title: Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family.
abstract: This study investigated the prevalence of insulin promoter factor-1(IPF-1) mutations in familial early-onset diabetes mellitus in Trinidad. We screened 264 unrelated subjects with type 2 diabetes diagnosed before 40 yr of age and a family history of diabetes for mutations in the minimal promoter and coding region of the IPF-1 gene (IPF1). This study population included 169 patients of East Indian descent (Indo-Trinidadians), 66 of African descent (Afro-Trinidadians), and 29 of mixed ancestry. We identified five IPF1 variants, including one new missense mutation E224K, the previously described diabetes-associated duplication P242 P243dupP, two silent mutations in the codons for Leu54 (c.162G>A) and Ala256 (c.768C>A), and a substitution in the 5'-untranslated region (c.-18C>T). The E224K mutation was found in two unrelated diabetic Indo-Trinidadians and 0 of 60 controls. It was present on the same haplotype in both patients suggesting a founder effect. The E224K mutation cosegregated with early-onset diabetes or impaired glucose tolerance in a large family, suggestive of the type 4 form of maturity-onset diabetes of the young rather than type 2 diabetes. Functional studies of E224K showed reduced transactivation activity. IPF1 mutations leading to synthesis of a mutant protein may contribute to the development of familial early-onset diabetes/maturity-onset diabetes of the young in Indo-Trinidadians.
authors.affiliation: Department of Life Sciences, Faculty of Science and Agriculture, University of the West Indies, St. Augustine, Republic of Trinidad and Tobago. bcockburn@fans.uwi.tt
authors.forename: Brian N
authors.initials: BN
authors.lastname: Cockburn
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bermano
authors.forename: Laura-Lee G
authors.initials: LL
authors.lastname: Boodram
authors.forename: Surujpal
authors.initials: S
authors.lastname: Teelucksingh
authors.forename: Takafumi
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: Deepak
authors.initials: D
authors.lastname: Mahabir
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Allan
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
authors.forename: Kevin
authors.initials: K
authors.lastname: Docherty
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Bell
mesh_terms: D000328:Adult; D000349:Africa / Q000208:ethnology; D000368:Aged; D002460:Cell Line; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D018149:Glucose Intolerance / Q000235:genetics; D005951:Glucose Tolerance Test; D018698:Glutamic Acid / Q000235:genetics; D006239:Haplotypes; D006367:HeLa Cells; D018398:Homeodomain Proteins; D006801:Humans; D007194:India / Q000208:ethnology; D008239:Lysine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014300:Trinidad and Tobago
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D018698:Glutamic Acid; D008239:Lysine