Human insulin gene is a target gene of hepatocyte nuclear factor-1 alpha (HNF-1 alpha) and HNF-1 beta

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, early-onset, and impaired insulin secretion. The type 3 and type 5 forms of MODY result from mutatio ns in the genes encoding the transcription factor, hepatocyte nuclear facto r (HNF)-1 alpha and HNF-1 beta, respectively. The mechanism by which mutati ons in one allele of the HNF-1 gene impair pancreatic beta cell function is unclear. We studied the effects of wild-type and four mutant (L12H, R263C, P379fsdelCT, and L584S585fsinsTC) HNF-1 alpha, which were identified in Ja panese subjects with MODY3 on human insulin gene transcription. Both wild-t ype (WT) HNF-1 alpha and HNF-1 beta bound to the oligonucleotide containing the A3 element sequence in the human insulin promoter and transactivated t he insulin-luciferase reporter gene by 30- and 31-fold, respectively. In co ntrast, binding of L12H, R263C and L584S585fsinsTC-HNF-1 alpha to the probe was impaired. Transactivation activity by the four mutant HNF-1 alpha was reduced (4.3 to 43.3% of WT). These data suggest that the insulin gene is a candidate target gene of HNF-1 alpha/HNF-1 beta and the impairment of insu lin gene transcription by mutations in the HNF-1 gene might be involved in the pathogenesis of MODY. (C) 1999 Academic Press.