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Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes
Wendy M. Macfarlane, … , Kevin Docherty, Andrew T. Hattersley
Wendy M. Macfarlane, … , Kevin Docherty, Andrew T. Hattersley
Published November 1, 1999
Citation Information: J Clin Invest. 1999;104(9):R33-R39. https://doi.org/10.1172/JCI7449.
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Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes

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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 β 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 β-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.

Authors

Wendy M. Macfarlane, Timothy M. Frayling, Sian Ellard, Julie C. Evans, Lisa I.S. Allen, Michael P. Bulman, Susan Ayres, Maggie Shepherd, Penny Clark, Ann Millward, Andrew Demaine, Terence Wilkin, Kevin Docherty, Andrew T. Hattersley

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Figure 1

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Diabetic families who have probands with IPF-1 mutations. Shown is mutat...
Diabetic families who have probands with IPF-1 mutations. Shown is mutation status within families with either a MODY proband diagnosed before 25 years of age (MY54 and MY99) or type 2 diabetes diagnosed at 35–70 years of age (4/22, 4/25, 4/55, 4/116, 4/127, 4/159, and 4/185). Squares representing diabetic subjects are completely filled, and squares representing patients with impaired glucose tolerance are half-filled. Family number and mutation designation is given above the pedigree. Individual mutation status is given: N = normal, M = mutation. For affected subjects, age at diagnosis, followed by treatment requirement (OHA = oral hypoglycemic agents; Ins = insulin), is given. For unaffected subjects, age at testing, followed by either 2-hour glucose value after oral glucose load or by fasting blood glucose value (FBG) or not tested (NT), is given.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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