Study by Sun Xiaoxi and Zhang Feng Identifies ACTL7A as a Male Gene Causing Early Embryonic Arrest

Obtaining viable, transferable embryos is key to successful in vitro fertilization (IVF). Yet in clinical practice, some couples show repeated early embryonic arrest despite seemingly normal sperm and oocytes. Clinicians generally attribute this to female rather than male factors, especially when sperm is diagnosed as normal by clinical standards. Until now, there had been no reports of male genetic factors causing early embryonic development failure.

Professor Sun Xiaoxi of the Obstetrics and Gynecology Hospital of Fudan University and the Shanghai Ji'ai Genetics and Infertility Center, in collaboration with Professor Zhang Feng and Researcher Shi Huijuan of the Shanghai Institute of Planned Parenthood Research, identified ACTL7A as the first mutant gene associated with male genetic factors causing early embryonic arrest, and clarified the pathogenic mechanism of ACTL7A mutations. The team also found that oocyte artificial activation (AOA) technology can successfully overcome the embryonic arrest caused by ACTL7A/Actl7a mutations and enable Actl7a-mutant male mice to produce healthy offspring, offering a therapeutic direction for such patients. On August 28, the results were published online in Science Advances under the title "Disruption in ACTL7A causes acrosomal ultrastructural defects in human and mouse sperm as a novel male factor inducing early embryonic arrest."

This study was conducted on a consanguineous family with two infertile brothers, both married for many years without children. Clinical diagnosis showed normal sperm morphology and routine semen parameters in both brothers, and all examinations of their spouses were also normal. However, multiple assisted reproductive technology (ART) treatments resulted in embryonic development arrest for both couples, with no viable embryos to transfer. Eventually, both couples achieved healthy offspring through donor-sperm IVF. This clinical information ruled out female factors, suggesting that early embryonic arrest might be caused solely by male factors. Whole-exome sequencing of the family revealed that both brothers carried a homozygous missense mutation of ACTL7A.

The researchers then used gene editing to establish a mouse model with the same Actl7a point mutation as the patients. The mutation did not affect sperm density, motility or the development of the reproductive system in male mice, but caused male infertility. Transmission electron microscopy showed that the acrosomes of sperm from both patients and mutant mice exhibited folding and detachment, failing to attach to the sperm nuclear membrane — indicating acrosomal ultrastructural defects. Subsequent studies revealed that ACTL7A-mutation-induced acrosomal defects led to decreased expression of PLC-zeta (sperm oocyte activation factor, SOAF), and the PLC-zeta signal in the sperm equatorial region — where the first fusion with the oocyte and SOAF release occur — disappeared. Thus, ACTL7A mutations cause acrosomal defects, which in turn alter the expression and distribution of PLC-zeta, leading to early embryonic development failure. Based on these findings, the researchers performed ICSI-AOA (intracytoplasmic sperm injection combined with artificial oocyte activation) using strontium chloride (SrCl2), which successfully enabled fertilization of oocytes by mutant mouse sperm, blastocyst formation and the birth of healthy offspring after embryo transfer. This lays a foundation for future clinical treatment of such patients during ART.

The researchers noted that early embryonic arrest has long been a major challenge in assisted reproductive centers and is generally attributed to female factors. This study is the first to identify male genetic factors and their underlying mechanism causing early embryonic arrest, and to explore intervention strategies, providing a new direction for the diagnosis and treatment of such patients.

Starting from a clinical problem, the study identified a new pathogenic gene through basic research, elucidated its mechanism, and found an intervention strategy — a typical case of translational medicine.

Professor Sun Xiaoxi, Professor Zhang Feng and Researcher Shi Huijuan are the co-corresponding authors. Postdoctoral Fellow Xin Aijie (Obstetrics and Gynecology Hospital of Fudan University / Shanghai Institute of Planned Parenthood Research), Director Chen Guowu, Dr. Qu Ronggui and Postdoctoral Fellow Zhang Ling (Obstetrics and Gynecology Hospital of Fudan University / Shanghai Ji'ai Genetics and Infertility Center) are the co-first authors. The project was supported by the Shanghai Science and Technology Commission, Shanghai Health Commission, National Natural Science Foundation of China, Shanghai Key Clinical Medical Center, and the Shanghai Municipal Major Science and Technology Program "International Human Phenome Project (Phase I)," among others.