Functional and Structural Impact of Deleterious Missense Single Nucleotide Polymorphisms in the NR3C1, CYP3A5, and TNF-α Genes: An In Silico Analysis

Abstract

Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 (CYP3A5) play a key role in glucocorticoid resistance susceptibility in humans. Possible causative mutations could be used as therapeutic targets and diagnostic markers for glucocorticoid resistance. This study evaluated the missense SNPs of TNF-α, NR3C1, and CYP3A5 to predict their impact on amino acid changes, protein interaction, and functional stability. The protein sequence of dbSNP was obtained and used online in silico method to screen deleterious mutants for the in silico analysis. In the coding regions of TNF-α, NR3C1, and CYP3A5, 14 deleterious mutations were discovered. The protein functional and stability changes in the amino acid between native and mutant energy were identified by analyzing the changes in the hydrogen bonding of these mutants from native, which were all measured using Swiss PDB and PyMOL. F446S and R439K had the highest root-mean-square deviation (RMSD) values among the 14 deleterious mutants. Additionally, the conserved region of amino acid protein interaction was analyzed. This study could aid in the discovery of new detrimental mutations in TNF-α, NR3C1, and CYP3A5, as well as the development of long-term therapy for corticosteroid resistance in several inflammatory diseases. However, more research into the deleterious mutations of the TNF-α, NR3C1, and CYP3A5 genes is needed to determine their role in corticosteroid resistance.

NR3C1 rs6198 Variant May Be Involved in the Relationship of Graves’ Disease with Stressful Events

“…Many single nucleotide polymorphisms (SNPs) of the NR3C1 gene have already been found to be directly or indirectly related (through GC action or GC resistance) to different mental disorders, especially the stress-related ones and autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and membranous nephropathy [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Recent bioinformatics studies have suggested that there are several polymorphisms in the NR3C1 gene, as well as in other genes such as TNF, CYP3A5 and FKBP5 , that have deleterious potential to cause GC resistance [ 14 , 15 ]. Some investigations have suggested a relationship between NR3C1 SNPs rs6189/rs6190, rs41423247, and rs6198 and autoimmune diseases, but studies on GD are still lacking [ 2 , 7 , 8 , 11 , 16 ].…”