Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes

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Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes

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dc.contributor.author Macfarlane, Wendy M. en_GB
dc.contributor.author Frayling, Timothy M. en_GB
dc.contributor.author Ellard, Sian en_GB
dc.contributor.author Evans, Julie C. en_GB
dc.contributor.author Allen, Lisa I. S. en_GB
dc.contributor.author Bulman, Michael P. en_GB
dc.contributor.author Ayres, Susan en_GB
dc.contributor.author Shepherd, Maggie en_GB
dc.contributor.author Clark, Penny en_GB
dc.contributor.author Millward, Ann en_GB
dc.contributor.author Demaine, Andrew en_GB
dc.contributor.author Wilkin, Terence en_GB
dc.contributor.author Docherty, Kevin en_GB
dc.contributor.author Hattersley, Andrew T. en_GB
dc.date.accessioned 2007-05-14T09:22:25Z en_GB
dc.date.accessioned 2011-01-25T10:08:03Z en_US
dc.date.accessioned 2013-03-20T17:07:39Z
dc.date.issued 1999-11-01 en_GB
dc.description.abstract The transcription factor insulin promoter factor-1 (IPF-1) plays a central role in both the development of the pancreas and the regulation of insulin gene expression in the mature pancreatic beta cell. A dominant-negative frameshift mutation in the IPF-l gene was identified in a single family and shown to cause pancreatic agenesis when homozygous and maturity-onset diabetes of the young (MODY) when heterozygous. We studied the role of IPF-1 in Caucasian diabetic and nondiabetic subjects from the United Kingdom. Three novel IPF-1 missense mutations (C18R, D76N, and R197H) were identified in patients with type 2 diabetes. Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human beta-cell line Nes2y. These mutations are present in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25-53 years of age. We conclude that mutations in the IPF-1 gene may predispose to type 2 diabetes and are a rare cause of MODY and pancreatic agenesis, with the phenotype depending upon the severity of the mutation. en_GB
dc.identifier.citation Journal of Clinical Investigation, 1999, 104(9):R33-R39 en_GB
dc.identifier.uri http://hdl.handle.net/10036/11783 en_GB
dc.language.iso en_US en_GB
dc.publisher American Society for Clinical Investigation en_GB
dc.rights Copyright © 1999, American Society for Clinical Investigation en_GB
dc.title Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes en_GB
dc.type Article en_GB
dc.date.available 1999-11-01 en_GB
dc.date.available 2007-05-14T09:22:25Z en_GB
dc.date.available 2011-01-25T10:08:03Z en_US
dc.date.available 2013-03-20T17:07:39Z
dc.identifier.issn 0021-9738 en_GB
dc.format.dig YES en_GB
dc.identifier.journal Journal of Clinical Investigation en_GB
dc.identifier.pmcid 481047 en_GB
dc.identifier.pmid 10545530 en_GB


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