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

Cervin, CamillaLund University,Lunds universitet,Diabetes - klinisk obesitasforskning,Forskargrupper vid Lunds universitet,Diabetes - Clinical Obesity,Lund University Research Groups (author)

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.

Liljeström, Brita (author)
Tuomi, Tiinamaija (author)
Heikkinen, Seija (author)
Tapanainen, Juha S (author)
Groop, LeifLund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups(Swepub:lu)endo-lgr (author)
Cilio, CorradoLund University,Lunds universitet,Diabetes - immunovirologi,Forskargrupper vid Lunds universitet,Diabetes - Immunovirology,Lund University Research Groups(Swepub:lu)endo-cci (author)
Diabetes - klinisk obesitasforskningForskargrupper vid Lunds universitet (creator_code:org_t)

By the author/editor: Cervin, Camilla; Liljeström, Brit ...; Tuomi, Tiinamaij ...; Heikkinen, Seija; Tapanainen, Juha ...; Groop, Leif; show more...; Cilio, Corrado; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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