Comprehensive in silico prioritization of pathogenic nsSNPs in human β-adducin gene towards finding its relation with cancer

The adducin family consists of three closely related proteins ADD1 (alpha-isoform), ADD2 (beta-isoform) and ADD3 (gamma-isoform) with similar domain structures. Adducins exist as heterodimers or tetramers composed of either alpha/beta or alpha/gamma heterodimers. Experimental evidences implicate the involvement of ADD2 variants in hypertension, renal dysfunction, impaired locomotor function and learning abilities. Non-synonymous SNPs (nsSNPs) are potentially damaging in nature as they results in amino acid substitutions. In human, a total 476 nsSNPs of ADD2 gene are reported in Ensembl and in the present work, computational prioritization has revealed 27 nsSNPs as highly deleterious and destabilizing in nature. Pan-cancer transcriptomic analyses reveal differential ADD2 expression in adrenal, breast, colon, lung, ovary, pancreas, testis, thyroid, and uterine cancer. In several cancers, overexpression of ADD2 is also found to be associated with lower overall survival rate and more patients at risk. It was also found that several nsSNPs of ADD2 had direct, proximal, distal and network rewriting PTM effects in different cancers and thereby account for potential structural and functional alterations. The coding mutations in ADD2 can affect overall gene expression in colon adenocarcinoma, melanoma, gastric cancer, and uterine cancer. The hub proteins, from the PPI network of these differentially expressed genes, are involved in positive regulation of acute inflammatory response to antigenic stimulus, acute phase response, G protein-coupled receptor signaling pathway. The present study is hypothetically driven and performed using public databases. Further experimental works are necessary to understand the role of ADD2 nsSNPs in tumor development and metastatic transition.