Identification of WDR62 variants as a genetic contributor for human infertility

Abstract

WDR62 is crucial for the initiation of germ cell meiosis in mice. In Wdr62 -deficient male mice, germ cells are arrested at the metaphase I stage of meiosis due to asymmetric centrosome distribution and abnormal spindle assembly. In our study, two homozygous WDR62 variants (c .375C > G [Tyr125Ter] and c.1804G > A [p.Asp602Asn]) were identified in the two oligoasthenoteratozoospermia (OAT) individuals. WDR62 protein expression sharply decreased, as shown by western blotting. Phenotype analysis revealed decreased sperm counts as well as abnormal morphologies with sperm flagellar defects and acrosomal hypoplasia in patients harboring WDR62 mutations. Transmission electron microscopy (TEM) revealed that the spermatozoa from the patients exhibited a disorganized and defective ultrastructure in both the head and flagellum. Mechanistically, WDR62 might regulate spermatogenesis by interacting with key molecules involved in sperm development, such as DPY19L2, CFAP52, IQCH and ACR. Additionally, we correlated poor intracytoplasmic sperm injection (ICSI) prognosis with patients carrying WDR62 mutations. This study is the first to establish a direct link between WDR62 mutations and male sterility in humans, providing important insights for the genetic diagnosis and assisted reproductive technology of OAT patients. • Homozygous WDR62 mutations in oligoasthenoteratozoospermia patients identify a novel human sterility gene. • WDR62 deficiency causes severe sperm defects via disrupted spermatogenic protein interactions. • WDR62 mutations correlate with poor intracytoplasmic sperm injection outcomes.