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.
Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. sachi-tky@umin.ac.jp
Sachiko
S
Kitanaka
Yuko
Y
Miki
Yasuhide
Y
Hayashi
Takashi
T
Igarashi
D000293:Adolescent; D017668:Age of Onset; D000818:Animals; D001659:Biliary Tract / Q000503:physiopathology; D019556:COS Cells; D006528:Carcinoma, Hepatocellular; D002779:Cholestasis / Q000235:genetics / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D006367:HeLa Cells; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008099:Liver / Q000503:physiopathology; D008107:Liver Diseases / Q000235:genetics / Q000503:physiopathology; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000502:physiology
D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta