Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes-associated transcription factor

Biochem Biophys Res Commun. 1999 Dec 9;266(1):196-202. doi: 10.1006/bbrc.1999.1747.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Amino Acid Substitution / genetics*
  • Animals
  • Binding, Competitive
  • CHO Cells
  • Cell Nucleus / metabolism
  • Cricetinae
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Dimerization
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Humans
  • Islets of Langerhans / metabolism
  • Mice
  • Middle Aged
  • Nuclear Proteins*
  • Oligodeoxyribonucleotides / genetics
  • Oligodeoxyribonucleotides / metabolism
  • Prealbumin / genetics
  • Promoter Regions, Genetic / genetics
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Structure-Activity Relationship
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • HNF1A protein, human
  • HNF1B protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Hnf1b protein, mouse
  • Nuclear Proteins
  • Oligodeoxyribonucleotides
  • Prealbumin
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta