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

• Published in: The journal of clinical endocrinology and metabolism Vol. 89; no. 2; pp. 971 - 978
• Main Authors: Cockburn, Brian N., Bermano, Giovanna, Boodram, Laura-Lee G., Teelucksingh, Surujpal, Tsuchiya, Takafumi, Mahabir, Deepak, Allan, Andrew B., Stein, Roland, Docherty, Kevin, Bell, Graeme I.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-02-2004; Copyright by The Endocrine Society
• Subjects: Adult; Africa - ethnology; Aged; Biological and medical sciences; Cell Line; Diabetes Mellitus - genetics; Endocrinopathies; Female; Founder Effect; Fundamental and applied biological sciences. Psychology; Glucose Intolerance - genetics; Glucose Tolerance Test; Glutamic Acid - genetics; Haplotypes; HeLa Cells; Homeodomain Proteins; Humans; India - ethnology; Lysine - genetics; Male; Medical sciences; Middle Aged; Mutation; Mutation, Missense; Pedigree; Trans-Activators - genetics; Trans-Activators - metabolism; Transcriptional Activation; Trinidad and Tobago; Vertebrates: endocrinology; Trinidad and Tobago; Africa; India; Endocrinopathy; Pancreatic hormone; Family study; Transcription promoter; Diabetes mellitus; Identification; Mutation; Insulin; Endocrinology
• DOI: 10.1210/jc.2003-031282
• EISSN: 1945-7197
• ISSN: 0021-972X

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.