Mutations in the SMPX gene can disrupt the regular activity of the SMPX protein, which is involved in the hearing process. Recent reports showing a link between nonsynonymous single-nucleotide polymorphisms (nsSNPs) in SMPX and hearing loss, thus classifying deleterious SNPs in SMPX will be an uphill task before designing a more extensive population study. In this study, damaging nsSNPs of SMPX from the dbSNP database were identified by using 13 bioinformatics tools. Initially, the impact of nsSNPs in the SMPX gene were evaluated through different in silico predictors; and the deleterious convergent changes were analyzed by energy-minimization-guided residual network analysis. In addition, the pathogenic effects of mutations in SMPX-mediated protein-protein interactions were also characterized by structural modeling and binding energy calculations. A total of four mutations (N19D, A29T, K54N, and S71L) were found to be highly deleterious by all the tools, which are located at highly conserved regions. Furthermore, all four mutants showed structural alterations, and the communities of amino acids for mutant proteins were readily changed, compared to the wild-type. Among them, A29T (rs772775896) was revealed as the most damaging nsSNP, which caused significant structural deviation of the SMPX protein, as a result reducing the binding affinity to other functional partners. These findings reflect the computational insights into the deleterious role of nsSNPs in SMPX, which might be helpful for subjecting wet-lab confirmatory analysis.
Keywords: SMPX; in silico; mutation; nonsynonymous.
© 2019 John Wiley & Sons Ltd/University College London.