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Erschienen in:
01.04.2003 | Article
T130I mutation in HNF-4α gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects
Erschienen in: Diabetologia | Ausgabe 4/2003
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Aims/hypothesis
Mutations in hepatocyte nuclear factor (HNF)-4α 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-4α gene. The transactivation ability of T130I-HNF-4α 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-4α transcriptional activity was not impaired compared with wild-type HNF-4α 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-4α 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-4α gene might be involved in the development of Type 2 diabetes in the Japanese population.