当前位置： SCI文献检索 > Molecular Genetics & Genomic Medicine期刊下所有文献 > Identification and functional analysis of c.422_423InsT, a novel mutation of the HNF1A gene in a patient with diabetes.

Identification and functional analysis of c.422_423InsT, a novel mutation of the HNF1A gene in a patient with diabetes.

Abstract：

BACKGROUND: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. METHODS AND RESULTS: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. CONCLUSION: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 β-cell genes. Consequently, its screening should be included in the genetic analysis of diabetic patients after more functional studies are performed.

journal_name

Mol Genet Genomic Med

journal_title

Molecular genetics & genomic medicine

authors

Magaña-Cerino JM,Luna-Arias JP,Labra-Barrios ML,Avendaño-Borromeo B,Boldo-León XM,Martínez-López MC

doi

10.1002/mgg3.261

subject

Has Abstract

pub_date

2016-11-30 00:00:00

pages

50-65

issue

issn

2324-9269

pii

MGG3261

journal_volume

pub_type

杂志文章

在线工具

Identification and functional analysis of c.422_423InsT, a novel mutation of the HNF1A gene in a patient with diabetes.