The investigation of nonsynonymous SNPs of human SLC6A4 gene associated with depression: An in silico approach

Abstract

Genetic polymorphism of the SLC6A4 gene is associated with several behavioral disorders, including depression. Since studying the total nonsynonymous single nucleotide polymorphisms (nsSNPs) of the SLC6A4 gene at the population level is a difficult task, we aim to utilize in silico approach to detect the most deleterious nsSNPs of the SLC6A4 gene. In our study, 7 computational tools were used in the initial stage, including SIFT, Polyphen-2, PROVEAN, SNAP2, PhD-SNP, PANTHER, and SNPs&GO to find out the most damaging nsSNPs. In the second phase, we performed structural, functional, and stability analysis of SLC6A4 protein by popular computation tools, including I-Mutant 2.0 and MutPred2. Also, the ConSurf server was utilized to find the conserved region of the SLC6A4 protein to determine the relationship between these conserved regions with high-risk nsSNPs. Based on these analyses, 5 high-risk mutations of the SLC6A4 protein were selected. Then, we carried out comparative modeling by using the Robetta server and aligned the mutant protein model with the native protein structure. Later, we performed the post-translational modification and functional domain analysis of the SLC6A4 protein. This study concludes that Arginine → Tryptophan at position 79 and Arginine → Cysteine at position 104 are the two significant mutations in SLC6A4 protein which might play an essential role in causing diseases. Future studies should take these high-risk nsSNPs (rs1221448303, rs200953188) into consideration while exploring diseases related to the SLC6A4 gene. Besides, our research is the first-ever comprehensive in silico investigation of the SLC6A4 gene. Thus, the findings of this study could be beneficial for developing precision medicines against diseases caused by SLC6A4 malfunction. Furthermore, extensive wet-lab research and experiments on various model organisms might be helpful to investigate the precise role of these damaging nsSNPs of the SLC6A4 gene.

Prediction and assessment of deleterious and disease causing nonsynonymous single nucleotide polymorphisms (nsSNPs) in human FOXP4 gene: An in-silico study

“…SNPs play an important role in gene and protein-regulated diseases in humans [ 39 ]. Several in silico studies of polymorphisms to predict nsSNPs as harmful or neutral have been performed [ [40] , [41] , [42] , [43] ].…”

Functional analysis of epilepsy‐associated GABAA receptor mutations using Caenorhabditis elegans

“…There are currently over 150 annotated epilepsy‐associated variants in the major γ‐aminobutyric acid type A (GABA A ) receptor subunits 14,15 ; however, confirmation of functional defects is lacking for the vast majority of these variants. Various websites are available for predicting pathogenicity for single nucleotide polymorphisms 30–32 ; however, these remain predictions that can prove conflicting and ideally require in vivo validation. In this paper, we functionally characterize in vivo two specific point mutations in the GABA A receptor that have been linked with epilepsy, concluding that they both are loss of function and possibly act as functional null mutations.…”