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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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-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
Volume104
Publication statusPublished - 1999

Keywords

  • HOMEODOMAIN PROTEIN
  • TRANSCRIPTION FACTOR
  • COMMON-CAUSE
  • GLUCOKINASE GENE
  • YOUNG
  • ACTIVATION
  • MELLITUS
  • CELLS
  • IPF1
  • TRANSACTIVATION

Cite this

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.