HNF-1α G574S is a functional variant with decreased transactivation activity

Aim: To assess the functional consequence of the hepatocyte nuclear factor 1α gene (HNF-1α) G574S variant previously proposed as a diabetes susceptibility allele, in a group of Mexican Type 2 diabetic patients with end-stage renal disease (ESRD). Methods: The transcriptional activity of the HNF-1α G574S recombinant protein on the human insulin promoter was assessed by transfection assays in RINm5f and HepG2 cell lines. Results: Two unrelated Mexican diabetic patients with no known African ancestry were found to carry the G574S variant. This substitution was not found among unrelated healthy control subjects. Whereas the G574S HNF-1α transcription activation of the human insulin promoter was 40% lower than that of the wild-type protein in RINm5f β cells, no difference was found in a hepatic cell line (HepG2). Conclusions: G574S affects the transactivation potential of HNF-1α on the insulin promoter in pancreatic β-cells. Although it has been difficult to prove its role in the development of diabetes in case-control association studies, this variant exhibits functional effects consistent with it being a potential diabetes susceptibility allele.