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Here, we present two cases of male infertility linked to novel <jats:italic>TDRD6<\/jats:italic> variants, associated with oligoasthenoteratozoospermia (OAT) and early embryonic arrest. To investigate the underlying mechanisms and promising therapeutic approaches, <jats:italic>Tdrd6<\/jats:italic> knock\u2010in and knock\u2010out mice were generated. The <jats:italic>Tdrd6<\/jats:italic> variant male mice demonstrated OAT and embryonic arrest, mirroring the clinical observations of our patients. Sperm from both affected individuals and mice exhibited aberrant localization of phospholipase C zeta and oocyte activation deficiency (OAD). The application of artificial oocyte activation (AOA) effectively overcame the infertility caused by the variants, facilitating successful pregnancies and live births in both human and mice. Additionally, our research revealed that OAD influences the expression of multitude of genes at the 2\u2010pronuclear (2PN) stage, with the <jats:italic>Mos<\/jats:italic> gene playing a pivotal role in early embryonic arrest. The injection of <jats:italic>Mos<\/jats:italic> mRNA can mitigate this arrest. To our knowledge, this is the first study to show that sperm\u2010related OAD affects gene expression at the 2PN stage and elucidate how AOA overcomes male factor\u2010derived embryonic arrest, enabling successful pregnancies and live births.<\/jats:p>","DOI":"10.1002\/mco2.70038","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:39:31Z","timestamp":1736123971000},"source":"Crossref","is-referenced-by-count":2,"title":["Altered zygotic gene expression caused by sperm with <i>Tdrd6<\/i> variants disrupts early embryonic development"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1864-5782","authenticated-orcid":false,"given":"Zhijie","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Assisted Reproduction Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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