2. Academic Validation
  3. 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

  • EMBO Mol Med. 2021 Dec 7;13(12):e14887. doi: 10.15252/emmm.202114887.
Yin-Li Zhang 1 2,  Wei Zheng 3 4,  Peipei Ren 1 2,  Huiling Hu 3 4,  Xiaomei Tong 1 2,  Shuo-Ping Zhang 3 4,  Xiang Li 1 2,  Haichao Wang 1 2,  Jun-Chao Jiang 5,  Jiamin Jin 1 2,  Weijie Yang 1 2,  Lanrui Cao 5,  Yuanlin He 6,  Yerong Ma 1 2,  Yingyi Zhang 1 2,  Yifan Gu 3 4,  Liang Hu 3 4,  Keli Luo 3 4,  Fei Gong 3 4,  Guang-Xiu Lu 3 4,  Ge Lin 3 4,  Heng-Yu Fan 2 5,  Songying Zhang 1 2
Affiliations

Affiliations

  • 1 Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China.
  • 3 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.
  • 4 Laboratory of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, China.
  • 5 Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 6 Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
PMID: 34779126 DOI: 10.15252/emmm.202114887
Abstract

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.

Keywords

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

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