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).
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
Further reading
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- Cell Biology
- Developmental Biology
The rete ovarii (RO) is an appendage of the ovary that has been given little attention. Although the RO appears in drawings of the ovary in early versions of Gray’s Anatomy, it disappeared from recent textbooks, and is often dismissed as a functionless vestige in the adult ovary. Using PAX8 immunostaining and confocal microscopy, we characterized the fetal development of the RO in the context of the mouse ovary. The RO consists of three distinct regions that persist in adult life, the intraovarian rete (IOR), the extraovarian rete (EOR), and the connecting rete (CR). While the cells of the IOR appear to form solid cords within the ovary, the EOR rapidly develops into a convoluted tubular epithelium ending in a distal dilated tip. Cells of the EOR are ciliated and exhibit cellular trafficking capabilities. The CR, connecting the EOR to the IOR, gradually acquires tubular epithelial characteristics by birth. Using microinjections into the distal dilated tip of the EOR, we found that luminal contents flow toward the ovary. Mass spectrometry revealed that the EOR lumen contains secreted proteins potentially important for ovarian function. We show that the cells of the EOR are closely associated with vasculature and macrophages, and are contacted by neuronal projections, consistent with a role as a sensory appendage of the ovary. The direct proximity of the RO to the ovary and its integration with the extraovarian landscape suggest that it plays an important role in ovary development and homeostasis.
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- Cell Biology
- Developmental Biology
Long thought to have little relevance to ovarian physiology, the rete ovarii may have a role in follicular dynamics and reproductive health.
