Dataset Information

Identification of an HNF1A p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family.

ABSTRACT: The diagnosis of maturity onset diabetes of the young (MODY) is a challenging process in view of the extensive clinical and genetic heterogeneity of the disease. Mutations in the gene encoding hepatocyte nuclear factor 1? (HNF1A) are responsible for most forms of monogenic diabetes in Northern European populations. Genetic analysis through a combination of whole exome sequencing and Sanger sequencing in three Maltese siblings and their father identified a rare duplication/frameshift mutation in exon 4 of HNF1A that lies within a known mutational hotspot in this gene. In this report, we provide the first description of an HNF1A-MODY3 phenotype in a Maltese family. The findings reported are relevant and new to a regional population, where the epidemiology of atypical diabetes has never been studied before. This report is of clinical interest as it highlights how monogenic diabetes can be misdiagnosed as either type 1, type 2, or gestational diabetes. It also reinforces the need for a better characterisation of monogenic diabetes in Mediterranean countries, particularly in island populations such as Malta with a high prevalence of diabetes.

SUBMITTER: Pace NP

PROVIDER: S-EPMC6383084 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Identification of an <i>HNF1A</i> p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family.

Pace Nikolai Paul NP Rizzo Christopher C Abela Alexia A Gruppetta Mark M Fava Stephen S Felice Alex A Vassallo Josanne J

Clinical medicine insights. Case reports 20190220

The diagnosis of maturity onset diabetes of the young (MODY) is a challenging process in view of the extensive clinical and genetic heterogeneity of the disease. Mutations in the gene encoding hepatocyte nuclear factor 1α (<i>HNF1A</i>) are responsible for most forms of monogenic diabetes in Northern European populations. Genetic analysis through a combination of whole exome sequencing and Sanger sequencing in three Maltese siblings and their father identified a rare duplication/frameshift mutat ...[more]

PMID: 30814848

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Project description:HNF1A gene regulates liver-specific genes, and genes that have a role in glucose metabolism, transport, and secretion of insulin. HNF1A gene mutations are frequently associated with type 2 diabetes. HNF1A protein has three domains: the dimerization domain, the DNA-binding domain, and the trans-activation domain. Some mutations in the dimerization or DNA-binding domains have no influence on the normal allele, while others have dominant negative effects. The I27L, A98V, and S487N polymorphisms are common variants of the HNF1A gene; they have been found in T2D and non-diabetic subjects.We searched for mutations in the first three exons of the HNF1A gen in an Amerindian population of 71 diabetic patients. DNA sequencing revealed the previously reported I27L polymorphism (c.79A>C) in 53% of diabetic patients and in 67% of the control group. Thus, the I27L/L27L polymorphism might be a marker of Amerindians. In addition, we found the c.422_423InsT mutation in the HNF1A gene of one patient, which had not been previously reported. This mutation resulted in a frame shift of the open reading frame and a new translation stop in codon 187, leading to a truncated polypeptide of 186 amino acids (Q141Hfs*47). This novel mutation affects the DNA-binding capacity of the mutant HNF1A protein by EMSA; its intracellular localization by fluorescence and confocal microscopy, and a dominant-negative effect affecting the DNA-binding capacity of the normal HNF1A by EMSA. We also studied the homology modeling structure to understand the effect of this mutation on its DNA-binding capacity and its dominant negative effect.The HNF1A Q141Hfs*47 mutant polypeptide has no DNA-binding capacity and exerts a dominant negative effect on the HNF1A protein. Therefore, it might produce severe phenotypic effects on the expression levels of a set of ?-cell genes. Consequently, its screening should be included in the genetic analysis of diabetic patients after more functional studies are performed.

Dataset Information

Identification of an HNF1A p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family.

Publications

Identification of an <i>HNF1A</i> p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family.

Similar Datasets

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