Abstract
Oocyte maturation defects are major phenotypes resulting in female infertility. Although many genetic factors have been found to be responsible for these phenotypes, the underlying pathogenic genes and variants remain to be identified. The anaphase promoting complex or cyclosome (APC/C) is known to be essential in the metaphase-to-anaphase transition. In this study, we identified two homozygous missense variants (c.986A > G, p.Y329C and c.988C > T, p.R330C) in CDC23 that are responsible for female infertility characterized by oocyte maturation defects in three infertile individuals. CDC23 (cell division cycle 23) is one of the core subunits of the APC/C. In vitro experiments showed that the variant c.986A > G (p.Y329C) led to a decrease in CDC23 protein level and the variant c.988C > T (p.R330C) changed the localization of CDC23 in HeLa cells and mouse oocytes. In vivo studies showed that Cdc23Y329C/Y329C mice successfully mimicked the patients’ phenotype by causing low expression of CDC23 and APC4 and the accumulation of securin and cyclin B1 in oocytes. AZ3146 treatment was able to rescue the phenotype. Taken together, our findings reveal the important roles of CDC23 in human oocyte maturation and provide a new genetic marker for female infertility.
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Source data of CDC23 protein feature are from UniProt
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Acknowledgements
We would like to thank the patients and their families and the female healthy volunteers who participated in this study.
Funding
This work was supported by the National Key Research and Development Program of China (2021YFC2700100), the National Natural Science Foundation of China (82288102, 32130029, 82171643, 81971450,81971382), New Cornerstone Science Foundation through the XPLORER PRIZE, the Project of the Shanghai Municipal Science and Technology Commission (21XD1420300) and the China Postdoctoral Science Fund (2022M712147).
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HF, ZZ, WZ, YG, and QM contributed equally to this work. LW and QS conceived and designed the study. WZ, YG, QM, LW, JZ, and GL contributed to the recruitment and characterization of the patients. BC organized the medical records and analyzed the whole-exome data. HF, ZZ, WW, JD, YZ, RL, and HG performed the experiments. HF and ZZ analyzed the data. HF, ZZ, and QS drafted the article and revised the manuscript. All authors approved the final manuscript to be published and were accounted for all aspects of the work.
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Our study was approved by the ethics committee of the Medical College of Fudan University and the Reproductive Study Ethics Committees of the hospitals, and written informed consent was obtained from the affected individuals.
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Fan, H., Zhou, Z., Zheng, W. et al. Homozygous variants in CDC23 cause female infertility characterized by oocyte maturation defects. Hum. Genet. 142, 1621–1631 (2023). https://doi.org/10.1007/s00439-023-02606-5
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DOI: https://doi.org/10.1007/s00439-023-02606-5