Promoter-Specific Repression of Hepatocyte Nuclear Factor (HNF)-1β and HNF-1α Transcriptional Activity by an HNF-1β Missense Mutant Associated with Type 5 Maturity-Onset Diabetes of the Young with Hepatic and Biliary Manifestations

Abstract

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