Novel association of PhosphoSerine PHosphatase (PSPH) gene mutations with male infertility identified through whole exome sequencing of South Indians

Male infertility (MI) is mainly caused by spermatogenic failure, and despite long years of assisted reproductive therapy, a significant number of cases remain idiopathic. Oligoasthenozoospermia (OA) is one of the most severe idiopathic MI forms, conditioned with decreased sperm motility and count. However, its pathology remains unclear, but few genetic factors have been identified. The main aim of this study was to find genetic variations in spermatogenic genes with severe OA. Semen and blood samples were collected from 250 MI subjects. Semen analysis, karyotyping, and Y microdeletion was performed to retain purely idiopathic MI cases (n = 247). 40 OA cases were identified, of which four severe cases were subjected to whole-exome sequencing, bioinformatics analyses, and pathway analysis, followed by validation of pathogenic variants in the remaining 36 OA cases through Sanger sequencing. We identified six variants in exon5 of gene PSPH, of which four variants were predicted to be pathogenic and two damaging mutations in exon4. In this study, we propose the novel role of the PSPH gene in their different mechanistic pathways. Detailed pathway analysis of enzyme PSPH involved in l-serine biosynthesis demonstrated that its dysfunction could cause a decrease in sperm count and sperm motility. The hypothesized function of PSPH in eliciting OA has been described.