ACROSIN deficiency identified as a cause of total fertilization failure and thus, male infertility in humans

In a most recent study, Hua and colleagues have identified a rare homozygous nonsense mutation in the ACR gene as a causative factor for male infertility, specifically leading to Total Fertilization Failure (TFF) during in vitro fertilization (IVF) attempts. The findings, published in Human Reproduction, shed light on the genetic basis of TFF, offering new hope and guidance for affected individuals.

The study, focused on two Chinese brothers experiencing repeated TFF in their IVF attempts, unveiled a novel ACR mutation, p.Trp56X, responsible for Acrosin deficiency. Acrosin, a major acrosomal protease crucial for sperm penetration through the zona pellucida (ZP), was found to be completely absent in the mutant sperm, leading to acrosome detachment and a distinctive ultrastructural defects in the sperm head. Importantly, the researchers discovered that TFF occurred with ACR mutations. Additionally, alternative assisted reproductive technologies – Intracytoplasmic Sperm Injection (ICSI) or Subzonal Insemination without artificial oocyte activation (AOA), yielded successful fertilization outcomes. The study also emphasizes on the significance of ACR in sperm-ZP interactions, highlighting the role of Acrosin in ZP lysis during fertilization. This newfound understanding contributes to the broader comprehension of TFF, particularly in cases where abnormal spermatozoa-ZP interactions are implicated. The researchers propose that ACROSIN deficiency and abnormal acrosomal development may disrupt spermatozoa-ZP interactions, specifically hindering ZP penetration and causing TFF. Unlike disruptions in other fertilization-related factors, such as PLC-zeta, which lead to oocyte activation deficiency, ACROSIN deficiency was shown to solely impede ZP penetration without affecting sperm-oocyte binding or membrane fusion.

While this study aids in understanding the genetic etiologies of TFF, the researchers acknowledge the need for further investigation and independent pedigrees to strengthen the evidence supporting ACR mutation-related TFF. In conclusion, this pioneering research establishes a direct link between biallelic ACR mutations and male infertility with TFF, providing a crucial foundation for improved diagnosis and treatment. The recommendation of ICSI without AOA for ACR mutation-related TFF could potentially revolutionize fertility interventions, offering renewed hope for couples facing this challenging condition. For more information, readers are advised to follow-up the study on DOI: 10.1093/humrep/dead059.

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