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Corrado Cilio

Professor

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Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha (MODY3) gene.

Author

  • Camilla Cervin
  • Marju Orho-Melander
  • Martin Ridderstråle
  • M Lehto
  • Sebastian Barg
  • Leif Groop
  • Corrado Cilio

Summary, in English

AIMS/HYPOTHESIS: Maturity onset diabetes of the young type 3 (MODY3) is a monogenic form of diabetes mellitus caused by mutations in the gene encoding for hepatocyte nuclear factor 1 alpha, HNF1 alpha. In this study we have examined the in vivo and in vitro effects of a mutation (L107I) outside the DNA binding and dimerization domains in the N terminal part of the HNF1 alpha gene. METHODS: Beta-cell function of the affected family members was assessed by an oral glucose tolerance test. Functional tests were carried out to explain the role of the mutation in vitro by transcriptional activity assay, Western blotting, DNA-binding assays and subcellular localization experiments. RESULTS: Affected family members showed an 86% decreased insulin response to glucose when compared to age-matched healthy control subjects. In vitro the mutation showed a 79% decrease in transcriptional activity as compared to wild type HNF1 alpha in HeLa cells lacking HNF1 alpha. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1 alpha suggesting that the decreased activity was not mediated by a dominant negative mechanism. The L107I/HNF1alpha protein showed normal nuclear targeting but impaired binding to an HNF1 alpha consensus sequence. CONCLUSION/INTERPRETATION: Our results suggest that the L107I substitution represents a MODY3 mutation which impairs beta-cell function by a loss-of-function mechanism.

Department/s

  • Diabetes - Clinical Obesity
  • Diabetes - Cardiovascular Disease
  • Islet cell physiology
  • Genomics, Diabetes and Endocrinology
  • Diabetes - Immunovirology

Publishing year

2002

Language

English

Pages

1703-1708

Publication/Series

Diabetologia

Volume

45

Issue

12

Document type

Journal article

Publisher

Springer

Topic

  • Endocrinology and Diabetes

Keywords

  • MODY
  • DNA binding
  • HNF1 α
  • Type II diabetes
  • gene expression
  • cell lines
  • mutation
  • metabolism
  • insulin

Status

Published

Research group

  • Diabetes - Clinical Obesity
  • Diabetes - Cardiovascular Disease
  • Islet cell physiology
  • Genomics, Diabetes and Endocrinology
  • Diabetes - Immunovirology

ISBN/ISSN/Other

  • ISSN: 1432-0428