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

Abstract

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 nondiabetic 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 lateonset 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. [Diabetologia (2003) 46:567-573]

PXR, CAR and HNF4α genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients

“…The second SNP Thr130Ile is a rare variant that was previously described, is located in the DNA-binding domain and has been associated with reduced function in hepatocyte cell lines as well as higher incidence of maturity onset diabetes mellitus and lower HDL cholesterol. 25,31 This SNP was present at a low allele frequency of 1% in our study population; therefore, any potential effect on drug pharmacokinetics or pharmacodynamics could not be determined.…”

Genetic and clinical characteristics of Korean maturity-onset diabetes of the young (MODY) patients

“…The T130I variant, which affects a residue in the DNA binding region, is thought to be a polymorphism because this missense mutation is found in 0-5% of nondiabetic Caucasians [17,19] and insulin and C-peptide secretion is unaltered in healthy carriers [19]. A recent Japanese study [20] suggested that the T130I variant might be associated with lateonset type 2 DM in Japanese subjects because it is found more frequently in type 2 DM patients than in the general population (3.5% versus 0.8%) and it is associated with loss of function in hepatocytes. However, this study maintained that the T1301 variant's significance in the development of type 2 DM needs to be further investigated.…”

Genetics of type 2 diabetes

“…These genes play a role in the development of the liver, in the regulation of hepatic metabolic functions, and in the development and functioning of beta cells. Variants in these genes that do not lead to MODY have been found to be associated with decreased insulin secretion and an increase in the risk of T2D in various populations, but as with other candidate genes, their role in worldwide diabetes prevalence appears to be relatively small [36][37][38] .…”