title: Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus.
abstract: Type 2 diabetes mellitus is a common disabling disease with onset in middle-aged individuals, caused by an imbalance between insulin production and action. Genetic studies point to major genetic components, but, with the exception of maturity-onset diabetes of the young (MODY), specific diabetes susceptibility genes remain to be identified. Recent studies showed that a dominant negative mutation in the insulin promoter factor-1 (IPF-1), a pancreatic beta-cell specific transcription factor, causes pancreatic agenesis and MODY. Thus, we investigated 192 French, non-MODY type 2 diabetic families for mutations in IPF-1. We identified 3 novel IPF-1 mutations, including 2 substitutions (Q59L and D76N) and an in-frame proline insertion (InsCCG243). Functional transactivation assays of these IPF-1 mutant isoforms in a beta-pancreatic tumor cell line transfected with a transcriptional reporter and IPF-1 expression plasmids demonstrate a significant inhibition of basal insulin promoter activity (stronger with the InsCCG243 mutant). We find that the InsCCG243 mutation is linked, in 2 families, to an autosomal dominant-like late-onset form of type 2 diabetes, in which insulin secretion becomes progressively impaired. The lower penetrance D76N and Q59L mutations were more prevalent and were associated with a relative risk of 12.6 for diabetes and with decreased glucose-stimulated insulin-secretion in nondiabetic subjects. We propose that IPF-1 mutations can cause MODY or apparently monogenic late-onset diabetes and that they represent a significant risk factor for type 2 diabetes in humans.
authors.affiliation: Institute of Biology of Lille-CNRS UPRES A8090, Pasteur Institute, 59000 Lille, France.
authors.forename: E H
authors.initials: EH
authors.lastname: Hani
authors.forename: D A
authors.initials: DA
authors.lastname: Stoffers
authors.forename: J C
authors.initials: JC
authors.lastname: Chèvre
authors.forename: E
authors.initials: E
authors.lastname: Durand
authors.forename: V
authors.initials: V
authors.lastname: Stanojevic
authors.forename: C
authors.initials: C
authors.lastname: Dina
authors.forename: J F
authors.initials: JF
authors.lastname: Habener
authors.forename: P
authors.initials: P
authors.lastname: Froguel
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D015500:Chloramphenicol O-Acetyltransferase