Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation

Early embryonic arrest and fragmentation (EEAF) is a common phenomenon leading to female infertility, but the genetic determinants remain largely unknown. The Moloney sarcoma oncogene (MOS) encodes a serine/threonine kinase that activates the ERK signaling cascade during oocyte maturation in vertebrates. Here, we identified four rare variants of MOS in three infertile female individuals with EEAF that followed a recessive inheritance pattern. These MOS variants encoded proteins that resulted in decreased phosphorylated ERK1/2 levels in cells and oocytes, and displayed attenuated rescuing effects on cortical F-actin assembly. Using oocyte-specific Erk1/2 knockout mice, we verified that MOS-ERK signal pathway inactivation in oocytes caused EEAF as human. The RNA sequencing data revealed that maternal mRNA clearance was disrupted in human mature oocytes either with MOS homozygous variant or with U0126 treatment, especially genes relative to mitochondrial function. Mitochondrial dysfunction was observed in oocytes with ERK1/2 deficiency or inactivation. In conclusion, this study not only uncovers biallelic MOS variants causes EEAF but also demonstrates that MOS-ERK signaling pathway drives human oocyte cytoplasmic maturation to prevent EEAF.

早期胚胎停滞与碎裂（Early embryonic arrest and fragmentation，EEAF）是引发女性不孕症的常见表型，但其遗传决定因素迄今仍不明确。莫洛尼肉瘤癌基因（Moloney sarcoma oncogene，MOS）编码一种丝氨酸/苏氨酸激酶，可在脊椎动物卵母细胞成熟过程中激活ERK信号级联反应。本研究从3例符合隐性遗传模式的EEAF不孕女性个体中，鉴定出4个MOS罕见变异。上述MOS变异所编码的蛋白，会降低细胞及卵母细胞内磷酸化ERK1/2的表达水平，并在皮层F-肌动蛋白组装实验中表现出减弱的拯救效应。通过构建卵母细胞特异性Erk1/2敲除小鼠，本研究验证了卵母细胞内MOS-ERK信号通路失活，会如同人类病例中一样引发EEAF。RNA测序数据分析显示，携带MOS纯合变异的人类成熟卵母细胞，或经U0126处理的卵母细胞，其母源mRNA清除过程均发生紊乱，尤以与线粒体功能相关的基因受影响最为显著。在ERK1/2缺失或通路失活的卵母细胞中，均可观察到线粒体功能障碍。综上，本研究不仅揭示双等位基因MOS变异可导致EEAF，同时证实MOS-ERK信号通路通过调控人类卵母细胞胞质成熟，进而预防EEAF的发生。