A ComprehensiveIn SilicoAnalysis of the Functional and Structural Impact of SNPs in theIGF1RGene

Abstract

Insulin-like growth factor 1 receptor (IGF1R) acts as a critical mediator of cell proliferation and survival. Many single nucleotide polymorphisms (SNPs) found in the IGF1R gene have been associated with various diseases, including both breast and prostate cancer. The genetics of these diseases could be better understood by knowing the functions of these SNPs. In this study, we performed a comprehensive analysis of the functional and structural impact of all known SNPs in this gene using publicly available computational prediction tools. Out of a total of 2412 SNPs in IGF1R retrieved from dbSNP, we found 32 nsSNPs, 58 sSNPs, 83 mRNA 3′ UTR SNPs, and 2225 intronic SNPs. Among the nsSNPs, a total of six missense nsSNPs were found to be damaging by both a sequence homology-based tool (SIFT) and a structural homology-based method (PolyPhen), and one nonsense nsSNP was found. Further, we modeled mutant proteins and compared the total energy values with the native IGF1R protein, and showed that a mutation from arginine to cysteine at position 1216 (rs61740868) on the surface of the protein caused the greatest impact on stability. Also, the FASTSNP tool suggested that 31 sSNPs and 3 intronic SNPs might affect splicing regulation. Based on our investigation, we report potential candidate SNPs for future studies on IGF1R mutations.

IGF receptor gene variants in normal adolescents: effect on stature

“…This study differs from those in that we focused on a few specific genetic variations in IGF1R that plausibly attenuate IGF1 signaling and measured the effect in a normal adolescent population. We find that harboring a single copy of certain IGF1R variants leads to a substantial (4 cm) decrease in height on average, an observation supported by a recent computational analysis that predicts functional effects of these specific variants (22). This indicates that variation in height within healthy individuals may be explained, in some cases, by larger effects of a small subset of gene variants, rather than the combined small effects of many genes.…”

Clinically Significant Missense Variants in Human GALNT3, GALNT8, GALNT12, and GALNT13 Genes: Intriguing In Silico Findings

“…From overall functional analysis, both SIFT and PolyPhen predicted 10 (83%) variants to be highly deleterious. Although there is significant difference in SIFT and PolyPhen‐2 algorithms [de Alencar and Lopes, ], the concordance analysis of SIFT and PolyPhen results showed 10 (83%) variants (c.485G>A, c.815C>A, c.1076C>A, c.1720T>G, c.1076G>A, c.889C>T, c.1187A>G, c.1472C>T, c.937G>A, and c.1427G>A) with damaging effects on relevant proteins. Moreover, good coherence is found for predictions taken from PANTHER and PolyPhen‐2, simulated 11 (92%) nsSNPs (except c.3G>A) to be deleterious.…”

First ComprehensiveIn SilicoAnalysis of the Functional and Structural Consequences of SNPs in HumanGalNAc-T1Gene

“…So far, approximately 900 variants located in noncoding, coding, and regulatory regions of human GalNAc-T1 gene are described in dbSNP database to date. With the advent of high throughput (whole exome and genome) sequencing practices, the number of genetic variations is growing day by day in an efficient manner [18, 24, 41, 42]. Hence, an important task of human genetics lies in delineating those amino acid variants which can impose specific structural and functional consequences on protein function [41].…”