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: Brian N Cockburn, Giovanna Bermano, Laura-Lee G Boodram, Surujpal Teelucksingh, Takafumi Tsuchiya, Deepak Mahabir, Andrew B Allan, Roland Stein, Kevin Docherty, Graeme I Bell
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 89 Issue 2 Pg. 971-8 (Feb 2004) ISSN: 0021-972X [Print] United States
• PMID: 14764823 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Homeodomain Proteins
• Trans-Activators
• pancreatic and duodenal homeobox 1 protein
• Glutamic Acid
• Lysine

Topics

• Adult
• Africa (ethnology)
• Aged
• Cell Line
• Diabetes Mellitus (genetics)
• Female
• Founder Effect
• Glucose Intolerance (genetics)
• Glucose Tolerance Test
• Glutamic Acid (genetics)
• Haplotypes
• HeLa Cells
• Homeodomain Proteins
• Humans
• India (ethnology)
• Lysine (genetics)
• Male
• Middle Aged
• Mutation
• Mutation, Missense
• Pedigree
• Trans-Activators (genetics, metabolism)
• Transcriptional Activation
• Trinidad and Tobago