Clinically Significant Missense Variants in Human GALNT3, GALNT8, GALNT12, and GALNT13 Genes: Intriguing In Silico Findings. Issue 2 (February 2014)

• Record Type: Journal Article
• Authors: Hussain, Muhammad Ramzan M.; Nasir, Jamal; Al‐Aama, Jumana Yousuf
• Is Part Of: Journal of cellular biochemistry. Volume 115:Issue 2(2014:Feb.)
• Page Start: 313
• Page End: 327
• Publication Date: 2014-02
• Subjects: Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.24666
• Languages: English
• ISSNs: 0730-2312

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jcb24666-sec-0001" sec-type="section"> <p>Aberrant glycosylation by <italic>N</italic>‐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 <italic>GALNT3</italic>, <italic>GALNT8</italic>, <italic>GALNT12</italic>, and <italic>GALNT13</italic> 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‐<italic>GALNT3</italic> 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‐<italic>GALNT12</italic>, 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 <italic>GALNT12</italic> 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. J. Cell. Biochem. 115: 313–327, 2014. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>