title: Naturally occurring mutations in the human HNF4alpha gene impair the function of the transcription factor to a varying degree.
abstract: The hepatocyte nuclear factor (HNF)4alpha, a member of the nuclear receptor superfamily, regulates genes that play a critical role in embryogenesis and metabolism. Recent studies have shown that mutations in the human HNF4alpha gene cause a rare form of type 2 diabetes, maturity onset diabetes of the young (MODY1). To investigate the properties of these naturally occurring HNF4alpha mutations we analysed five MODY1 mutations (R154X, R127W, V255M, Q268X and E276Q) and one other mutation (D69A), which we found in HepG2 hepatoma cells. Activation of reporter genes in transfection assays and DNA binding studies showed that the MODY1-associated mutations result in a variable reduction in function, whereas the D69A mutation showed an increased activity on some promoters. None of the MODY mutants acted in a dominant negative manner, thus excluding inactivation of the wild-type factor as a critical event in MODY development. A MODY3-associated mutation in the HNF1alpha gene, a well-known target gene of HNF4alpha, results in a dramatic loss of the HNF4 binding site in the promoter, indicating that mutations in the HNF4alpha gene might cause MODY through impaired HNF1alpha gene function. Based on these data we propose a two-hit model for MODY development.
authors.affiliation: Institut für Zellbiologie, Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Lausen
authors.forename: H
authors.initials: H
authors.lastname: Thomas
authors.forename: I
authors.initials: I
authors.lastname: Lemm
authors.forename: M
authors.initials: M
authors.lastname: Bulman
authors.forename: M
authors.initials: M
authors.lastname: Borgschulze
authors.forename: A
authors.initials: A
authors.lastname: Lingott
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: G U
authors.initials: GU
authors.lastname: Ryffel
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: 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; C403128:MLX protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta