This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cockburn, B. N. Articles by Bell, G. I. Search for Related Content PubMed PubMed Citation Articles by Cockburn, B. N. Articles by Bell, G. I.

Insulin Promoter Factor-1 Mutations and Diabetes in Trinidad: Identification of a Novel Diabetes-Associated Mutation (E224K) in an Indo-Trinidadian Family

Department of Life Sciences (B.N.C., L.G.B.), Faculty of Science and Agriculture, University of the West Indies, St. Augustine, Republic of Trinidad and Tobago; Department of Molecular and Cell Biology (G.B., A.B.A., K.D.), University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom; Department of Biochemistry and Molecular Biology (B.N.C., L.G.B., T.T., G.I.B.), The University of Chicago, Chicago, Illinois 60637; Department of Clinical Medical Sciences (S.T.), Faculty of Medical Sciences, University of the West Indies, St. Augustine, Republic of Trinidad and Tobago; Nutrition and Metabolism Unit (D.M.), Ministry of Health, Republic of Trinidad and Tobago; and Department of Molecular Physiology and Biophysics (R.S.), Vanderbilt University Medical School, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: B. N. Cockburn, Ph.D., Department of Life Sciences, Faculty of Science and Agriculture, University of the West Indies, St. Augustine, Republic of Trinidad and Tobago. E-mail: bcockburn{at}fans.uwi.tt.

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.

This work was supported by grants from the University of the West Indies Research and Publications Fund, the U.S. Public Health Service (DK-20595, DK-50203, and DK-44840), and the Wellcome Trust. G.I.B. is an Investigator of the Howard Hughes Medical Institute.

Abbreviations: CAT, Chloramphenicol acetyl transferase; HOMA-R, homeostatic model assessment insulin resistance; IGT, impaired glucose tolerance; IPF-1, insulin promoter factor-1; MODY, maturity-onset diabetes of the young; OGTT, oral glucose tolerance testing; PDX-1, pancreatic duodenal homeobox-1; SV, simian virus; TK, thymidine kinase; WT, wild-type.

This article has been cited by other articles:

				M.-J. Boucher, L. Selander, L. Carlsson, and H. Edlund Phosphorylation Marks IPF1/PDX1 Protein for Degradation by Glycogen Synthase Kinase 3-dependent Mechanisms J. Biol. Chem., March 10, 2006; 281(10): 6395 - 6403. [Abstract] [Full Text] [PDF]