Actin-like protein 7A
acrosomal vesicle
Disruption in <i>ACTL7A</i> causes acrosomal ultrastructural defects in human and mouse sperm as a novel male factor inducing early embryonic arrest.
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 <i>ACTL7A</i> in both brothers. This mutation is deleterious and causes sperm acrosomal ultrastructural defects. The <i>Actl7a</i> 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 <i>ACTL7A</i>/<i>Actl7a</i>-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 <i>Actl7a</i>-mutated sperm-derived infertility, which is meaningful in the future practice of IVF/ICSI for the <i>ACTL7A</i>-associated male infertility.