The homozygous p.Tyr228Cys variant in CDC20 causes oocyte maturation arrest: an additional evidence supporting the causality between CDC20 mutation and female infertility

Xu, Yao; Zhu, Xiurong; Wang, Miao; Cai, Luyi; Ge, Qiulin; Fu, Yonglun; Jin, Liping

doi:10.1007/s10815-021-02269-z

Cited by 5 publications

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“…12,14,15 Thus, such mutations are rare in human disease, 12,16 and the clinical significance of mutations in CDC20 have been investigated in only a handful of studies in an animal model or human context. [17][18][19][20][21][22][23] Although CDC20 is overexpressed in the majority of human cancers, 16,[24][25][26][27][28][29][30] the involvement of CDC20 mutations in cancer has never been established in humans.…”

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confidence: 99%

Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer

et al. 2022

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CDC20 is a co-activator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with ovarian germ cell tumors in two families. Functional characterization showed these mutants retain APC/C activation activity but have impaired binding to BUBR1, a component of the SAC. Expression of L151R and N331K variants promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. Generation of mice carrying the N331K variant using CRISPR-Cas9 showed that, while homozygous N331K mice were non-viable, heterozygotes displayed accelerated oncogenicity of Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor-promoting genes.

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