HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kitanaka, S. Articles by Igarashi, T. Search for Related Content PubMed PubMed Citation Articles by Kitanaka, S. Articles by Igarashi, T.

Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan

(Requests for offprints should be addressed to S Kitanaka who is now at Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan; Email: sachi-tky{at}umin.ac.jp)

Mutations in hepatocyte nuclear factor-1ß (HNF-1ß) lead to type 5 maturity-onset diabetes of the young (MODY5). Moreover, mutations in the HNF-1ß gene might cause multiorgan abnormalities including renal diseases, genital malformations, and abnormal liver function. The objective of this study was to investigate the molecular mechanism of diabetes mellitus, intrauterine growth retardation, and cholestasis observed in MODY5 patients. We analyzed the transactivity of wild-type and three mutant HNF-1ß on native human insulin, IGF-I, and multidrug resistance protein 2 (MRP2) promoters in combination with HNF-1, using a reporter-assay system in transiently transfected mammalian cells. In the human insulin gene promoter, we found that the cooperation of HNF-1 and HNF-1ß is prominent. Absence of this cooperation was observed in all of the HNF-1ß mutants. In the human IGF-I and MRP2 promoters, we found that the HNF-1ß His153Asn (H153N) mutant had a mutant-specific repressive effect on both HNF-1 and wild-type HNF-1ß transactivity. Absence of the cooperation of HNF-1ß mutants with HNF-1 in the human insulin gene promoter might be one cause of defective insulin secretion. The H153N mutant-specific repression of HNF-1 and HNF-1ß transactivity in human IGF-I and MRP2 promoters might explain the case-specific clinical features of growth retardation and cholestasis observed only in early infancy. We found differential property of HNF-1/HNF-1ß activity and the effect of HNF-1ß mutants by the promoters. We consider that analyses of HNF-1ß mutants on the intended human native promoters in combination with HNF-1 may be useful in investigating the molecular mechanisms of the various features in MODY5.