Homozygous Loss of , but not its Haploinsufficiency, Leads to Male Infertility and Fertilization Failure.

The gene has been associated with male infertility. Male chimera mice were infertile, supporting the prevailing view that haploinsufficiency causes male infertility. In this study, we identified a heterozygous mutation on , c.72C>A (p.Cys24Ter) in the male partner of a patient couple, who had a previous fertilization failure (FF) after intracytoplasmic sperm injection (ICSI) and became pregnant after ICSI together with artificial oocyte activation (AOA). To investigate the role of in FF and oocyte activation, we constructed knockout mice. Surprisingly, male mice, but not male mice, are infertile, and have reduced sperm counts and abnormal sperm morphology. Importantly, AOA treatment enhances the 2-cell embryo rate of ICSI embryos injected with sperm, indicating that FF caused by male deficiency is overcome by AOA. Mechanistically, loss of PLCζ around the acrosome might be the reason for FF of sperm. Taken together, our data indicated that homozygous knockout of , but not haploinsufficiency, leads to male infertility and FF.