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 ResultsWe 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.ConclusionThe 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.
Highlights
The maturity onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by an autosomal dominant inheritance; the onset usually happens before the 25 years of age and is characterized by an impaired insulin secretion with minimal or no defect of the insulin action (Fajans and Bell 2001)
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)
We studied the homology modeling structure to understand the effect of this mutation on its DNA-binding capacity and its dominant negative effect
Summary
The maturity onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by an autosomal dominant inheritance; the onset usually happens before the 25 years of age and is characterized by an impaired insulin secretion with minimal or no defect of the insulin action (Fajans and Bell 2001). Recent studies have demonstrated heterozygous mutations in genes encoding 11 forms of MODY, including the hepatocyte nuclear factor-4a encoding the gene (HNF4A)(MODY 1), the glucokinase gene or GCK (MODY 2), the hepatocyte nuclear factor1a that encodes HNF1A (MODY 3), the pancreas/duodenum homeobox protein 1 (PDX1, known as IPF-1) (MODY 4), the hepatocyte nuclear factor-1b encoding the gene HNF1B (MODY 5), the neurogenic differentiation 1 that encodes the gene (NEUROD1)(MODY 6), the Kruppel-like factor 11 (KLF11) (MODY 7), the carboxylester lipase encoding the gene (CEL) (MODY 8), the paired box gene 4 (PAX4) (MODY 9), insulin gene (INS) (MODY 10), the tyrosine kinase B-lymphocyte specific gene (BLK) (MODY 11), the potassium voltage-gated channel subfamily J member 11 (KCNJ11 gene) (MODY13), and the adapter protein containing PH domain, PTB domain and leucine zipper motif 1, known as DCC-interacting protein 13-a encoded by the APPL1 gene (MODY14) Those cases of as yet unknown genetic derangement have been classified as MODYX (Online Mendelian Inheritance in Man [OMIM], MIM entry 606391). The I27L, A98V, and S487N polymorphisms are common variants of the HNF1A gene; they have been found in T2D and non-diabetic subjects
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