Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
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DOI：
10.15252/emmm.202114887
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发表时间：
2021-12-07
影响因子：
11.1
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Zhang YL;Zheng W;Ren P;Hu H;Tong X;Zhang SP;Li X;Wang H;Jiang JC;Jin J;Yang W;Cao L;He Y;Ma Y;Zhang Y;Gu Y;Hu L;Luo K;Gong F;Lu GX;Lin G;Fan HY;Zhang S
早期胚胎停滞和碎裂(EEAF)是导致女性不孕的一种常见现象，但遗传决定因素仍很大程度上尚不清楚。Moloney肉瘤癌基因(MOS)编码一种丝氨酸/苏氨酸激酶，在脊椎动物卵母细胞成熟过程中激活ERK信号级联反应。在这里，我们在三名患有EEAF的不育女性个体中发现了四种罕见的MOS变异，这些个体遵循隐性遗传模式。这些MOS变异体编码的蛋白质导致细胞和卵母细胞中磷酸化的ERK1/2水平降低，并对皮质F-肌动蛋白组装显示出减弱的挽救作用。利用卵母细胞特异性ERK1/2基因敲除小鼠，我们验证了卵母细胞中MOS-ERK信号通路的失活导致了与人类一样的EEAF。RNA测序数据显示，在人类成熟卵母细胞中，无论是MOS纯合子突变还是U0126处理，母体mRNA清除都受到干扰，尤其是与线粒体功能相关的基因。在ERK1/2缺失或失活的卵母细胞中观察到线粒体功能障碍。综上所述，本研究不仅发现了双等位基因MOS变异导致EEAF，而且证明了MOS-ERK信号通路通过驱动人卵母细胞胞质成熟来预防EEAF。MOS基因的双等位基因变异可导致反复发生的早期胚胎停滞和碎裂(EEAF)和女性不育。在人类和小鼠中，MOS变异体损害MOS-ERK信号级联的激活，阻止母体mRNAs的大量衰退，阻碍胚胎发育。
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 level 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. Biallelic variants in MOS gene cause recurrent early embryonic arrest and fragmentation (EEAF) and female infertility. MOS variants impair activation of MOS‐ERK signal cascade, prevent substantial maternal mRNAs decay and hamper embryonic development both in human and mice.
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DOI：
10.1073/pnas.93.14.7032
发表时间：
1996-07-09
影响因子：
11.1
作者：
Choi, TS;Fukasawa, K;VandeWoude, GF
通讯作者：
VandeWoude, GF
影响因子：
64.8
作者：
COLLEDGE, WH;CARLTON, MBL;EVANS, MJ
通讯作者：
EVANS, MJ
影响因子：
4
作者：
Mu, Jian;Wang, Wenjing;Wang, Lei
通讯作者：
Wang, Lei
ZAR1 和 ZAR2 通过调节母体转录组和 mRNA 翻译激活，是卵母细胞减数分裂成熟所必需的
影响因子：
14.9
作者：
Rong, Yan;Ji, Shu-Yan;Fan, Heng-Yu
通讯作者：
Fan, Heng-Yu
影响因子：
16
作者：
Pyakurel, Aswin;Savoia, Claudia;Hess, Daniel;Scorrano, Luca
通讯作者：
Scorrano, Luca