Novel mutations in genes encoding subcortical maternal complex proteins may cause human embryonic developmental arrest

Wang, Xueqian; Song, Di; Mykytenko, Dmytro; Kuang, Yanping; Lv, Qifeng; Li, Bin; Chen, Biaobang; Mao, Xiaoyan; Xu, Yao; Zukin, V.; Mazur, P.; Mu, Jian; Zheng, Yue; Zhou, Zhou; Li, Qiaoli; Liu, Suying; Jin, Li; He, Lin; Sang, Qing; Sun, Zilong; Dong, Xi; Wang, Lei

doi:10.1016/j.rbmo.2018.03.009

Cited by 84 publications

(63 citation statements)

References 28 publications

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“…The absence of CPLs is related to the disorganized distribution of organelles in oocytes in response to depletion of any SCMC genes, suggesting that the SCMC functions in regulating organelle distribution, probably by the CPLs in mouse oocytes and female fertility. Accumulating evidence suggests that mutations of human SCMC genes are related to female reproductive disorders, including recurrent embryonic loss, molar pregnancies and imprinting disorders (Amoushahi et al, 2019;Begemann et al, 2018;Lu et al, 2017;Mu et al, 2019;Nguyen et al, 2018;Wang et al, 2018). Further studies of phenotypes in Nlrp4f and other SCMC gene mutants and exploration of the relationships between the SCMC and its proteins, CPLs and oocyte quality will contribute to an understanding of human OET and the pathogenesis of reproductive diseases.…”

Section: Discussionmentioning

confidence: 99%

The subcortical maternal complex protein Nlrp4f is involved in cytoplasmic lattice formation and organelle distribution

et al. 2019

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In mammalian oocytes and embryos, the subcortical maternal complex (SCMC) and cytoplasmic lattices (CPLs) are two closely related structures. Their detailed compositions and functions remain largely unclear. Here, we characterize Nlrp4f as a novel component associated with the SCMC and CPLs. Disruption of maternal Nlrp4f leads to decreased fecundity and delayed preimplantation development in the mouse. Lack of Nlrp4f affects organelle distribution in mouse oocytes and early embryos. Depletion of Nlrp4f disrupts CPL formation but does not affect the interactions of other SCMC proteins. Interestingly, the loss of Khdc3 or Tle6, two other SCMC proteins, also disrupts CPL formation in mouse oocytes. Thus, the absence of CPLs and aberrant distribution of organelles in the oocytes caused by disruption of the examined SCMC genes, including previously reported Zbed3, Nlrp5, Ooep and Padi6, indicate that the SCMC is required for CPL formation and organelle distribution. Consistent with the role of the SCMC in CPL formation, the SCMC forms before CPLs during mouse oogenesis. Together, our results suggest that the SCMC protein Nlrp4f is involved in CPL formation and organelle distribution in mouse oocytes.

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Section: Discussionmentioning

confidence: 99%

The subcortical maternal complex protein Nlrp4f is involved in cytoplasmic lattice formation and organelle distribution

et al. 2019

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“…This complex is required for development of mouse embryos past the 2‐cell stage and controls formation of cytoplasmic lattices, F‐actin dynamic, distribution of ER and mitochondria, and mRNA degradation during the oocyte to embryo transition (Amoushahi et al, 2019). A recent clinical study showed that mutations in SCMC genes lead to embryonic arrest, with embryos failing to form blastocysts, including arrest well after the earliest SCMC actions and indicates more long‐term impacts of early SCMC functions (Figure 1; X. Wang et al, 2018).…”

Section: Subcortical Maternal Complex (Scmc) Effectsmentioning

confidence: 99%

Listening to mother: Long‐term maternal effects in mammalian development

Ruebel

Latham

2020

Molecular Reproduction Devel

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The oocyte is a complex cell that executes many crucial and unique functions at the start of each life. These functions are fulfilled by a unique collection of macromolecules and other factors, all of which collectively support meiosis, oocyte activation, and embryo development. This review focuses on the effects of oocyte components on developmental processes that occur after the initial stages of embryogenesis. These include long-term effects on genome function, metabolism, lineage allocation, postnatal progeny health, and even subsequent generations.Factors that regulate chromatin structure, genome programming, and mitochondrial function are elements that contribute to these oocyte functions. K E Y W O R D S chromatin, embryo gene regulation, maternal effect, oocyte 400 |

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“…Early embryonic arrest is referred to as preimplantation embryo lethality and the arrested cleaved embryos that could not form blastocysts. The subcortical maternal complex (consisting of PADI6, TLE6, KHDC3L, OOEP, NLRP2 and NLRP5) has been reported to play important roles in embryogenesis, and we previously identified mutations in some of these proteins (PADI6, TLE6, KHDC3L, NLRP2 and NLRP5) as being responsible for early embryonic arrest 6–8. In addition, some rare variants in TUBB8 and PATL2 have also been found to cause low-quality embryos 9–13.…”

Section: Introductionmentioning

confidence: 99%

Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest

et al. 2019

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BackgroundAbnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in female infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in female infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown.ObjectiveWe aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest.MethodsWhole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay.ResultsWe identified a novel homozygous missense mutation (c.397T>G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G>A) in the meiotic gene REC114. REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114, while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation.ConclusionsOur study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human female meiosis and fertility.

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Novel mutations in genes encoding subcortical maternal complex proteins may cause human embryonic developmental arrest

Cited by 84 publications

References 28 publications

The subcortical maternal complex protein Nlrp4f is involved in cytoplasmic lattice formation and organelle distribution

The subcortical maternal complex protein Nlrp4f is involved in cytoplasmic lattice formation and organelle distribution

Listening to mother: Long‐term maternal effects in mammalian development

Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest

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