Homozygous variants in CDC23 cause female infertility characterized by oocyte maturation defects

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...

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Bibliographic Details
Published in:Human genetics 2023-11, Vol.142 (11), p.1621-1631
Main Authors: Fan, Huizhen, Zhou, Zhou, Zheng, Wei, Guan, Yichun, Meng, Qingxia, Wang, Wenjing, Dong, Jie, Wan, Liuxia, Zhu, Jiawei, Zeng, Yang, Liu, Ruyi, Gu, Hao, Lin, Ge, Chen, Biaobang, Sang, Qing, Wang, Lei
Format: Article
Language:English
Subjects:
Anaphase
Biomedical and Life Sciences
Biomedicine
Cell division
Cyclin B1
Gene Function
Genetic aspects
Genetic factors
Genetic markers
Human Genetics
Infertility
Infertility, Female
Localization
Metabolic Diseases
Metaphase
Molecular Medicine
Oocytes
Original Investigation
Phenotypes
Securin
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Summary: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 Cdc23 Y329C/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.
ISSN:0340-6717
1432-1203
DOI:10.1007/s00439-023-02606-5