Diabetes, Vol 46, Issue 10 1648-1651, Copyright © 1997 by American Diabetes Association

ARTICLES

Maturity-onset diabetes of the young due to a mutation in the hepatocyte nuclear factor-4 alpha binding site in the promoter of the hepatocyte nuclear factor-1 alpha gene

C Gragnoli, T Lindner, BN Cockburn, PJ Kaisaki, F Gragnoli, G Marozzi and GI Bell
Howard Hughes Medical Institute, University of Chicago, Illinois, USA.

Recent studies have shown that mutations in the transcription factor hepatocyte nuclear factor (HNF)-1 alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). These studies have identified mutations in the mRNA and protein coding regions of this gene that result in the synthesis of an abnormal mRNA or protein. Here, we report an Italian family in which an A-->C substitution at nucleotide-58 of the promoter region of the HNF-1 alpha gene cosegregates with MODY. This mutation is located in a highly conserved region of the promoter and disrupts the binding site for the transcription factor HNF-4 alpha, mutations in the gene encoding HNF-4 alpha being another cause of MODY (MODY1). This result demonstrates that decreased levels of HNF-1 alpha per se can cause MODY. Moreover, it indicates that both the promoter and coding regions of the HNF-1 alpha gene should be screened for mutations in subjects thought to have MODY because of mutations in this gene.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				P. Lu, G. B. Rha, M. Melikishvili, G. Wu, B. C. Adkins, M. G. Fried, and Y.-I. Chi Structural Basis of Natural Promoter Recognition by a Unique Nuclear Receptor, HNF4{alpha}: DIABETES GENE PRODUCT J. Biol. Chem., November 28, 2008; 283(48): 33685 - 33697. [Abstract] [Full Text] [PDF]

				G. Benoit, A. Cooney, V. Giguere, H. Ingraham, M. Lazar, G. Muscat, T. Perlmann, J.-P. Renaud, J. Schwabe, F. Sladek, et al. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors Pharmacol. Rev., December 1, 2006; 58(4): 798 - 836. [Abstract] [Full Text] [PDF]

				Y. Inoue, A.-M. Yu, S. H. Yim, X. Ma, K. W. Krausz, J. Inoue, C. C. Xiang, M. J. Brownstein, G. Eggertsen, I. Bjorkhem, et al. Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4{alpha} J. Lipid Res., January 1, 2006; 47(1): 215 - 227. [Abstract] [Full Text] [PDF]

				M. S. Winzell, G. Pacini, C. B. Wollheim, and B. Ahren Beta-Cell-Targeted Expression of a Dominant-Negative Mutant of Hepatocyte Nuclear Factor-1{alpha} in Mice: Diabetes Model with {beta}-Cell Dysfunction Partially Rescued by Nonglucose Secretagogues Diabetes, December 1, 2004; 53(suppl_3): S92 - S96. [Abstract] [Full Text] [PDF]

				L. W. Harries, A. T. Hattersley, and S. Ellard Messenger RNA Transcripts of the Hepatocyte Nuclear Factor-1{alpha} Gene Containing Premature Termination Codons Are Subject to Nonsense-Mediated Decay Diabetes, February 1, 2004; 53(2): 500 - 504. [Abstract] [Full Text]

				J. Eeckhoute, E. Moerman, T. Bouckenooghe, B. Lukoviak, F. Pattou, P. Formstecher, J. Kerr-Conte, B. Vandewalle, and B. Laine Hepatocyte Nuclear Factor 4{alpha} Isoforms Originated from the P1 Promoter Are Expressed in Human Pancreatic {beta}-Cells and Exhibit Stronger Transcriptional Potentials than P2 Promoter-Driven Isoforms Endocrinology, May 1, 2003; 144(5): 1686 - 1694. [Abstract] [Full Text] [PDF]

				H. Wang, K. Hagenfeldt-Johansson, L. A. Otten, B. R. Gauthier, P. L. Herrera, and C. B. Wollheim Experimental Models of Transcription Factor-Associated Maturity-Onset Diabetes of the Young Diabetes, December 1, 2002; 51(90003): S333 - 342. [Abstract] [Full Text] [PDF]

				J. Ferrer A Genetic Switch in Pancreatic {beta}-Cells: Implications for Differentiation and Haploinsufficiency Diabetes, August 1, 2002; 51(8): 2355 - 2362. [Abstract] [Full Text] [PDF]

				R. Bartoov-Shifman, R. Hertz, H. Wang, C. B. Wollheim, J. Bar-Tana, and M. D. Walker Activation of the Insulin Gene Promoter through a Direct Effect of Hepatocyte Nuclear Factor 4alpha J. Biol. Chem., July 12, 2002; 277(29): 25914 - 25919. [Abstract] [Full Text] [PDF]

				Y. Inoue, G. P. Hayhurst, J. Inoue, M. Mori, and F. J. Gonzalez Defective Ureagenesis in Mice Carrying a Liver-specific Disruption of Hepatocyte Nuclear Factor 4alpha (HNF4alpha ). HNF4alpha REGULATES ORNITHINE TRANSCARBAMYLASE IN VIVO J. Biol. Chem., July 5, 2002; 277(28): 25257 - 25265. [Abstract] [Full Text] [PDF]

