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Corrado Cilio

Professor

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Cosegregation of MIDD and MODY in a Pedigree: Functional and Clinical Consequences.

Author

  • Camilla Cervin
  • Brita Liljeström
  • Tiinamaija Tuomi
  • Seija Heikkinen
  • Juha S Tapanainen
  • Leif Groop
  • Corrado Cilio

Summary, in English

The aim of this study was characterization of a family carrying two mutations known to cause monogenic forms of diabetes, the M626K mutation in the HNF1α gene (MODY3) and the A3243G in mtDNA. β-Cell function and insulin sensitivity were assessed with the Botnia clamp. Heteroplasmy of the A3243G mutation and variants in type 2 diabetes susceptibility genes were determined, and transcriptional activity, DNA binding, and subcellular localization of mutated HNF1α were studied. Thirteen family members carried the mutation in mtDNA; 6 of them also had the M626K mutation, whereas none had only the M626K mutation. The protective Ala12 allele in peroxisome proliferator–activated receptor (PPAR)γ was present in two nondiabetic individuals. Carriers of both mtDNA and HNF1α mutations showed an earlier age at onset of diabetes than carriers of only the mtDNA mutation (median 22 vs. 45 years) but no clear difference in β-cell function or insulin sensitivity. In vitro, the M626K mutation caused a 53% decrease in transcriptional activity in HeLa cells. The mutated protein showed normal nuclear targeting but increased DNA binding. These data demonstrate that several genetic factors might contribute to diabetes risk, even in families with mtDNA and HNF1α mutations.

Department/s

  • Diabetes - Clinical Obesity
  • Genomics, Diabetes and Endocrinology
  • Diabetes - Immunovirology

Publishing year

2004

Language

English

Pages

1894-1899

Publication/Series

Diabetes

Volume

53

Issue

7

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Clinical Obesity
  • Genomics, Diabetes and Endocrinology
  • Diabetes - Immunovirology

ISBN/ISSN/Other

  • ISSN: 1939-327X