Biallelic variants in MAD2L1BP (p31comet) cause female infertility characterized by oocyte maturation arrest
- University of Science and Technology of China, China
- Zhejiang University, China
- Shandong University, China
- Anhui Medical University, China
Abstract
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 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 variants 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.
Data availability
Source Data files have been provided for Figure 2, Figure 3 and Table 2. Sequencing data have been deposited in GEO under accession code GSE232488.
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Biallelic variants in MAD2L1BP (p31comet) cause female infertility characterized by oocyte maturation arrestNCBI Gene Expression Omnibus, GSE232488.
Article and author information
Author details
Funding
National Natural Science Foundation of China (81801440)
- Lingli Huang
National Natural Science Foundation of China (82192874)
- Han Zhao
National Natural Science Foundation of China (82171842)
- Han Zhao
National Natural Science Foundation of China (31970793)
- Jianqiang Bao
National Natural Science Foundation of China (32170856)
- Jianqiang Bao
the Ministry of Science and Technology of China (2019YFA0802600)
- Jianqiang Bao
the Fundamental Research Funds for the Central Universities (WK2070000156)
- Jianqiang Bao
Startup funding (KY9100000001)
- Jianqiang Bao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal care and experimental procedures were conducted in accordance with the Animal Research Committee guidelines of Zhejiang University (approval # ZJU20210252 to H.Y.F) and USTC (approval # 2019-N(A)-299 to J.Q.B).
Human subjects: Peripheral blood samples from all affected individuals and their available family members and ten Metaphase I (MI) arrested oocytes from the patient (F1: II-1) were donated for this study with written informed consent. This study was approved by the biomedical research ethics committees of Anhui Medical University on 1 March 2017(reference number 20170121; the Anhui Provincial Hospital Affiliated to Anhui Medical University, now renamed as the First Affiliated Hospital of USTC after December 2017).
Reviewing Editor
- Adèle L Marston, University of Edinburgh, United Kingdom
Version history
- Received: December 18, 2022
- Preprint posted: January 16, 2023 (view preprint)
- Accepted: June 15, 2023
- Accepted Manuscript published: June 19, 2023 (version 1)
- Version of Record published: July 4, 2023 (version 2)
Copyright
© 2023, Huang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Biallelic variants in MAD2L1BP (p31comet) cause female infertility characterized by oocyte maturation arrest
eLife 12:e85649.
https://doi.org/10.7554/eLife.85649
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Cylicins are testis-specific proteins, which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 (Cylc1/CYLC1) and the autosomal Cylicin 2 (Cylc2/CYLC2) genes, have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While Cylicins have been localized in the acrosomal region of round spermatids, they resemble a major component of the calyx within the perinuclear theca at the posterior part of mature sperm nuclei. However, the role of Cylicins during spermiogenesis has not yet been investigated. Here, we applied CRISPR/Cas9-mediated gene editing in zygotes to establish Cylc1- and Cylc2-deficient mouse lines as a model to study the function of these proteins. Cylc1 deficiency resulted in male subfertility, whereas Cylc2-/-, Cylc1-/yCylc2+/-, and Cylc1-/yCylc2-/- males were infertile. Phenotypical characterization revealed that loss of Cylicins prevents proper calyx assembly during spermiogenesis. This results in decreased epididymal sperm counts, impaired shedding of excess cytoplasm, and severe structural malformations, ultimately resulting in impaired sperm motility. Furthermore, exome sequencing identified an infertile man with a hemizygous variant in CYLC1 and a heterozygous variant in CYLC2, displaying morphological abnormalities of the sperm including the absence of the acrosome. Thus, our study highlights the relevance and importance of Cylicins for spermiogenic remodeling and male fertility in human and mouse, and provides the basis for further studies on unraveling the complex molecular interactions between perinuclear theca proteins required during spermiogenesis.
