α-Adducin nsSNPs affect mRNA secondary structure, protein modification and stability

Abstract

Adducins help stabilize the spectrin-actin interactions along with other accessory cytoskeletal proteins. Adducins exist as a tetramer composed of either α/β or α/γ heterodimers. Polymorphisms in α-adducin (ADD1) gene have been shown to be associated with hypertension and erythrocyte deformability. Most of the non-synonymous single nucleotide polymorphisms (nsSNPs) of ADD1 are still uncharacterized in terms of their damaging potential. So, in the present study, computational approach has been undertaken to explore and extend the knowledge related to the effect of nsSNPs on α-adducin. In this study, thirty six nsSNPs were subjected to in silico analyses using different computational tools. It is observed that out of thirty six SNP sites of ADD1, position of sixteen residues is highly conserved. It has been found that four nsSNPs have a very low tolerance index (TI) of 0.00 and four nsSNPs show a TI score of 0.01. Fifteen nsSNPs which are predicted as deleterious by the SIFT Server, are also found to be probably damaging by Polyphen Server. Highest pathogenicity score is predicted for Y270N variant of ADD1, followed by R231C, R354C, R396Q, K148I, E376D, L387M, and L387V variants. Several nsSNPs of ADD1 are found to affect post-translational modifications such as methylation, glycosylation, phosphorylation, ubiquitination etc. The stability of the protein ADD1 is also affected by some nsSNPs and it has been found that twenty six variants show decrease in stability. It has also been observed that non-synonymous substitution like R354C, L387M and L387V of ADD1 lead to significant structural changes in ADD1 mRNA. The results obtained from the analyses reveal about prioritization of damaging nsSNPs in ADD1. Furthermore, the predicted disease associated nsSNPs can be analyzed in population based genotyping studies and in futuristic drug development in the area of ADD1 pharmacogenomics.