM." ], "offsets": [ [ 108, 1521 ] ] } ]

[ { "id": "1101", "type": "ProteinMutation", "text": [ "M235T" ], "offsets": [ [ 4, 9 ] ], "normalized": [] }, { "id": "1102", "type": "DNAMutation", "text": [ "T704C" ], "offsets": [ [ 327, 332 ] ], "normalized": [] }, { "id": "1103", "type": "ProteinMutation", "text": [ "M235T" ], "offsets": [ [ 913, 918 ] ], "normalized": [] } ]

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[ { "id": "1109", "type": "title", "text": [ "Atypical GH insensitivity syndrome and severe insulin-like growth factor-I deficiency resulting from compound heterozygous mutations of the GH receptor, including a novel frameshift mutation affecting the intracellular domain." ], "offsets": [ [ 0, 226 ] ] }, { "id": "1110", "type": "abstract", "text": [ "BACKGROUND/AIMS: GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding protein (GHBP), but clinical evidence of GH insensitivity. METHOD: Serum and DNA samples from the proband and his parents were analyzed. RESULTS: The child had a height of -4 SD, elevated serum GH concentrations, abnormally low serum IGF-I and IGFBP-3 concentrations and normal GHBP concentrations. DNA analysis revealed compound heterozygosity for mutations of GHR, including a previously reported R211H mutation and a novel duplication of a nucleotide in exon 9 (899dupC), the latter resulting in a frameshift and a premature stop codon. Treatment with recombinant DNA-derived IGF-I resulted in growth acceleration. CONCLUSION: Mutations affecting the intracellular domain of the GHR can result in GH insensitivity and IGF deficiency, despite normal serum concentrations of GHBP. The presence of clinical and biochemical evidence of GH resistance is sufficient to consider the possibility of aberrations of the GHR, even in the presence of normal serum GHBP concentrations." ], "offsets": [ [ 227, 1413 ] ] } ]

[ { "id": "1107", "type": "ProteinMutation", "text": [ "R211H" ], "offsets": [ [ 837, 842 ] ], "normalized": [] }, { "id": "1108", "type": "DNAMutation", "text": [ "899dupC" ], "offsets": [ [ 903, 910 ] ], "normalized": [] } ]

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[ { "id": "1113", "type": "title", "text": [ "Alteration in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses." ], "offsets": [ [ 0, 135 ] ] }, { "id": "1114", "type": "abstract", "text": [ "We have found a B2 repeat insertion in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6) in a mouse that developed a skin disorder with clinical and histopathological features resembling those seen in human neutrophilic dermatoses. Neutrophilic dermatoses are a group of complex heterogeneous autoinflammatory diseases that all demonstrate excessive neutrophil infiltration of the skin. Therefore, we tested the cDNA and genomic DNA sequences of PTPN6 from patients with Sweet's syndrome (SW) and pyoderma gangrenosum and found numerous novel splice variants in different combinations. Isoforms resulting from deletions of exons 2, 5, 11, and 15 and retention of intron 1 or 5 were the most common in a patients with a familial case of SW, who had a neonatal onset of an inflammatory disorder with skin lesions and a biopsy specimen consistent with SW. These isoforms were associated with a heterozygous E441G mutation and a heterozygous 1.7-kbp deletion in the promoter region of the PTPN6 gene. Although full-length PTPN6 was detected in all other patients with either pyoderma gangrenosum or SW, it was always associated with splice variants: a partial deletion of exon 4 with the complete deletion of exon 5, alterations that were not detected in healthy controls. The defect in transcriptional regulation of the hematopoietic PTPN6 appears to be involved in the pathogenesis of certain subsets of the heterogeneous group of neutrophilic dermatoses." ], "offsets": [ [ 136, 1613 ] ] } ]

[ { "id": "1112", "type": "ProteinMutation", "text": [ "E441G" ], "offsets": [ [ 1064, 1069 ] ], "normalized": [] } ]

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[ { "id": "1119", "type": "title", "text": [ "Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family." ], "offsets": [ [ 0, 117 ] ] }, { "id": "1120", "type": "abstract", "text": [ "BACKGROUND: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. OBJECTIVES AND METHODS: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. RESULTS: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. CONCLUSION: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases." ], "offsets": [ [ 118, 1818 ] ] } ]

[ { "id": "1116", "type": "ProteinMutation", "text": [ "P799L" ], "offsets": [ [ 931, 936 ] ], "normalized": [] }, { "id": "1117", "type": "ProteinMutation", "text": [ "F471del" ], "offsets": [ [ 1019, 1026 ] ], "normalized": [] }, { "id": "1118", "type": "ProteinMutation", "text": [ "R594H" ], "offsets": [ [ 1087, 1092 ] ], "normalized": [] } ]

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[ { "id": "1136", "type": "title", "text": [ "Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion." ], "offsets": [ [ 0, 93 ] ] }, { "id": "1137", "type": "abstract", "text": [ "BACKGROUND: Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, beta-cell dysfunction, or glucose intolerance. METHODS: We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. RESULTS: The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p >or= 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: p(additive) model <or= 0.009, effect sizes 8/8%, rs6232: pdominant model <or= 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p >or= 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom <or= 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism. CONCLUSIONS: Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis." ], "offsets": [ [ 94, 2071 ] ] } ]

[ { "id": "1122", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 383, 389 ] ], "normalized": [] }, { "id": "1123", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 394, 400 ] ], "normalized": [] }, { "id": "1124", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 613, 619 ] ], "normalized": [] }, { "id": "1125", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 624, 630 ] ], "normalized": [] }, { "id": "1126", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 916, 922 ] ], "normalized": [] }, { "id": "1127", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 936, 942 ] ], "normalized": [] }, { "id": "1128", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 1010, 1016 ] ], "normalized": [] }, { "id": "1129", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 1021, 1027 ] ], "normalized": [] }, { "id": "1130", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 1232, 1238 ] ], "normalized": [] }, { "id": "1131", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 1289, 1295 ] ], "normalized": [] }, { "id": "1132", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 1472, 1478 ] ], "normalized": [] }, { "id": "1133", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 1736, 1742 ] ], "normalized": [] }, { "id": "1134", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 1968, 1974 ] ], "normalized": [] }, { "id": "1135", "type": "ProteinMutation", "text": [ "N221D" ], "offsets": [ [ 2009, 2014 ] ], "normalized": [] } ]

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