Abstract
Single-nucleotide polymorphisms (SNPs) associated with complex disorders can create, destroy, or modify protein coding sites. Single amino acid substitutions in the insulin receptor (INSR) are the most common forms of genetic variations that account for various diseases like Donohue syndrome or Leprechaunism, Rabson-Mendenhall syndrome, and type A insulin resistance. We analyzed the deleterious nonsynonymous SNPs (nsSNPs) in INSR gene based on different computational methods. Analysis of INSR was initiated with PROVEAN followed by PolyPhen and I-Mutant servers to investigate the effects of 57 nsSNPs retrieved from database of SNP (dbSNP). A total of 18 mutations that were found to exert damaging effects on the INSR protein structure and function were chosen for further analysis. Among these mutations, our computational analysis suggested that 13 nsSNPs decreased protein stability and might have resulted in loss of function. Therefore, the probability of their involvement in disease predisposition increases. In the lack of adequate prior reports on the possible deleterious effects of nsSNPs, we have systematically analyzed and characterized the functional variants in coding region that can alter the expression and function of INSR gene. In silico characterization of nsSNPs affecting INSR gene function can aid in better understanding of genetic differences in disease susceptibility.
Highlights
The insulin receptor (INSR) is a tyrosine kinase-specific transmembrane receptor that is activated by insulin, insulin growth factor I, and insulin growth factor II [1]
Donohue syndrome known as Leprechaunism is a rare and severe genetic autosomal recessive disorder due to defect in the INSR gene
The data of human INSR gene was collected from Online Mendelian Inheritance in Man (OMIM) and Entrez Gene on National Center for Biological Information (NCBI) web sites
Summary
The insulin receptor (INSR) is a tyrosine kinase-specific transmembrane receptor that is activated by insulin, insulin growth factor I, and insulin growth factor II [1]. The main activity of INSR is persuading uptake of glucose and because of a decrease in insulin receptor signaling leads to diabetes mellitus type 2. It is already proven that the presence of mutant receptors in the cell may have detrimental effects on the activity of the normal receptor. A previous study conducted with kinase-deficient INSRs transfected into cultured cells showed that such receptors suppressed the function of endogenous INSRs and functioned as dominant-negative mutations [4]. In most cases of insulin resistance, the mutation is expressed as a recessive form. Yamamoto-Honda et al [5] studied the function and consequences of recessive mutation in the INSR. Donohue syndrome known as Leprechaunism is a rare and severe genetic autosomal recessive disorder due to defect in the INSR gene
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