In silico prediction of the functional consequences of nsSNPs in human beta-catenin gene

Abstract

Beta-catenin (CTNNB1) is a multifunctional protein involved in the intercellular adherens junctions and in canonical Wnt/β-catenin signalling. In human, the CTNNB1 gene is located in chromosome 3p21 and the encoded protein is 781 amino acid long. Most of the mutations in β-catenin are activating mutations with missense mutation being the most common type. Mutations in β-catenin are reported to be associated with cancer and other human diseases. The structural and functional consequences for most of the non-synonymous SNPs (nsSNPs), present in the human CTNNB1 gene, are not known. In the present work, extensive bioinformatics analyses are used to discriminate pathogenic and harmless polymorphisms in CTNNB1. The Ensembl database has a huge collection of polymorphic variants. A total 349 nsSNPs of CTNNB1 were subjected to extensive sequence and structure based analyses using state-of-art computational tools. The sequence based screening of 349 nsSNPs had revealed 79 highly deleterious nsSNPs in CTNNB1. It was observed that out of 79 highly deleterious nsSNPs of CTNNB1 protein, the positions for 74 nsSNPs were highly conserved. The sequence based stability analysis revealed decreased stability for 275 variants. The nsSNPs were also predicted to affect post-translational modifications in CTNNB1 like O-linked and N-linked glycosylation, sulfation, phosphorylation, ADP-ribosylation, acetylation etc. The structure based stability analysis of these 79 highly deleterious nsSNPs had revealed 30 variants with structural destabilization. Furthermore, these computationally screened highly deleterious nsSNPs of CTNNB1 can be analyzed in population based genetic studies and may help understand CTNNB1 associated diseases. In the present study, we also showed that CTNNB1 deregulation was associated with survival outcome in patients with lung, gastric and ovarian cancer.