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

Department of Pediatrics (S.K., Y.M., Y.H., T.I.), Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655; and Japan Health Sciences Foundation (S.K.), Tokyo 103-0001, Japan

Address all correspondence and requests for reprints to: Sachiko Kitanaka, M.D., Ph.D., Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: sachi-tky{at}umin.ac.jp.

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

This work was supported by a Grant-in-Aid from the Ministry of Health and Welfare of Japan and from the Ministry of Education, Science, Sports, and Culture of Japan.

Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; GLUT2, glucose transporter-2; HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the young.

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