Mutations in the Genes Encoding the Transcription Factors Hepatocyte Nuclear Factor 1 Alpha (HNF1A) and 4 Alpha (HNF4A) in Maturity Onset Diabetes of the Young

Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, United Kingdom.
Human Mutation (Impact Factor: 5.14). 09/2006; 27(9):854-69. DOI: 10.1002/humu.20357
Source: PubMed


Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (often <25 years of age), and pancreatic beta-cell dysfunction. MODY is both clinically and genetically heterogeneous, with six different genes identified to date; glucokinase (GCK), hepatocyte nuclear factor-1 alpha (HNF1A, or TCF1), hepatocyte nuclear factor-4 alpha (HNF4A), insulin promoter factor-1 (IPF1 or PDX1), hepatocyte nuclear factor-1 beta (HNF1B or TCF2), and neurogenic differentiation 1 (NEUROD1). Mutations in the HNF1A gene are a common cause of MODY in the majority of populations studied. A total of 193 different mutations have been described in 373 families. The most common mutation is Pro291fs (P291fsinsC) in the polycytosine (poly C) tract of exon 4, which has been reported in 65 families. HNF4A mutations are rarer; 31 mutations reported in 40 families. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The identification of an HNF1A or 4A gene mutation confirms a diagnosis of MODY and has important implications for clinical management.

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Available from: Kevin Colcough, Mar 25, 2015
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    • "HNF1A-MODY represents the most common form of MODY [3-5]. Mutations in HNF4A are less common than mutations in HNF1A, however over 30 mutations have been identified to date [6]. HNF1A and HNF4A mutations cause a similar clinical phenotype of MODY, characterized by progressive beta-cell dysfunction, defects in glucose-stimulated insulin secretion [7,8] and sensitivity to low-dose sulphonylureas [9]. "
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    ABSTRACT: There is a significant clinical overlap between patients with hepatocyte nuclear factor (HNF)-1A and HNF4A maturity-onset diabetes of the young (MODY), two forms of monogenic diabetes. HNF1A and HNF4A are transcription factors that control common and partly overlapping sets of target genes. We have previously shown that elevated serum pancreatic stone protein / regenerating protein A (PSP/reg1A) levels can be detected in subjects with HNF1A-MODY. In this study, we investigated whether PSP/reg is differentially regulated by HNF1A and HNF4A. Quantitative real-time PCR (qPCR) and Western blotting were used to validate gene and protein expression in cellular models of HNF1A- and HNF4A-MODY. Serum PSP/reg1A levels and high-sensitivity C-reactive protein (hsCRP) were measured by ELISA in 31 HNF1A- and 9 HNF4A-MODY subjects. The two groups were matched for age, body mass index, diabetes duration, blood pressure, lipid profile and aspirin and statin use. Inducible repression of HNF1A and HNF4A function in INS-1 cells suggested that PSP/reg induction required HNF4A, but not HNF1A. In contrast, crp gene expression was significantly reduced by repression of HNF1A, but not HNF4A function. PSP/reg levels were significantly lower in HNF4A subjects when compared to HNF1A subjects [9.25 (7.85-12.85) ng/ml vs. 12.5 (10.61-17.87) ng/ml, U-test P = 0.025]. hsCRP levels were significantly lower in HNF1A-MODY [0.22 (0.17-0.35) mg/L] compared to HNF4A-MODY group [0.81 (0.38-1.41) mg/L, U-test P = 0.002], Parallel measurements of serum PSP/reg1A and hsCRP levels were able to discriminate HNF1A- and HNF4A-MODY subjects. Our study demonstrates that two distinct target genes, PSP/reg and crp, are differentially regulated by HNF1A and HNF4A, and provides clinical proof-of-concept that serum PSP/reg1A and hsCRP levels may distinguish HNF1A-MODY from HNF4A-MODY subjects.
    Journal of Translational Medicine 06/2013; 11(1):156. DOI:10.1186/1479-5876-11-156 · 3.93 Impact Factor
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    • "Heterozygous mutations in HNF4α results in a phenotype that resembles MODY3.[54] In addition, it has been observed that such patients are more sensitive to the hypoglycaemic effect of sulfonylureas.[5556] Mutations in HNF-4α have been reported to result in macrosomia and transient hyperinsulinemic hypoglycaemia in the neonatal period and these subjects subsequently develop an early onset diabetes mellitus (MODY1).[57] "
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    ABSTRACT: Diabetes is highly prevalent in India and the proportion of younger patients developing diabetes is on the increase. Apart from the more universally known type 1 diabetes and obesity related type 2 diabetes, monogenic forms of diabetes are also suspected to be prevalent in many young diabetic patients. The identification of the genetic basis of the disease not only guides in therapeutic decision making, but also aids in genetic counselling and prognostication. Genetic testing may establish the occurrence and frequency of early diabetes in our population. This review attempts to explore the utilities and horizons of molecular genetics in the field of maturity onset diabetes of the young (MODY), which include the commoner forms of monogenic diabetes.
    05/2013; 17(3):430-41. DOI:10.4103/2230-8210.111636
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    • "There is increasingly convincing evidence that glucose handling and insulin production are also disturbed in adult rodents and humans who carry heterozygous PAX6 mutations [19], [20], [21], [28]. This suggests that not only is PAX6 essential for pancreatic endocrine maintenance, but that correct dosage of the protein is required for this role, as it is for some other transcription factors associated with diabetes, such as HNF1A and HNF4A, in which heterozygous mutations have been found in a significant portion of MODY cases [35]. "
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    ABSTRACT: The transcription factor Pax6 is a developmental regulator with a crucial role in development of the eye, brain, and olfactory system. Pax6 is also required for correct development of the endocrine pancreas and specification of hormone producing endocrine cell types. Glucagon-producing cells are almost completely lost in Pax6-null embryos, and insulin-expressing beta and somatostatin-expressing delta cells are reduced. While the developmental role of Pax6 is well-established, investigation of a further role for Pax6 in the maintenance of adult pancreatic function is normally precluded due to neonatal lethality of Pax6-null mice. Here a tamoxifen-inducible ubiquitous Cre transgene was used to inactivate Pax6 at 6 months of age in a conditional mouse model to assess the effect of losing Pax6 function in adulthood. The effect on glucose homeostasis and the expression of key islet cell markers was measured. Homozygous Pax6 deletion mice, but not controls, presented with all the symptoms of classical diabetes leading to severe weight loss requiring termination of the experiment five weeks after first tamoxifen administration. Immunohistochemical analysis of the pancreata revealed almost complete loss of Pax6 and much reduced expression of insulin, glucagon, and somatostatin. Several other markers of islet cell function were also affected. Notably, strong upregulation in the number of ghrelin-expressing endocrine cells was observed. These findings demonstrate that Pax6 is essential for adult maintenance of glucose homeostasis and function of the endocrine pancreas.
    PLoS ONE 01/2013; 8(1):e54173. DOI:10.1371/journal.pone.0054173 · 3.23 Impact Factor
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