A comprehensive in silico analysis of the functional and structural consequences of the deleterious missense nonsynonymous SNPs in human GABRA6 gene

Abstract

Abstract Epilepsy, a prevalent neurological disorder, affects more than 50 million individuals worldwide and is characterized by recurring seizures. Nonsynonymous single nucleotide polymorphisms (nsSNPs) found within coding regions of epilepsy-related genes are believed to have significant impacts on protein function. This is due to their tendency to cause mutations in the encoded amino acids, which can subsequently lead to pathogenic alterations in protein structure and function. Consequently, nsSNPs have the potential to serve as diagnostic markers for epilepsy and other neuropsychiatric conditions. The primary objective of this study is to evaluate the deleterious effects of missense nsSNP mutations on the GABRA6 gene. The GABRA6 gene encodes the alpha-6 subunit of the \({\text{G}\text{A}\text{B}\text{A}}_{\text{A}}\) receptor and is associated with genes implicated in epilepsy. To achieve this, we employed various computational tools, including SIFT, PolyPhen-2, PROVEAN, Condel, SNPs&GO, PMut, SNAP2, MutPred2, and SNPeffect4.0, for predicting missense nsSNPs. Additionally, we used I-Mutant3.0 and MUpro to analyze protein stability, ConSurf to assess evolutionary conservation, FTSite and COACH to predict ligand binding sites, SOPMA and PSIPRED to analyze protein secondary structures, project HOPE to predict structural changes, and I-TASSER to model the 3D structure. Furthermore, structural validation was conducted using the PROCHECK and ERRAT servers, while molecular dynamics simulations were performed using GROMACS to gain a better understanding of the effects of mutations on protein structure. Among the 451 missense nsSNPs identified within the GABRA6 gene, three were found to have pathogenic effects on the structure and function of the protein, potentially contributing to the development of epilepsy or other neuropsychiatric disorders. Notably, two of these nsSNPs (W87S and W112R) were located within the ligand-binding domain, while the third (C310R) was situated in the transmembrane domain. These identified missense nsSNPs hold promise as potential diagnostic markers and drug targets.