Pathogenic variant in ACTL7A causes severe teratozoospermia characterized by bubble-shaped acrosomes and male infertility
Pathogenic variant in ACTL7A causes severe teratozoospermia characterized by bubble-shaped acrosomes and male infertility
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DOI：
10.1093/molehr/gaac028
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发表时间：
2022-07-29
影响因子：
4
通讯作者：
Lin, Ge
中科院分区：
文献类型：
--
作者：
Dai, Jing;Chen, Yongzhe;Lin, Ge
畸形精子症是男性不育的常见原因。然而，以泡状顶体（BSAs）为特征的畸形精子症尚未在男性中发现，其致病基因也未知。本研究是一个患有严重畸形精子症的患者，其特征是BSA并携带肌动蛋白样7A（ACTL 7A）的变体（c.1204G>A，p.Gly402Ser）。为了进一步验证，我们产生了携带与患者中的变体等同的变体的Actl 7a突变的小鼠模型（p.Gly407Ser）。我们发现纯合Act 17 a突变（Act 17 a（Mut/Mut））雄性小鼠不育，并且它们所有的精子都显示出顶体异常。我们用透射电镜观察到在Act 17 a（Mut/Mut）小鼠顶体发生过程中，顶体从核膜上脱落。此外，突变型ACTL 7A不能附着在精子顶体上，而是通过细胞质液滴排出，这导致小鼠附睾精子中ACTL 7A的缺失。突变精子不能激活卵母细胞，并且观察到伴随ACTL 7A的精子携带的卵母细胞激活因子磷脂酶C zeta（PLC zeta）放电，导致完全受精失败（TFF）。免疫沉淀，液相色谱-质谱分析表明，几个差异表达的蛋白质参与顶体组装和肌动蛋白丝组织。此外，通过钙离子载体暴露的辅助卵母细胞活化成功地克服了与ACTL 7A致病性变体的夫妇中的TFF。我们的研究定义了一种以BSA为特征的顶体异常的新表型，揭示了ACTL 7A致病变异的潜在机制，并为男性不育提供了遗传标记和潜在的治疗选择。
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 (Actl7a(Mut/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 Actl7a(Mut/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 (PLC zeta) 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.