R127W-HNF-4alpha is a loss of function mutation but not a rare polymorphism and causes Type II diabetes in a Japanese family with MODY1

Diabetologia. 2000 Apr;43(4):520-4. doi: 10.1007/s001250051338.

Abstract

Aims/hypothesis: Mutations in the hepatocyte nuclear factor (HNF)-4alpha gene cause the type 1 form of maturity-onset diabetes of the young (MODY1). The R127W mutation is a missense mutation located in the T-box region of HNF-4alpha that was first identified in a Japanese family with MODY. We have examined the functional properties of this mutation in order to clarify the molecular basis of MODY1.

Methods: The intracellular localisation, DNA binding ability, transactivation activity and functional synergism with the coactivator CREB-binding protein (CBP) of R127W-HNF-4alpha were investigated.

Results: The nuclear import and functional synergy with CBP of R127W-HNF-4alpha were normal. The DNA binding ability of the mutant was decreased as was its transcriptional activation of the HNF-1alpha and L-type pyruvate kinase (PKL) genes.

Conclusion/interpretation: The R127W mutation seems to be a loss-of-function mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cell Line
  • Cell Nucleus / chemistry
  • DNA / metabolism
  • DNA-Binding Proteins*
  • Diabetes Mellitus, Type 2 / genetics*
  • HeLa Cells
  • Hepatocyte Nuclear Factor 4
  • Humans
  • Japan
  • Mutation*
  • Mutation, Missense*
  • Pedigree
  • Phosphoproteins / analysis
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Pyruvate Kinase / genetics
  • Transcription Factors / analysis
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • MLX protein, human
  • Phosphoproteins
  • Transcription Factors
  • DNA
  • Pyruvate Kinase