title: 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.
authors.affiliation: Princess Al-Jawhara Al Brahim Center of Excellence in Research of Hereditary Disorders, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Muhammad Ramzan Manwar
authors.initials: MRM
authors.lastname: Hussain
authors.forename: Jamal
authors.initials: J
authors.lastname: Nasir
authors.forename: Jumana Yousuf
authors.initials: JY
authors.lastname: Al-Aama
mesh_terms: D002114:Calcinosis / Q000235:genetics* / Q000473:pathology; D003198:Computer Simulation; D004198:Disease Susceptibility; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013329:Structure-Activity Relationship; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C465011:GALNT12 protein, human; C000589774:GALNT13 protein, human
keywords: CLINICALLY SIGNIFICANT MUTATIONS; GALNT12; GALNT13; GALNT3