title: Anatomy of a homeoprotein revealed by the analysis of human MODY3 mutations.
abstract: Hepatocyte nuclear factor 1alpha (HNF1alpha) is an atypical dimeric homeodomain-containing protein that is expressed in liver, intestine, stomach, kidney, and pancreas. Mutations in the HNF1alpha gene are associated with an autosomal dominant form of non-insulin-dependent diabetes mellitus called maturity-onset diabetes of the young (MODY3). More than 80 different mutations have been identified so far, many of which involve highly conserved amino acid residues among vertebrate HNF1alpha. In the present work, we investigated the molecular mechanisms by which MODY3 mutations could affect HNF1alpha function. For this purpose, we analyzed the properties of 10 mutants resulting in amino acid substitutions or protein truncation. Some mutants have a reduced protein stability, whereas others are either defective in the DNA binding or impaired in their intrinsic trans-activation potential. Three mutants, characterized by a complete loss of trans-activation, behave as dominant negatives when transfected with the wild-type protein. These data define a clear causative relationship between MODY3 mutations and functional defects in HNF1alpha trans-activation. In addition, our analysis sheds new light on the structure of a homeoprotein playing a key role in pancreatic beta cell function.
authors.affiliation: Unité des Virus Oncogènes, Unité de Recherche Associée 1644, Centre National de la Recherche Scientifique, Département des Biotechnologies, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: M
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: A
authors.initials: A
authors.lastname: Abderrahmani
authors.forename: P
authors.initials: P
authors.lastname: Boutin
authors.forename: B
authors.initials: B
authors.lastname: Bailleul
authors.forename: P
authors.initials: P
authors.lastname: Froguel
authors.forename: M
authors.initials: M
authors.lastname: Yaniv
authors.forename: M
authors.initials: M
authors.lastname: Pontoglio
mesh_terms: D019943:Amino Acid Substitution; D004268:DNA-Binding Proteins / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D019281:Dimerization; D006420:Hemeproteins / Q000737:chemistry*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D006420:Hemeproteins; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta