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

• Published in: The Journal of clinical investigation Vol. 104; no. 9; pp. R33 - R39
• Main Authors: Macfarlane, W M, Frayling, T M, Ellard, S, Evans, J C, Allen, L I, Bulman, M P, Ayres, S, Shepherd, M, Clark, P, Millward, A, Demaine, A, Wilkin, T, Docherty, K, Hattersley, A T
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-11-1999
• Subjects: Adult; Aged; Blotting, Western; Cell Nucleus - metabolism; Cells, Cultured; Cytoplasm - metabolism; Diabetes Mellitus, Type 2 - genetics; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Glucose - metabolism; Homeodomain Proteins; Humans; Insulin - genetics; Male; Middle Aged; Mutation, Missense; Pedigree; Phenotype; Phosphorylation; Rapid Publication; Trans-Activators - genetics; Transcription, Genetic
• ISSN: 0021-9738
• DOI: 10.1172/jci7449

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-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.