4.7 Article

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

Journal

EMBO MOLECULAR MEDICINE
Volume 13, Issue 12, Pages -

Publisher

WILEY
DOI: 10.15252/emmm.202114887

Keywords

female infertility; human oocyte; maternal mRNA decay; mitochondria; MOS

Funding

  1. National Key Research and Development Program of China [2018YFC1004800, 2017YFC1001500]
  2. National Natural Science Foundation of China [82071640, 31701260, 82001633, 31930013]
  3. Key Projects Jointly Constructed by the Ministry and the Province of Zhejiang Medical and Health Science and Technology Project [WKJ-ZJ-2005]
  4. Natural Science Foundation of Zhejiang Province [LY21H040003, D22C068649]
  5. China Postdoctoral Science Foundation [2020M682575, 2021T140198]
  6. Changsha Municipal Natural Science Foundation [kq2007022]
  7. Hunan Provincial Grant for Innovative Province Construction [2019SK4012]

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Rare MOS variants were identified in infertile females with EEAF, leading to decreased ERK phosphorylation and disruption of maternal mRNA clearance related to mitochondrial function. Inactivation of the MOS-ERK signaling pathway drives EEAF by impairing oocyte cytoplasmic maturation in humans as shown in mice models.
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.

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