An in silico evaluation of deleterious nonsynonymous single nucleotide polymorphisms in the ErbB3 oncogene

Abstract

ErbB3 is a significant oncogenic target that is involved in the development of numerous malignancies. In the present in silico study, we evaluated the structural and functional impact of single nucleotide polymorphisms (SNPs) on the ErbB3 gene. The nonsynonymous SNPs (nsSNPs) are known to be deleterious or disease-causing variations because they alter protein sequence, structure, and function. Out of a total 531 SNPs in ErbB3, we investigated 77 coding nsSNPs and observed that 20 of them could be expected to alter the protein's function based on the predictions of both sequence homology-based (SIFT) and structural homology-based (Polyphen) algorithms. Thereafter, we computed the stability of mutants in units of free energy using I-Mutant 3.0, MuStab, and iPTree-STAB programs and identified seven crucial point mutations (V89M, V105G, C290Y, I418N, R669C, I744T, and A1131T) in epidermal growth factor receptor 3 that are manifested as nsSNPs. Furthermore, FASTSNP determined 14 synonymous SNPs that may have a profound impact on splicing regulation. The computational study identified seven novel hotspots predicted to maintain the native structural conformation and functional activity of ErbB3 and may account for cancer if mutated. © Mary Ann Liebert, Inc. 2013.