A recessive ACTL7A founder variant leads to male infertility due to acrosome detachment in Pakistani Pashtuns

Abstract

Male infertility affects more than 20 million men worldwide and is a major public health concern. Male infertility has a strong genetic basis, particularly for those unexplained cases. Here, through genetic analysis of three Pakistani families having eight infertile men with normal parameters in routine semen analysis, we identified a novel ACTL7A variant (c.149_150del, p.E50Afs*6), recessively co‐segregating with infertility in these three families. This variant leads to the loss of ACTL7A proteins in spermatozoa from patients. Transmission EM analyses revealed acrosome detachment from nuclei in 98.9% spermatozoa of patients. Interestingly, this ACTL7A variant was frequently detected in our sequenced Pakistani Pashtuns with a minor allele frequency of ~0.021 and all the carriers shared a common haplotype of about 240 kb flanking ACTL7A, indicating that it is likely originated from a single founder. Our findings reveal that a founder ACTL7A pathogenic variant confers a high genetic susceptibility for male infertility with normal routine semen parameters but acrosomal ultrastructural defects in Pakistani Pashtun descendants, and highlight that variants not rare should also be considered when trying to identify disease‐causing variants in ethnic groups with the tradition of intra‐ethnic marriages.

Novel Nuclear Roles for Testis-Specific ACTL7A and ACTL7B Supported byIn VivoCharacterizations and AI FacilitatedIn SilicoMechanistic Modeling with Implications for Epigenetic Regulation in Spermiogenesis

“…However, if the hypothetical courses of events caused by acrosomal instability were found true, it could affect a significant number of men with acrosomal defects and be categorized as a novel contributor to male infertility. Many human polymorphisms have been recently reported of single-point coding mutation in subacrosomal proteins like ACTL7A, ACTL7C, and ACTRT1 (Xin et al, 2020;Wei, Wang, et al, 2023;Zhou et al, 2023;Sha et al, 2021) that lead to both male infertility and peeling acrosomes. If the presented transcription changes in Actl7b -/-testes were caused in part by the exposure to acrosomal contents leading to accompanied inflammation, immune, and apoptotic responses, then a similar hypothesized pathology would be expected in men with these polymorphisms.…”