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

Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 02/2004; 89(2):971-8. DOI: 10.1210/jc.2003-031282
Source: PubMed


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.

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    • "In addition to its role in pancreas development, the Pdx1 protein is also a glucose-responsive regulator of the insulin gene in the b cells of the adult pancreas and is known to bind to the P1 enhancer 5# of the insulin gene (Ohlsson et al. 1993). As a consequence of this role, mutations in Pdx1 have also been implicated in type II diabetes mellitus and maturity onset diabetes of the young type IV (Hani et al. 1999; Macfarlane et al. 1999; Cockburn et al. 2004). The vertebrate Pdx1 gene was the only identified vertebrate member of the Xlox gene family, also called the Pdx gene family, which in turn is within the ANTP class of homeobox-containing genes (Wysocka-Diller et al. 1995; Holland et al. 2007). "
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    ABSTRACT: The Pdx1 or Ipf1 gene encodes an important homeodomain-containing protein with key roles in pancreas development and function. Mutations in human PDX1 are implicated in developmental defects and disease of the pancreas. Extensive research, including genome sequencing, has indicated that Pdx1 is the only member of its gene family in mammals, birds, amphibians, and ray-finned fish, and with the exception of teleost fish, this gene forms part of the ParaHox gene cluster along with Gsx1 and Cdx2. The ParaHox cluster, however, is a remnant of a 4-fold genome duplication; the three other ParaHox paralogues lack a Pdx-like gene in all vertebrate genomes examined to date. We have used bacterial artificial chromosome cloning and synteny analysis to show that the ancestor of living jawed vertebrates in fact had more ParaHox genes, including two Pdx genes (Pdx1 and Pdx2). Surprisingly, the two Pdx genes have been retained in parallel in two quite distantly related lineages, the cartilaginous fish (sharks, skates, and chimeras) and the Indonesian coelacanth, Latimeria menadoensis. The Pdx2 gene has been lost independently in ray-finned fish and in tetrapods.
    Full-text · Article · May 2010 · Molecular Biology and Evolution
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    • ". If results are normal, then the patient should be reevaluated every 3 years; if impaired glucose tolerance is detected, annual screening is then recommended. GDM identifies a population of women at high risk for developing subsequent T2DM; it represents an early stage in the natural history of the disease and therefore provides an opportunity for early intervention and reduction of the national prevalence of T2DM [18] [19]. "
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    ABSTRACT: Objective. To investigate the incidence of Gestational Diabetes Mellitus at the Mt. Hope Women's Hospital and to describe its epidemiological pattern. Design. A retrospective observational study (Jan 2005 to Dec 2007). Setting. A teaching hospital of The University of the West Indies. Population/Sample. Pregnant women who gave birth. Methods. A sample size of 720. The variables analyzed were: age, ethnicity, BMI of mother, family history of diabetes; history of GDM, obstetric history, birth weight and APGAR score of infant. Main Outcome Measures. (1) Incidence of cases of GDM. (2) Impact of the measured variable. Chi-squares, odds ratios and logistic regression were performed. Results. The incidence of GDM was 4.31% (95% C.I. 2.31%, 6.31%). The proportion of GDM patients for the years 2005, 2006, and 2007 were 1.67%, 4.58%, and 6.67%, respectively. Age, Obesity Ethnicity, Family history of diabetes and a history of GDM were determined risk factors. Associations between GDM and (1) Mode of Delivery and (2) APGAR score of the baby were found. Discussion & Conclusion. There was an apparent increase in the incidence of GDM. Additional studies should be conducted to measure the occurrence of GDM in Trinidad and Tobago. Efforts to promote public awareness and a healthy lifestyle should be made to reverse this trend.
    Full-text · Article · May 2009 · Obstetrics and Gynecology International
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    • "Expression vectors were full length mouse PDX-1, mouse PDX-1(1- 210), pGBKT7-PDX-1(144–283) and GST-PDX-1(206–283) [12], rat PDX-1 [13], human PDX-1 [14], zebrafish PDX-1 [15], Flag-PCIF1 [12], Gal-4 PDX-1 [6], Gal-4 BCL6 POZ and Gal-4 PLZF POZ [16], human PDX-1 wild-type and E224K [3] and GST-TRAF and GST- POZ [17]. Reporters were the PDX-1-responsive somatostatin promoter reporter (TAAT) 5 -65 SMS-CAT [13] and the Gal4 responsive reporters G51bCAT [12] and Gal4SV40Luc. "
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    ABSTRACT: PCIF1 is a TRAF and POZ domain containing nuclear factor that interacts with and inhibits transactivation of pancreatic homeodomain transcription factor PDX-1. Here, we demonstrate interaction of endogenous PDX-1 and PCIF1 in MIN6 insulinoma cells. Within PCIF1, the TRAF and POZ domains are both required for physical and functional interaction with the C-terminus of PDX-1, whereas the C-terminal domain of PCIF1 directs its nuclear localization. A human PDX-1 mutation associated with diabetes, E224K, disrupts the ability of PCIF1 to inhibit PDX-1 transactivation, suggesting that the interaction between PDX-1 and PCIF1 is required for normal glucose homeostasis. Inhibition of transactivation occurs by a mechanism distinct from the classical role of POZ domains to recruit co-repressors and histone deacetylases. Understanding the functional roles of PCIF1 domains may have application to therapeutic beta-cell replacement strategies involving PDX-1 for the treatment of diabetes.
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