title: Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes.
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-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.
authors.affiliation: Department of Molecular and Cell Biology, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: W M
authors.initials: WM
authors.lastname: Macfarlane
authors.forename: T M
authors.initials: TM
authors.lastname: Frayling
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: J C
authors.initials: JC
authors.lastname: Evans
authors.forename: L I
authors.initials: LI
authors.lastname: Allen
authors.forename: M P
authors.initials: MP
authors.lastname: Bulman
authors.forename: S
authors.initials: S
authors.lastname: Ayres
authors.forename: M
authors.initials: M
authors.lastname: Shepherd
authors.forename: P
authors.initials: P
authors.lastname: Clark
authors.forename: A
authors.initials: A
authors.lastname: Millward
authors.forename: A
authors.initials: A
authors.lastname: Demaine
authors.forename: T
authors.initials: T
authors.lastname: Wilkin
authors.forename: K
authors.initials: K
authors.lastname: Docherty
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010766:Phosphorylation; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose