Novel Mutations in CDC20 Are Associated with Female Infertility Due to Oocyte Maturation Abnormality and Early Embryonic Arrest
Novel Mutations in CDC20 Are Associated with Female Infertility Due to Oocyte Maturation Abnormality and Early Embryonic Arrest
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CDC20 的新突变与卵母细胞成熟异常和早期胚胎停滞导致的女性不孕有关
DOI：
10.1007/s43032-021-00524-3
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发表时间：
2021-03-08
影响因子：
2.9
通讯作者：
Tong, Xianhong
中科院分区：
文献类型：
--
作者：
Huang, Lingli;Wang, Fengsong;Tong, Xianhong
细胞分裂周期20（CDC 20）蛋白是后期促进复合物/环体（APC/C）的共激活剂，其是有丝分裂退出和减数分裂退出所需的，在C-末端含有7个WD 40重复序列，负责蛋白质-蛋白质相互作用。最近，一项先前的研究表明，CDC 20的双等位基因突变是导致女性不育的原因，卵母细胞成熟和胚胎发育异常。本研究旨在进一步确定CDC 20的新突变以及该突变在我们队列中的患病率。研究对象为50例卵母细胞成熟异常和早期胚胎阻滞的原发不孕女性。从外周血样品中分离基因组DNA。通过桑格测序对CDC 20的所有编码区进行突变筛选。通过计算机模拟评估鉴定的变体对CDC 20蛋白的致病性。两个CDC 20变异体，无义突变p.R262* 和错义突变p.A211T，在50个无关的受影响个体中的一个女性中鉴定，占该队列的相对较小比例（2%）。计算机模拟分析表明，p.R262* 不会导致蛋白质的产生或在C-末端缺少5个WD 40重复序列的截短蛋白质的产生;并且p.A211T可能干扰深疏水口袋的形成，从而干扰CDC 20蛋白与APC/C底物的结合。这项研究在CDC 20中发现了两个新的突变，进一步扩大了该基因的突变谱。我们的研究结果进一步证实，CDC 20的双等位基因突变发生在一个比例的不孕女性卵母细胞成熟异常和早期胚胎停滞。
The cell division cycle 20 (CDC20) protein is a co-activator of anaphase-promoting complex/cyclosome (APC/C), required for mitotic exit and also meiotic exit, containing seven WD40 repeats in the C-terminus responsible for protein-protein interactions. Recently, a previous study has shown that biallelic mutations in CDC20 are causative for female infertility with abnormalities in oocyte maturation and embryonic development. This study is to further identify new mutations of CDC20 and the prevalence of variants in our cohort. A cohort of 50 primary infertile females with oocyte maturation abnormality and early embryonic arrest were recruited. Genomic DNA was isolated from peripheral blood samples. Mutation screening of all the coding regions of CDC20 was performed by Sanger sequencing. The pathogenicity of the identified variants on the CDC20 protein was accessed in silico. Two CDC20 variants, a nonsense mutation p.R262* and a missense mutation p.A211T, identified in one female of 50 unrelated affected individuals, accounting for a relative small proportion of this cohort (2%). In silico analysis revealed that the p.R262* would cause no production of protein or a truncated protein lacking five WD40 repeats in the C-terminus; and that p.A211T may interfere with the formation of a deep hydrophobic pocket and thus disturb the binding of CDC20 protein to the substrates of APC/C. This study identified two novel mutations in CDC20, further expanding the mutation spectrum of this gene. Our findings further confirm that biallelic mutations in CDC20 occur in a proportion of infertile females with oocyte maturation abnormality and early embryonic arrest.