Early embryonic arrest is a challenge for in vitro fertilization (IVF). No genetic factors were previously revealed in the sperm-derived arrest of embryonic development. Here, we reported two infertile brothers presenting normal in conventional semen analysis, but both couples had no embryos for transfer after several IVF and intracytoplasmic sperm injection (ICSI). Whole-exome sequencing identified a homozygous missense mutation of ACTL7A in both brothers. This mutation is deleterious and causes sperm acrosomal ultrastructural defects. The Actl7a knock-in mouse model was generated, and male mutated mice showed sperm acrosomal defects, which were completely consistent with the observations in patients. Furthermore, the sperm from ACTL7A/Actl7a-mutated men and mice showed reduced expression and abnormal localization of PLCζ as a potential cause of embryonic arrest and failure of fertilization. Artificial oocyte activation could successfully overcome the Actl7a-mutated sperm-derived infertility, which is meaningful in the future practice of IVF/ICSI for the ACTL7A-associated male infertility.

Background: Human ␤-defensins are predominantly expressed in the male reproductive system, but their functions remain unknown. Results: Recombinant human DEFB114 rescues human sperm motility and D-GalN-sensitized mice under LPS challenges through its LPS-neutralizing activity. Conclusion: Recombinant DEFB114 peptides have therapeutic potential for LPS-induced inflammatory diseases.Significance: This work contributes to unveiling novel functions of human ␤-defensins that are crucial for addressing their physiological and pathological mechanisms.