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  • 1
    ISSN: 1432-0428
    Keywords: Keywords MODY ; HNF-1α ; insulin ; arginine ; mutation.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Mutations in the hepatocyte nuclear factor-1α gene are a common cause of the type 3 form of maturity-onset diabetes of the young. We examined the clinical features and molecular basis of hepatocyte nuclear factor-1α (HNF-1α) diabetes. Methods. Thirty-seven Japanese subjects with early onset Type II (non-insulin-dependent) diabetes mellitus and 45 with Type I (insulin-dependent) diabetes mellitus were screened for mutations in this gene. Functional properties of mutant HNF-1α were also investigated. Results. Three new mutations [G415R, R272C and A site of the promoter ( + 102G-to-C)] were found. Insulin secretion was impaired in the three subjects. Insulin and glucagon secretory responses to arginine in the subject with the R272C mutation were also diminished. Molecular biological studies indicated that the G415R mutation generated a protein with about 50 % of the activity of wild-type HNF-1α. The R272C mutation had no transactivating or DNA binding activity and acted in a dominant negative manner. The + 102 G-to-C mutation in the A site of the promoter activity was associated with an increase in promoter activity and it had 42–75 % more activity than the wild-type sequence. Conclusion/interpretation. Mutations in the HNF-1α gene may affect the normal islet function by different molecular mechanisms. [Diabetologia (1999) 42: 621–626]
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Keywords Keywords. HNF-3β ; HNF-1α ; mutation ; genetics.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Hepatocyte nuclear factor (HNF)-3β, a transcription factor expressed in pancreatic beta cells, is an upstream regulator of HNF-1α/MODY3, HNF-4α/MODY1 and IPF1/MODY5 genes. Our previous screening of MODY subjects showed that mutations in the HNF-3 β gene are not a common cause of this form of diabetes in the Japanese. We tested the hypothesis that mutations in the HNF-3 β gene cause late-onset Type II (non-insulin-dependent) diabetes mellitus in this population. Methods. Genotyping of the polymorphic TCC repeat in the HNF-3 β gene was done in 112 Japanese subjects with Type II diabetes (age at diagnosis 〉 35 and family history of Type II diabetes among their second-degree relatives) and 96 Japanese control subjects. Furthermore, we screened 57 Type II diabetic patients for mutations of the HNF-3 β gene. Transactivation activity of variant HNF-3β was investigated by transfection assay. Results. The distribution of alleles of the TCC repeat was similar between diabetic and control groups. Mutation screening identified two missense mutations, A86T and G114E. Neither mutation was observed in 225 control subjects. The transactivation activity of G114E-HNF-3β was similar to that of wild type-HNF-3β. In contrast, the activity of A86T-HNF-3β was statistically significantly reduced to 83–86 % of that of wild type. Conclusions/Interpretation. The A86T mutation in the HNF-3 β gene might be involved in the development of late-onset Type II diabetes in a small group of Japanese people. [Diabetologia (2000) 43: 1197–1200]
    Type of Medium: Electronic Resource
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