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

W M Macfarlane, T M Frayling, S Ellard, J C Evans, L I S Allen, M P Bulman, S Ayres, M Shepherd, P Clark, A Millward, A Demaine, T Wilkin, K Docherty, A T Hattersley

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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-1 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.

Original languageEnglish
Number of pages7
JournalThe Journal of Clinical Investigation
Publication statusPublished - 1999


  • IPF1

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Macfarlane, W. M., Frayling, T. M., Ellard, S., Evans, J. C., Allen, L. I. S., Bulman, M. P., Ayres, S., Shepherd, M., Clark, P., Millward, A., Demaine, A., Wilkin, T., Docherty, K., & Hattersley, A. T. (1999). Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. The Journal of Clinical Investigation, 104.