title: Cosegregation of MIDD and MODY in a pedigree: functional and clinical consequences.
abstract: 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 HNF1alpha gene (MODY3) and the A3243G in mtDNA. Beta-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 HNF1alpha 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 HNF1alpha 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 beta-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 HNF1alpha mutations.
authors.affiliation: Department of Endocrinology, Malmö University Hospital, S-205 02 Malmö, Sweden. camilla.cervin@endo.mas.lu.se
authors.forename: Camilla
authors.initials: C
authors.lastname: Cervin
authors.forename: Brita
authors.initials: B
authors.lastname: Liljeström
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Seija
authors.initials: S
authors.lastname: Heikkinen
authors.forename: Juha S
authors.initials: JS
authors.lastname: Tapanainen
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Corrado M
authors.initials: CM
authors.lastname: Cilio
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D020090:Chromosome Segregation; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003638:Deafness / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D006367:HeLa Cells; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D008239:Lysine; D008297:Male; D008715:Methionine; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D008715:Methionine; D008239:Lysine