Identification, analysis of deleterious SNPs of the human GSR gene and their effects on the structure and functions of associated proteins and other diseases

Abstract

Hereditary glutathione reductase deficiency, caused by mutations of the GSR gene, is an autosomal recessive disorder characterized by decreased glutathione disulfide (GSSG) reduction activity and increased thermal instability. This study implemented computational analysis to screen the most likely mutation that might be associated with hereditary glutathione reductase deficiency and other diseases. Using ten online computational tools, the study revealed four nsSNPs among the 17 nsSNPs identified as most deleterious and disease associated. Structural analyses and evolutionary confirmation study of native and mutant GSR proteins using the HOPE project and ConSruf. HOPE revealed more flexibility in the native GSR structure than in the mutant structure. The mutation in GSR might be responsible for changes in the structural conformation and function of the GSR protein and might also play a significant role in inducing hereditary glutathione reductase deficiency. LD and haplotype studies of the gene revealed that the identified variations rs2978663 and rs8190955 may be responsible for obstructive heart defects (OHDs) and hereditary anemia, respectively. These interethnic differences in the frequencies of SNPs and haplotypes might help explain the unpredictability that has been reported in association studies and can contribute to predicting the pharmacokinetics and pharmacodynamics of drugs that make use of GSR.

Proteome changes in a human retinal pigment epithelial cell line during oxidative stress and following antioxidant treatment

“…Exposure to tBHP led to the upregulation of GSR (+17.7-fold) and GGCT (26.1-fold), while GSS expression was not affected ( Table 1 ). GSS is an ATPase that catalyzes the production of glutathione from γ-glutamylcysteine and glycine, while GSR is a flavoprotein responsible for reducing oxidized glutathione and therefore maintaining glutathione in a reduced state ( 14 , 15 ). As such, the up-or down-regulation of GSS and GSR are critical for cellular detoxification and antioxidant activity.…”

Critical Roles of the Cysteine–Glutathione Axis in the Production of γ-Glutamyl Peptides in the Nervous System

“…A deficiency of GSR is very rare in humans, and only 18 mutations in the GSR gene have been reported by 2022 [94]. Mutations in GSR appear to cause changes in the structure and function of the GSR protein, which may be associated with obstructive heart defects and hereditary anemia.…”

Inside the genome: understanding genetic influences on oxidative stress

“…This enzyme plays a crucial role in maintaining the reduced form of GSH. This action mediated by GR is integral for replenishing the pool of GSH ( Vyas et al, 2022 ). Mutations in the GSR gene can cause hereditary glutathione reductase deficiency, affecting cellular redox potential and increasing oxidative stress levels, especially in red blood cells.…”

“…Mutations in the GSR gene can cause hereditary glutathione reductase deficiency, affecting cellular redox potential and increasing oxidative stress levels, especially in red blood cells. This deficiency is linked to conditions such as hereditary hemolytic anemia ( Vyas et al, 2022 ). In the polymorphism, rs8190955 in the GSR gene, individuals with the C allele have optimum levels of GR while individuals with T allele are associated with a GR deficiency.…”

“…On the other hand, heterozygous individuals and homozygous mutant individuals with the CT and TT genotypes, respectively, have impaired cellular redox potential and increased oxidative stress levels in red blood cells, owing to the GR deficiency. This deficiency is associated with hereditary hemolytic anemia ( Vyas et al, 2022 ).…”