The First Affiliated Hospital of USTC, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, Hefei National Research Center for Physical Sciences at the Microscale, Institute of Health and Medicine, Hefei Comprehensive National Science Center, University of Science and Technology of China, Hefei, China.
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China.
Clin Genet. 2023 Nov;104(5):564-570. doi: 10.1111/cge.14383. Epub 2023 Jun 7.
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.
男性不育症影响着全球超过 2000 万男性，是一个主要的公共卫生关注点。男性不育症有很强的遗传基础，特别是对于那些原因不明的病例。在这里，通过对三个有 8 名常规精液分析参数正常但不育的巴基斯坦男性家庭的遗传分析，我们在这些家庭中发现了一个新的 ACTL7A 变体（c.149_150del，p.E50Afs*6），呈隐性遗传与不育共分离。该变体导致患者精子中的 ACTL7A 蛋白丢失。透射电镜分析显示，患者 98.9%的精子顶体与核分离。有趣的是，这种 ACTL7A 变体在我们测序的巴基斯坦普什图人中经常被检测到，其次要等位基因频率约为 0.021，所有携带者都共享约 240kb 侧翼 ACTL7A 的共同单倍型，表明它可能源自一个单一的祖先。我们的研究结果表明，一个起源于祖先的 ACTL7A 致病变体赋予巴基斯坦普什图人后裔具有正常常规精液参数但顶体超微结构缺陷的男性不育症的高遗传易感性，强调在具有同种族内婚传统的族群中，当试图识别致病变体时，不应忽视罕见的变体。
