T130I Mutation in HNF-4alpha Gene Is a Loss-Of-Function Mutation in Hepatocytes and Is Associated With Late-Onset Type 2 Diabetes Mellitus in Japanese Subjects

Diabetologia. 2003 Apr;46(4):567-73. doi: 10.1007/s00125-003-1067-y. Epub 2003 Mar 25.


Aims/hypothesis: Mutations in hepatocyte nuclear factor (HNF)-4alpha gene cause a form of maturity-onset diabetes of the young (MODY1). The T130I mutation is a rare missense mutation, which affects a conserved amino acid in a DNA binding domain. This mutation can be found in the general population, so this variant alone does not cause MODY. However, its significance in the development of late-onset Type 2 diabetes is not known.

Methods: We screened 423 unrelated Japanese patients with late-onset Type 2 diabetes and 354 unrelated non-diabetic control subjects for the T130I mutation in the HNF-4alpha gene. The transactivation ability of T130I-HNF-4alpha was assessed using reporter gene assay.

Results: The frequency of the T130I mutation was higher in Type 2 diabetic patients ( p=0.015, odds ratio 4.3, 95%CI 1.24-14.98) than control subjects. The serum HDL-cholesterol concentration was lower in Type 2 diabetic patients with the T130I mutation compared with those without this mutation ( p=0.006). Reporter gene analysis showed that T130I-HNF-4alpha transcriptional activity was not impaired compared with wild-type HNF-4alpha in Hela and MIN6 cells, but it was reduced in HepG2 and primary cultured mouse hepatocytes (27-78% of wild type, p<0.05).

Conclusion/interpretation: Our findings suggest that T130I-HNF-4alpha is a loss-of-function mutation in hepatocytes and that this mutation is associated with late-onset Type 2 diabetes in Japanese subjects. The T130I mutation in the HNF-4alpha gene might be involved in the development of Type 2 diabetes in the Japanese population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Aged
  • Asian Continental Ancestry Group / genetics*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genetic Testing
  • Hepatocyte Nuclear Factor 4
  • Humans
  • Japan
  • Male
  • Mutation, Missense / genetics
  • Mutation, Missense / physiology
  • Phosphoproteins / genetics*
  • Phosphoproteins / physiology*
  • Transcription Factors / genetics*
  • Transcription Factors / physiology*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • MLX protein, human
  • Phosphoproteins
  • Tcfl4 protein, mouse
  • Transcription Factors