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Diabetes 53:1894-1899, 2004
© 2004 by the American Diabetes Association, Inc.

Brief Genetics Report

Cosegregation of MIDD and MODY in a Pedigree

Functional and Clinical Consequences

Camilla Cervin1, Brita Liljeström2,3,4, Tiinamaija Tuomi2,4, Seija Heikkinen2,4, Juha S. Tapanainen5, Leif Groop1, and Corrado M. Cilio1,6

1 Department of Endocrinology, Wallenberg Laboratory, Malmö University Hospital, Malmö, Sweden
2 Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
3 Clinic for Genetic Diseases, The Family Federation, Helsinki, Finland
4 Folkhalsan Research Center, Helsinki, Finland
5 Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland
6 Department of Pediatrics, Wallenberg Laboratory, Malmö University Hospital, Malmö, Sweden

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 HNF1{alpha} gene (MODY3) and the A3243G in mtDNA. ß-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 HNF1{alpha} 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){gamma} was present in two nondiabetic individuals. Carriers of both mtDNA and HNF1{alpha} 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 ß-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 HNF1{alpha} mutations.

Address correspondencereprint requests to Camilla Cervin, Department of Endocrinology, Malmö University Hospital, S-205 02 Malmö, Sweden. E-mail: camilla.cervin{at}endo.mas.lu.se

Abbreviations: HNF, hepatocyte nuclear factor; MIDD, maternally inherited diabetes and deafness; MODY, maturity-onset diabetes of the young; PBL, peripheral blood lymphocyte


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Copyright © 2004 by the American Diabetes Association.