In Silico Prediction of Deleterious Non-Synonymous SNPs of Human GABRA2 gene and Altered Protein Structure and Function – A Link to Alcohol Dependence?

Alcohol Dependence is a serious and common public health problem around the globe. Genetic factors contribute to the risk of alcohol dependence. Mapping and identifying the specific genes that influence alcohol dependence and factors that alter the genetic expression are the thrust areas. Single-nucleotide polymorphisms (SNPs) in GABRA2 are associated with impulsiveness-related traits. The present study looked at non-synonymous SNPs with the potential to affect the structural and functional properties of the protein. The missense variants in the GABRA2 gene from sequences available in the NCBI database were analyzed using different bioinformatics tools. The modeled protein structures of the mutant proteins were compared with the native protein to determine stability changes. The identified deleterious variants were mostly present in the neurotransmitter-gated ion-channel ligand-binding domain and predicted to cause potential structural and functional changes in the protein. Among the 14 mutants, R58T was found to have the highest energy of -19646 KJ/mol, even after energy minimization, when compared with the native structure. The remaining 13 mutants were found to have lower energy values ranging from − 13567 to -13857 KJ/mol and 10 mutants were found in the conserved regions of the protein sequence. With a better understanding of the genetic basis of alcohol dependence, it is possible to pre-screen 'at-risk' individuals and design personalized early intervention, especially among the youth population.