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In silico and in vitro analyses of the pathological relevance of the R258H mutation of hepatocyte nuclear factor 4? identified in maturity-onset diabetes of the young type 1.

ABSTRACT: Mutations of the hepatocyte nuclear factor 4? (HNF4?) gene give rise to maturity-onset diabetes of the young type 1. Although many such mutations have been identified in affected individuals, part of these mutations has been characterized with regard to their pathological relevance. We here identified a missense mutation (c.773G>A, p.R258H) of HNF4A in a mother and daughter with early-onset diabetes and impaired insulin secretion. In silico simulation and in vitro luciferase reporter analyses showed that the mutation impairs the stability of self-dimerization and the transactivation activity of HNF4?. Although arginine-258 does not appear to participate directly in dimerization, its mutation alters the electrostatic surface potential of the dimer interface. Our results thus suggest that this mutation impairs the function of HNF4? and thereby contributes to the pathogenesis of maturity-onset diabetes of the young type 1.

SUBMITTER: Sugawara K

PROVIDER: S-EPMC6497599 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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In silico and in vitro analyses of the pathological relevance of the R258H mutation of hepatocyte nuclear factor 4α identified in maturity-onset diabetes of the young type 1.

Sugawara Kenji K Nomura Kazuhiro K Okada Yuko Y Sugano Aki A Matsumoto Masaaki M Takarada Toru T Takeuchi Atsuko A Awano Hiroyuki H Hirota Yushi Y Nishio Hisahide H Takaoka Yutaka Y Ogawa Wataru W

Journal of diabetes investigation 20181210 3

Mutations of the hepatocyte nuclear factor 4α (HNF4α) gene give rise to maturity-onset diabetes of the young type 1. Although many such mutations have been identified in affected individuals, part of these mutations has been characterized with regard to their pathological relevance. We here identified a missense mutation (c.773G>A, p.R258H) of HNF4A in a mother and daughter with early-onset diabetes and impaired insulin secretion. In silico simulation and in vitro luciferase reporter analyses sh ...[more]

PMID: 30325586

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Project description:SummaryHepatocyte nuclear factor 1β (HNF1B) gene is located on chromosome 17q12. It is a transcription factor implicated in the early embryonic development of multiple organs. HNF1B-associated disease is a multi-system disorder with variable clinical phenotypes. There are increasing reports suggesting that the 17q12 deletion syndrome should be suspected in patients with maturity-onset diabetes of the young type 5 (MODY5) due to the deletion of HNF1B gene. In contrast to classical 17q12 syndrome in childhood with neurological disorders and autism, patients with HNF1B-MODY deletion rarely had neuropsychological disorders or learning disabilities. The diagnosis of 17q12 deletion syndrome highlighted the phenotypic heterogeneity of HNF1B-MODY patients. In this study, we report the clinical course of a Thai woman with young-onset diabetes mellitus and hypertriglyceridemia as a predominant feature due to HNF1B deletion as part of the 17q12 deletion syndrome. Our findings and others suggest that hypertriglyceridemia should be considered a syndromic feature of HNF1B-MODY. Our case also highlights the need to use sequencing with dosage analyses to detect point mutations and copy number variations to avoid missing a whole deletion of HNF1B.Learning pointsMaturity-onset diabetes of the young type 5 (MODY5) may be caused by heterozygous point mutations or whole gene deletion of HNF1B. Recent studies revealed that complete deletion of the HNF1B gene may be part of the 17q12 deletion syndrome with multi-system involvement. The length of the deletion can contribute to the phenotypic variability in patients with HNF1B-MODY due to whole gene deletion. Using next-generation sequencing alone to diagnose MODY could miss a whole gene deletion or copy number variations. Specialized detection methods such as microarray analysis or low-pass whole genome sequencing are required to accurately diagnose HNF1B-MODY as a component of the 17q12 deletion syndrome. Molecular diagnosis is necessary to distinguish other acquired cystic kidney diseases in patients with type 2 diabetes which could phenocopy HNF1B-MODY. Hypertriglyceridemia is a possible metabolic feature in patients with HNF1B-MODY due to 17q12 deletion syndrome.

Dataset Information

In silico and in vitro analyses of the pathological relevance of the R258H mutation of hepatocyte nuclear factor 4? identified in maturity-onset diabetes of the young type 1.

Publications

In silico and in vitro analyses of the pathological relevance of the R258H mutation of hepatocyte nuclear factor 4α identified in maturity-onset diabetes of the young type 1.

Similar Datasets

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