Published September 1, 2000 - More info
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.
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
J. Clin. Invest.106:411–420 (2000)
During the preparation of this manuscript for publication, an error was introduced in Figure 2. The correct version, accompanied by the legend, appears below.
Localization of IPF-1 mutants. Western blot analysis of cytoplasmic (lanes 1-5) or nuclear (lanes 6-10) samples prepared from Nes2y cells which were incubated in low (3 mM) or high (20 mM) glucose concentrations. Lanes 1 and 6 represent untransfected Nes2y cells, lanes 2 and 7 cells expressing normal IPF-1, lanes 3 and 8 cells expressing C18R, lanes 4 and 9 cells expressing D76N, and lanes 5 and 10 cells expressinfg R197H. Analysis was preformed using a specific IPF-1 antibody, with 1 μg of each extract being used. Results are representative of three separate experiments.