Biallelic mutations in CDC20 cause female infertility characterized by abnormalities in oocyte maturation and early embryonic development.
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ABSTRACT:
SUBMITTER: Zhao L
PROVIDER: S-EPMC7719138 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
Publications
Biallelic mutations in CDC20 cause female infertility characterized by abnormalities in oocyte maturation and early embryonic development.
Zhao Lin L Xue Songguo S Yao Zhongyuan Z Shi Juanzi J Chen Biaobang B Wu Ling L Sun Lihua L Xu Yao Y Yan Zheng Z Li Bin B Mao Xiaoyan X Fu Jing J Zhang Zhihua Z Mu Jian J Wang Wenjing W Du Jing J Liu Shuai S Dong Jie J Wang Weijie W Li Qiaoli Q He Lin L Jin Li L Liang Xiaozhen X Kuang Yanping Y Sun Xiaoxi X Wang Lei L Sang Qing Q
Protein & cell 20201201 12
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Project description: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.
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Project description:Human oocyte maturation arrest represents one of the severe conditions for female patients with primary infertility. However, the genetic factors underlying this human disease remain largely unknown. The spindle assembly checkpoint (SAC) is an intricate surveillance mechanism that ensures accurate segregation of chromosomes throughout cell cycles. Once the kinetochores of chromosomes are correctly attached to bipolar spindles and the SAC is satisfied, the MAD2L1BP, best known as p31comet, binds mitosis arrest deficient 2 (MAD2) and recruits the AAA+-ATPase TRIP13 to disassemble the mitotic checkpoint complex (MCC), leading to the cell-cycle progression. In this study, by whole-exome sequencing (WES), we identified homozygous and compound heterozygous MAD2L1BP variants in three families with female patients diagnosed with primary infertility owing to oocyte metaphase I (MI) arrest. Functional studies revealed that the protein variants resulting from the C-terminal truncation of MAD2L1BP lost their binding ability to MAD2. cRNA microinjection of full-length or truncated MAD2L1BP uncovered their discordant roles in driving the extrusion of polar body 1 (PB1) in mouse oocytes. Furthermore, the patient's oocytes carrying the mutated MAD2L1BP resumed polar body extrusion (PBE) when rescued by microinjection of full-length MAD2L1BP cRNAs. Together, our studies identified and characterized novel biallelic variants in MAD2L1BP responsible for human oocyte maturation arrest at MI, and thus prompted new therapeutic avenues for curing female primary infertility.
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Project description:PurposeThis study aims to identify the genetic causes of 12 women with primary infertility characterized by primarily oocyte maturation abnormality and consequent early embryonic arrest.MethodsGenomic DNA was isolated from peripheral blood samples. Whole-exome sequencing was performed on the probands, and the identified variants were confirmed by Sanger sequencing. The pathogenicity of the identified variants on the protein was accessed in silico. And we used qRT-PCR to detect the possible effects of the novel mutation on the mRNA level of NLRP5.ResultsA novel homozygous frameshift variant (p.V429Efs*30) in NLRP5 and compound heterozygous variants with a novel frameshift variant (p.A297Efs*20) and a recurrent variant (c. 223-14_223-2delCCCTCCTGTTCCA) in PATL2 were identified in two unrelated affected individuals. qRT-PCR showed an obvious decrease of the mutant NLRP5 mRNA. In addition, the truncated proteins of NLRP5 and PATL2 were predicted to be non-functional due to the deletion of the most or the whole region of the critical functional domain(s) respectively.ConclusionsThis study identified novel mutations in NLRP5 and PATL2, further expanding the mutational and phenotypic spectrum of both genes. This is the first report of the NLRP5 mutations that associates with oocyte maturation abnormality in humans.
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Project description:Early embryonic arrest is one of the major causes of female infertility. However, because of difficulties in phenotypic evaluation, genetic determinants of human early embryonic arrest are largely unknown. With the development of assisted reproductive technology, the phenotype of early human embryonic arrest can now be carefully evaluated. Here, we describe a consanguineous family with a recessive inheritance pattern of female infertility characterized by recurrent early embryonic arrest in cycles of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). We have identified a homozygous PADI6 nonsense mutation (c.1141C>T [p.Gln381(?)]) that is responsible for the phenotype. Mutational analysis of PADI6 in a cohort of 36 individuals whose embryos displayed developmental arrest identified two affected individuals with compound-heterozygous mutations (c.2009_2010del [p.Glu670Glyfs(?)48] and c.633T>A [p.His211Gln]; c.1618G>A [p.Gly540Arg] and c.970C>T [p.Gln324(?)]). Immunostaining indicated a lack of PADI6 in affected individuals' oocytes. In addition, the amount of phosphorylated RNA polymerase II and expression levels of seven genes involved in zygotic genome activation were reduced in the affected individuals' embryos. This phenotype is consistent with Padi6 knockout mice. These findings deepen our understanding of the genetic basis of human early embryonic arrest, which has been a largely ignored Mendelian phenotype. Our findings lay the foundation for uncovering other genetic causes of infertility resulting from early embryonic arrest.
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