WFS1 Deficiency Impairs PIAS4‐Associated SUMOylation and Increases Ubiquitin‐Mediated Spermatogenesis‐Related Protein Degradation Leading to Testicular Male Infertility

Although hundreds of genes have been shown to impair fertility in animal models, the identification of corresponding genetic causes in humans remains largely unknown. Here, we identified biallelic pathogenic variants in WFS1 in three unrelated infertile men presenting with oligoasthenoteratozoospermia and fertilization failure. Remarkably, using the establishment of a Wfs1 knockout (KO) mouse model, we found that WFS1 deficiency leads to disorganized sperm mitochondrial sheath assembly, structural abnormalities in the sperm head-neck junction, and defects in the sperm acrosome, which are consistent with the infertile phenotypes observed in affected individuals. Furthermore, meiotic defects were observed in spermatocytes from KO mice, particularly manifested as impaired sex chromosome synapsis. Mechanistically, WFS1 interacts with PIAS4 to promote the SUMOylation of key spermatogenesis-associated proteins, including SUN5, HSF5, CFAP74, and IZUMO4, which in turn competitively inhibits their K48-linked ubiquitin-mediated degradation during spermatogenesis. Collectively, our study was the first to establish a critical role for WFS1 in human reproduction and to uncover the molecular mechanisms underlying WFS1-mediated regulation of spermatogenesis. These findings provided both fundamental insights and important clinical implications for reproductive medicine.