title: Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes-associated transcription factor.
abstract: Mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha) cause maturity-onset diabetes of the young type 3 (MODY3), a form of diabetes mellitus characterized by autosomal dominant inheritance, early onset, and pancreatic beta-cell dysfunction. We have examined the effects of five diabetes-associated mutations (L12H, G191D, R263C, P379fsdelCT, and L584S585fsinsTC) on HNF-1alpha function including DNA binding ability, intracellular localization, and transactivation activity. L12H, P379fsdelCT, and L584S585fsinsTC mutations were found in patients with a clinical diagnosis of MODY, while G191D and R263C mutations were identified in patients diagnosed with type 2 diabetes. These mutations had diverse effects on the functional properties of HNF-1alpha. Comparison of the functional data with clinical information suggested that transactivation activity of mutant HNF-1alpha in beta cells like MIN6 may be the primary determinants of the phenotypic differences observed among diabetic patients with HNF-1alpha mutations.
authors.affiliation: Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.forename: K
authors.initials: K
authors.lastname: Yamagata
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: J
authors.initials: J
authors.lastname: Miyagawa
authors.forename: J
authors.initials: J
authors.lastname: Takeda
authors.forename: N
authors.initials: N
authors.lastname: Iwasaki
authors.forename: H
authors.initials: H
authors.lastname: Iwahashi
authors.forename: I
authors.initials: I
authors.lastname: Yoshiuchi
authors.forename: M
authors.initials: M
authors.lastname: Namba
authors.forename: J
authors.initials: J
authors.lastname: Miyazaki
authors.forename: T
authors.initials: T
authors.lastname: Hanafusa
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D019281:Dimerization; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism; D011228:Prealbumin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D011228:Prealbumin; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta