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Novel monogenic diabetes mutations in the P2 promoter of the HNF4A gene are associated with impaired function in vitro.

Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, Universität Duisburg-Essen, Germany.
Diabetic Medicine (Impact Factor: 3.24). 06/2010; 27(6):631-5. DOI: 10.1111/j.1464-5491.2010.03003.x
Source: PubMed

ABSTRACT Mutations in HNF4A cause a form of monogenic beta-cell diabetes. We aimed to identify mutations in the pancreas-specific P2 promoter of HNF4A in families with suspected HNF4A diabetes and to show that they impaired the function of the promoter in vitro.
We screened families with a clinical suspicion of HNF4A monogenic beta-cell diabetes for mutations in the HNF4A P2 promoter. We investigated the function of the previously reported HNF4A P2 promoter mutation -192C>G linked to late-onset diabetes in several families, along with two new segregating mutations, in vitro using a modified luciferase reporter assay system with enhanced sensitivity.
We identified two novel HNF4A P2 promoter mutations that co-segregate with diabetes in two families, -136A>G and -169C>T. Both families displayed phenotypes typical of HNF4A monogenic beta-cell diabetes, including at least two affected generations, good response to sulphonylurea treatment and increased birthweight and/or neonatal hypoglycaemia. We show that both of these novel mutations and -192C>G impair the function of the promoter in transient transfection assays.
Two novel mutations identified here and the previously identified late-onset diabetes mutation, -192C>G, impair the function of the HNF4A P2 promoter in vitro.

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