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.

Abstract

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.

• Authors: Q Zhu, K Yamagata, A Miura, N Shihara, Y Horikawa, J Takeda, J Miyagawa, Y Matsuzawa
• Journal: Diabetologia (Diabetologia) Vol. 46 Issue 4 Pg. 567-73 (Apr 2003) ISSN: 0012-186X [Print] Germany
• PMID: 12669197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Age of Onset
• Aged
• Asian People (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, physiology)
• Phosphoproteins (genetics, physiology)
• Transcription Factors (genetics, physiology)