				D. Q. Shih and M. Stoffel Dissecting the transcriptional network of pancreatic islets during development and differentiation PNAS, December 4, 2001; 98(25): 14189 - 14191. [Full Text] [PDF]

				D. Q. Shih, S. Screenan, K. N. Munoz, L. Philipson, M. Pontoglio, M. Yaniv, K. S. Polonsky, and M. Stoffel Loss of HNF-1{alpha} Function in Mice Leads to Abnormal Expression of Genes Involved in Pancreatic Islet Development and Metabolism Diabetes, November 1, 2001; 50(11): 2472 - 2480. [Abstract] [Full Text] [PDF]

				H. Thomas, K. Jaschkowitz, M. Bulman, T. M. Frayling, S. M.S. Mitchell, S. Roosen, A. Lingott-Frieg, C. J. Tack, S. Ellard, G. U. Ryffel, et al. A distant upstream promoter of the HNF-4{alpha} gene connects the transcription factors involved in maturity-onset diabetes of the young Hum. Mol. Genet., September 1, 2001; 10(19): 2089 - 2097. [Abstract] [Full Text] [PDF]

				I. Leclerc, C. Lenzner, L. Gourdon, S. Vaulont, A. Kahn, and B. Viollet Hepatocyte Nuclear Factor-4{alpha} Involved in Type 1 Maturity-Onset Diabetes of the Young Is a Novel Target of AMP-Activated Protein Kinase Diabetes, July 1, 2001; 50(7): 1515 - 1521. [Abstract] [Full Text] [PDF]

				P. N. Black, N. J. Færgeman, and C. C. DiRusso Long-Chain Acyl-CoA-Dependent Regulation of Gene Expression in Bacteria, Yeast and Mammals J. Nutr., February 1, 2000; 130(2): 305 - 305. [Abstract] [Full Text]

				J. Lausen, H. Thomas, I. Lemm, M. Bulman, M. Borgschulze, A. Lingott, A. T. Hattersley, and G. U. Ryffel Naturally occurring mutations in the human HNF4{alpha} gene impair the function of the transcription factor to a varying degree Nucleic Acids Res., January 15, 2000; 28(2): 430 - 437. [Abstract] [Full Text] [PDF]

				E. Kawasaki, Y. Sera, K. Yamakawa, T. Abe, M. Ozaki, S. Uotani, N. Ohtsu, H. Takino, H. Yamasaki, Y. Yamaguchi, et al. Identification and Functional Analysis of Mutations in the Hepatocyte Nuclear Factor-1{alpha} Gene in Anti-Islet Autoantibody-Negative Japanese Patients with Type 1 Diabetes J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 331 - 335. [Abstract] [Full Text]

				R. A. Hegele, H. Cao, S. B. Harris, A. J. G. Hanley, B. Zinman, and P. W. Connelly The Private Hepatocyte Nuclear Factor-1{alpha} G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree Arterioscler. Thromb. Vasc. Biol., January 1, 2000; 20(1): 217 - 222. [Abstract] [Full Text] [PDF]

				V. Giguère Orphan Nuclear Receptors: From Gene to Function Endocr. Rev., October 1, 1999; 20(5): 689 - 725. [Abstract] [Full Text]

				R. A. Hegele, H. Cao, S. B. Harris, A. J. G. Hanley, and B. Zinman The Hepatic Nuclear Factor-1{alpha} G319S Variant Is Associated with Early-Onset Type 2 Diabetes in Canadian Oji-Cree J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1077 - 1082. [Abstract] [Full Text]

				J.-C. Wang, J. M. Stafford, and D. K. Granner SRC-1 and GRIP1 Coactivate Transcription with Hepatocyte Nuclear Factor 4 J. Biol. Chem., November 20, 1998; 273(47): 30847 - 30850. [Abstract] [Full Text] [PDF]

				S. C. Elbein, K. Teng, P. Yount, and E. Scroggin Linkage and Molecular Scanning Analyses of MODY3/Hepatocyte Nuclear Factor-1{alpha} Gene in Typical Familial Type 2 Diabetes: Evidence for Novel Mutations in Exons 8 and 10 J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 2059 - 2065. [Abstract] [Full Text]

				H. Wang, P. Maechler, P. A. Antinozzi, K. A. Hagenfeldt, and C. B. Wollheim Hepatocyte Nuclear Factor 4alpha Regulates the Expression of Pancreatic beta -Cell Genes Implicated in Glucose Metabolism and Nutrient-induced Insulin Secretion J. Biol. Chem., November 10, 2000; 275(46): 35953 - 35959. [Abstract] [Full Text] [PDF]

				H. Nishigori, H. Tomura, N. Tonooka, M. Kanamori, S. Yamada, K. Sho, I. Inoue, N. Kikuchi, K. Onigata, I. Kojima, et al. Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects PNAS, January 16, 2001; 98(2): 575 - 580. [Abstract] [Full Text] [PDF]