Informatics in Medicine Unlocked (Jan 2020)
In silico analysis of likely pathogenic variants in human GGCX gene
Abstract
Genetic polymorphisms in the GGCX gene have been associated with many vitamin K-dependent protein disorders including vitamin K-dependent clotting factors deficiency, osteoporosis, vascular calcification disorders, and pseudoxanthoma elasticum syndrome (PXE). Identifying functional SNPs in disease-associated genes is difficult experimentally; thus it is better to first explore putative functional SNPs. In this study, computational tools have been utilized to identify nsSNPs which are deleterious to the function, stability, and structure of GGCX enzyme, and might be causative agents of these diseases. In silico analysis was performed using different bioinformatics tools, including: SIFT, PolyPhen-2, SNPs&Go, PhD-SNP, and PROVEAN, to predict the SNPs functional effect on the protein, while I-Mutant and MUpro were used to check the stability of the protein upon SNP, and Project Hope was used to predict the SNPs structural effect. The study revealed six previously reported disease-causing SNPs including: rs121909682 (R476H), rs121909681(R476G, R476C), rs121909675 (L394R), rs1486505438 (493C), rs1341151059 (K218Q), and 37 non-reported SNPs including: R694C, R693C, N605K, F543S, L538R, G537E, P536S, P484L, P484S, R480G, F467C, I465T, Q446P, D442G, M401T, G396S, G393V, T391K, N388D, Y379C, L319P, H287R, R276S, L264P, Y227C, A214V, Y211C, R204H, L163P, N159H, W157R, W157G, G132D, A126P, R68L, R68H, and R68C. Most of these non-reported SNPs are located in or close to a conserved domain region, which make them strong candidates for causing diseases related to vitamin K-dependent proteins. Future studies should consider these nsSNPs as main targets in various diseases involving GGCX dysfunction. This is the first study in which GGCX gene variants were analyzed using in silico tools; hence they can be assistive when considering experimental studies for disease related to these polymorphisms. Furthermore, mutational studies might be helpful in exploring the precise effects of these SNPs.
