HNF-1αG319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community

摘要

The prevalence of type 2 diabetes mellitus in the Oji-Cree of northwestern Ontario is the third highest in the world. A private mutation, G319S, in HNF1A, which encodes hepatic nuclear factor-1α(HNF-1α), was associated with Oji-Cree type 2 diabetes and was found in ≈40/100 of affected subjects. The G319S mutation reduced the in vitro ability of HNF-1αto activate transcription by ≈50/100, with no effect on DNA binding or protein stability. There was no evidence of a dominant negative effect of the mutant protein. The impact of the G319S mutation at the population level was assessed by classifying subjects with type 2 diabetes according to HNF1A genotype and plotting the cumulative age of onset of diabetes.