Identification and Analysis of Deleterious SNPs of Human GSR Gene: Their Effects on Structure and Functions of Associated Protein and Other Diseases

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 4 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.

Steroidal 5α-Reductase: A Therapeutic Target for Prostate Disorders

Steroidal 5α-reductase is a system of NADPH dependent enzyme that catalyzes the irreversible conversion of Δ4–3-ketosteroid precursor (testosterone) to its corresponding 5α-reduced metabolite (dihydrotestosterone). Initial role of DHT was discovered through males pseudohermaphroditism, a genetic disorder with complete or partial 5α-reductase deficiency accompanied with features at critical juncture of fetal and postnatal development. However, excessive DHT production, has brought a revolution in revealing the etiology of complications like prostate cancer and benign prostatic hyperplasia. Over the last two decades, converging lines of evidences have highlighted the role of 5α-reductase inhibitors in the treatment of these androgen dependent disorders. Finasteride and Dutasteride, are the two clinically approved inhibitors available in the market, that helps in reducing the prostate volume by blocking the 5a-reductase enzyme.