Identification of deleterious single nucleotide polymorphism (SNP)s on the human TBX5 gene & prediction of their structural & functional consequences: An in silico approach

Abstract

AbstractT-box transcription factor 5 (TBX5) gene encodes the transcription factor TBX5, which plays a crucial role in developing the heart and upper limbs. Damaging single nucleotide variants in this gene alters the protein structure, disturbs the functions of TBX5, and ultimately causes Holt-Oram Syndrome (HOS). By analyzing available single nucleotide polymorphism information in the dbSNP database, this study was designed to identify the most deleterious TBX5 SNPs through silico approaches and predict their structural and functional consequences.Fifty-eight missense substitutions were found damaging by sequences homology-based tools like SIFT and PROVEAN and structure homology-based tools like PolyPhen-2. These SNPs were further scrutinized by various disease association meta-predictor tools. Additionally, the conservation profile of amino acid residues, their surface accessibility, stability, and structural integrity of the native protein upon mutations was assessed. From these analyses, finally 5 SNPs were detected as the most damaging ones [rs1565941579 (P85S), rs1269970792 (W121R), rs772248871 (V153D), rs769113870 (E208D), and rs1318021626 (I222N)]. Analyses of stop-loss, nonsense, UTR, and splice site SNPs were also conducted.Through integrative bioinformatics analyses, this study has identified SNPs that are deleterious to the TBX5 protein structure and have the potential to cause HOS. Further wet-lab experiments can validate these findings.