Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice
Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice
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DOI：
10.1016/j.ajhg.2021.02.004
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发表时间：
2021-03-04
影响因子：
9.8
通讯作者：
Lin, Ge
中科院分区：
文献类型：
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作者：
Dai, Jing;Zhang, Tianlei;Lin, Ge
完全受精失败（TFF）可能发生在体外受精（IVF）治疗过程中，甚至在卵胞浆内单精子注射（ICSI）后。各种男性或女性因素都可能导致TFF。越来越多的证据表明，编码1-磷脂酰肌醇4,5-二磷酸磷酸二酯酶zeta-1 （PLCz）的PLCZ1的遗传变异参与卵母细胞活化，是TFF的关键男性因素。在本研究中，我们探索了男性个体中导致TFF的遗传变异。筛选TFF或受精率低（受精率< 20%）的夫妇54对，通过小鼠卵母细胞活化试验确定21对有男性不育因素。对这21个男性个体进行全外显子组测序，在3个个体中发现了ACTL9 （actin like 9）的3个纯合致病变异。ACTL9变异导致核周卵泡（PT）超微结构异常，PLCz在头部缺失，而在突变精子的颈部存在，这导致卵母细胞正常钙振荡失败和随后的TFF。ACTL9突变小鼠模型进一步证实了ACTL9在ICSI后PT结构和TFF中的关键作用。此外，通过钙离子载体暴露辅助卵母细胞激活成功地克服了TFF，并在携带ACTL9变异的夫妇中实现了活产。这些发现确定了ACTL9在PT结构和PLCz的正确定位中的作用。结果也为没有成功受精的ICSI患者提供了遗传标记和治疗选择。
Total fertilization failure (TFF) can occur during in vitro fertilization (IVF) treatments, even following intracytoplasmic sperm injection (ICSI). Various male or female factors could contribute to TFF. Increasing evidence suggested that genetic variations in PLCZ1, which encodes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (PLCz), is involved in oocyte activation and is a key male factor in TFF. In the present study, we explored the genetic variants in male individuals that led to TFF. A total of 54 couples with TFF or poor fertilization (fertilization rate < 20%) were screened, and 21 couples were determined to have a male infertility factor by the mouse oocyte activation test. Whole-exome sequencing of these 21 male individuals identified three homozygous pathogenic variants in ACTL9 (actin like 9) in three individuals. ACTL9 variations led to abnormal ultrastructure of the perinuclear theca (PT), and PLCz was absent in the head and present in the neck of the mutant sperm, which contributed to failed normal calcium oscillations in oocytes and subsequent TFF. The key roles of ACTL9 in the PT structure and TFF after ICSI were further confirmed in an Actl9-mutated mouse model. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF and achieved live births in a couple with an ACTL9 variant. These findings identified the role of ACTL9 in the PT structure and the correct localization of PLCz. The results also provide a genetic marker and a therapeutic option for individuals who have undergone ICSI without successful fertilization.