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dc.contributor.authorMacfarlane, Wendy M.en_GB
dc.contributor.authorFrayling, Timothy M.en_GB
dc.contributor.authorEllard, Sianen_GB
dc.contributor.authorEvans, Julie C.en_GB
dc.contributor.authorAllen, Lisa I. S.en_GB
dc.contributor.authorBulman, Michael P.en_GB
dc.contributor.authorAyres, Susanen_GB
dc.contributor.authorShepherd, Maggie H.en_GB
dc.contributor.authorClark, Pennyen_GB
dc.contributor.authorMillward, Annen_GB
dc.contributor.authorDemaine, Andrewen_GB
dc.contributor.authorWilkin, Terenceen_GB
dc.contributor.authorDocherty, Kevinen_GB
dc.contributor.authorHattersley, Andrew T.en_GB
dc.description.abstractThe 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.citationJournal of Clinical Investigation, 1999, 104(9):R33-R39en_GB
dc.publisherAmerican Society for Clinical Investigationen_GB
dc.rightsCopyright © 1999, American Society for Clinical Investigationen_GB
dc.titleMissense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetesen_GB
dc.identifier.journalJournal of Clinical Investigationen_GB

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