title: IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes.
abstract: Maturity-onset diabetes of the young (MODY) is a monogenic autosomal-dominant form of diabetes mellitus with onset before 25 years of age. Genetic variation in insulin promoter factor-1 (IPF1) (MODY4) is uncommon but may contribute to early- or late-onset diabetes as part of a polygenic background. IPF1 is a homeodomain transcription factor required for pancreas development. Our aim was to identify whether IPF1 gene mutations play a role in Italian early-onset type 2 diabetic (T2D) patients and what functional impact mutations may have in the beta cell. We screened 40 Italian early-onset type 2 diabetic probands for IPF1 mutations, performed oral glucose tolerance tests in the unaffected family members, and performed in vitro functional studies of the mutant variant. In an extended family (Italy-6) of 46 members with clinical phenotypes of gestational diabetes, MODY, and T2D, a single nucleotide change of CCT to ACT was identified at codon 33 resulting in a Pro to Thr substitution (P33T) in the IPF1 transactivation domain that also contributes to an altered metabolic status in the unaffected NM subjects. Of the 22 genotyped Italy-6 members, 9 carried the P33T allele (NM), of whom 5 have either T2D or elevated fasting glucose levels. Oral glucose tolerance tests showed higher glucose levels at 90 minutes in unaffected NM compared with unaffected NN subjects. Of the 5 female pregnant carriers of the IPF1 mutation, 4 had pregnancies complicated by reduced birth weights, miscarriages, or early postnatal deaths. In studies in vitro, the IPF1 mutant protein (P33T) showed a reduction in DNA-binding and transcriptional activation functions as compared to the wild-type IPF1 protein. Our findings suggest that the P33T IPF1 mutation may provide an increased susceptibility to the development of gestational diabetes and MODY4 in the Italy-6 pedigree.
authors.affiliation: Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston, MA 02114, USA. cgragnoli@partners.org
authors.forename: Claudia
authors.initials: C
authors.lastname: Gragnoli
authors.forename: Violeta
authors.initials: V
authors.lastname: Stanojevic
authors.forename: Antonio
authors.initials: A
authors.lastname: Gorini
authors.forename: Guido Menzinger
authors.initials: GM
authors.lastname: Von Preussenthal
authors.forename: Melissa K
authors.initials: MK
authors.lastname: Thomas
authors.forename: Joel F
authors.initials: JF
authors.lastname: Habener
mesh_terms: D000022:Abortion, Spontaneous / Q000235:genetics; D000328:Adult; D000818:Animals; D001724:Birth Weight; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D016640:Diabetes, Gestational / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics / Q000401:mortality; D007558:Italy; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D013045:Species Specificity; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein