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

Abstract

Aberrant glycosylation by N-acetylgalactosaminyl transferases (GALNTs) is a well-described pathological alteration that is widespread in hereditary diseases, prominently including human cancers, familial tumoral calcinosis and hyperostosis-hyperphosphatemia. In this study, we integrated different computational tools to perform the in silico analysis of clinically significant mutations (nsSNPs/single amino acid change) at both functional and structural levels, found in human GALNT3, GALNT8, GALNT12, and GALNT13 genes. From function and structure based insights, mutations encoding R162Q, T359K, C574G, G359D, R297W, D303N, Y396C, and D313N substitutions were concordantly predicted highly deleterious for relevant GALNTs proteins. From intriguing findings, T359K-GALNT3 was simulated with high contribution for disease susceptibility (tumor calcinosis) as compared to its partner variant T272K (Ichikawa et al. [2006] J. Clin. Endocrinol. Metab. 91:4472-4475). Similarly, the prediction of high damaging behavior, evolutionary conservation and structural destabilization for C574G were proposed as major contributing factors to regulate metabolic disorder underlying tumor calcinosis and hyperostosis-hyperphosphatemia syndrome. In case of R297W-GALNT12, prediction of highly deleterious effect and disruption in ionic interactions were anticipated with reduction in enzymatic activity, associated with bilateral breast cancer and primary colorectal cancers. The second GALNT12 mutation (D303N)-known splice variant-was predicted with disease severity as a result of decrease in charge density and buried behavior neighboring the catalytic B domain. In the lack of adequate in silico data about systematic characterization of clinically significant mutations in GALNTs genes, current study can be used as a significant tool to interpret the role of GALNTs reaction chemistry in disease-association risks in body.

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].…”

“…Of the 3 GalNAc-T1 variants tested, G258V was found to disturb the interaction of Arg266 of GalNAc-T1 with N-H of Thr (in GVTSA; tandem repeat region) of MUC1 [47]; thus, it might impair the possible transfer of GalNAc residue from UDP-GalNAc to hydroxyl group of Ser/Thr, during O -glycosylation reaction (Figure 7). Over expression, aberrant intracellular localization, and changes in glycosylation of MUC1 and MUC7 are often reported in tumors of colon, breast, ovarian, lung, and pancreatic origin [24, 48]. Since MUC1 plays an essential role in cellular signalling and microbial pathogenicity, it is conceivable to expect that G258V mutation is pathogenic to cellular integrity and susceptibility to certain human disease.…”

“…In the current investigation, the identification numbers (rs IDs) of each SNP of GalNAc-T1 gene obtained from NCBI were submitted as a query sequence to SIFT for homology searching. The SIFT value ≤ 0.05 indicates the deleterious effect of nonsynonymous variants on protein function [23, 24]. …”

“…The possible inputs to run the cSNP tools of PANTHER are the amino acid substitution and protein sequence. PANTHER subPSEC score ≤−3 classifies the amino acid substitution as deleterious or intolerant, whereas the score ≥−3 is predicted to be less deleterious [24]. …”

Colorectal cancer: A review of the genome-wide association studies in the kingdom of Saudi Arabia

“…In fact, in silico analyses of R297W-GALNT12 by researchers at King AbdulAziz University helped in the prediction of harmful effects and disruption of ionic interactions with consequent reduction of associated enzymatic activity reported in CRC. [ 45 ]…”