Pathogenic variant in ACTL7A causes severe teratozoospermia characterized by bubble-shaped acrosomes and male infertility.

Teratozoospermia is a common factor associated with male infertility. However, teratozoospermia characterized by bubble-shaped acrosomes (BSAs) has not yet been identified in men and the causative genes are unknown. The present study is of a patient with severe teratozoospermia characterized by BSA and carrying a variant (c.1204G>A, p.Gly402Ser) of actin-like 7A (ACTL7A). For further verification, we generated an Actl7a-mutated mouse model (p.Gly407Ser) carrying an equivalent variant to that in the patient. We found that homozygous Actl7a-mutated (Actl7aMut/Mut) male mice were sterile, and all their sperm showed acrosomal abnormalities. We detected by transmission electron microscopy that during acrosomal biogenesis, the acrosome detaches from the nuclear membrane in Actl7aMut/Mut mice. Furthermore, mutant ACTL7A failed to attach to the acroplaxome and was discharged by cytoplasmic droplets, which led to the absence of ACTL7A in epididymal spermatozoa in mice. The mutant sperm failed to activate the oocyte, and sperm-borne oocyte activation factor phospholipase C zeta (PLCζ) discharge accompanied by ACTL7A was observed, leading to total fertilization failure (TFF). Immunoprecipitation followed by liquid chromatography-mass spectrometry showed that several differentially expressed proteins participate in acrosome assembly and actin filament organization. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF in the couple with an ACTL7A pathogenic variant. Our study defined a novel phenotype of an acrosomal abnormality characterized by BSA, revealed the underlying mechanism of a pathogenic variant in ACTL7A and provided a genetic marker and potential therapeutic option for male infertility.