title: A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.
abstract: Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS) EP10-Institute of Biology, Pasteur Institute of Lille & CHRU-Lille, 59019 Lille, France.
authors.forename: E H
authors.initials: EH
authors.lastname: Hani
authors.forename: L
authors.initials: L
authors.lastname: Suaud
authors.forename: P
authors.initials: P
authors.lastname: Boutin
authors.forename: J C
authors.initials: JC
authors.lastname: Chèvre
authors.forename: E
authors.initials: E
authors.lastname: Durand
authors.forename: A
authors.initials: A
authors.lastname: Philippi
authors.forename: F
authors.initials: F
authors.lastname: Demenais
authors.forename: N
authors.initials: N
authors.lastname: Vionnet
authors.forename: H
authors.initials: H
authors.lastname: Furuta
authors.forename: G
authors.initials: G
authors.lastname: Velho
authors.forename: G I
authors.initials: GI
authors.lastname: Bell
authors.forename: B
authors.initials: B
authors.lastname: Laine
authors.forename: P
authors.initials: P
authors.lastname: Froguel
mesh_terms: D017668:Age of Onset; D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D019556:COS Cells; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005951:Glucose Tolerance Test; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007532:Isoleucine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D013937:Thymidine Kinase / Q000235:genetics; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D014633:Valine / Q000235:genetics
chemical_list: D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; C403128:MLX protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D007532:Isoleucine; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D013937:Thymidine Kinase; D014633:Valine