Promoter-specific repression of hepatocyte nuclear factor (HNF)-1 beta and HNF-1 alpha transcriptional activity by an HNF-1 beta missense mutant associated with Type 5 maturity-onset diabetes of the young with hepatic and biliary manifestations.

Mutations in the hepatocyte nuclear factor (HNF)-1 beta lead to type 5 maturity-onset diabetes of the young (MODY5). HNF-1 beta forms a homodimer or a heterodimer with HNF-1 alpha and regulates various target genes. HNF-1 beta mutations are rare, and no functional analysis has been performed in conjunction with HNF-1 alpha. HNF-1 beta is expressed in the liver and biliary system and controls liver-specific and bile acid-related genes. Moreover, liver-specific Hnf-1 beta knockout mice present with severe jaundice. However, no patients with HNF-1 beta mutations have biliary manifestations. In this report, we found a novel missense mutation in the HNF-1 beta gene in a patient with neonatal cholestasis and liver dysfunction together with the common features of MODY5. Functional analysis revealed that the mutant HNF-1 beta had diminished transcriptional activity by loss of the DNA binding activity. The mutant had a promoter-specific dominant-negative transcriptional effect on wild-type HNF- and inhibited its DNA binding. Moreover, the mutant had a promoter- and cell-specific transcriptional repressive effect on HNF-1 alpha and a promoter-specific inhibitory effect on HNF-1 alpha DNA binding. From these results, we considered that the different phenotype of patients with HNF-1 beta mutations might be caused by the different HNF-1 beta activity in conjunction with the different repression of HNF-1 alpha activity in selected promoters and tissues.