Exome sequencing links CEP120 mutation to maternally derived aneuploid conception risk
Exome sequencing links CEP120 mutation to maternally derived aneuploid conception risk
复制标题
DOI：
10.1093/humrep/deaa148
复制
发表时间：
2020-09-01
影响因子：
6.1
通讯作者：
Xing, Jinchuan
中科院分区：
文献类型：
--
作者：
Tyc, Katarzyna M.;El Yakoubi, Warif;Xing, Jinchuan
研究问题什么是增加非整倍体卵子产生风险的遗传因素？摘要答案中心体蛋白120（CEP 120）内的一个非同义变体rs 2303720在体外破坏小鼠的雌性减数分裂。已知的非整倍体卵子的产生，与高龄产妇作为一个确定的贡献因素，是IVF失败，早期流产和发育异常的主要原因。研究设计、规模、持续时间接受生育治疗的患者（n=166）被去识别并选择用于全外显子组测序。参与者/材料、设置、方法患者自我识别他们的种族群体，他们的年龄范围从22岁到49岁。该研究使用来自白色非西班牙裔患者的基因组进行，根据每次IVF程序期间获得的非整倍体囊胚的数量分为对照组（97）和病例组（69）。以下的基因优先策略，小鼠卵母细胞系统被用来验证功能的意义，发现相关的遗传variants.Main结果和机会的作用患者产生高比例的非整倍体胚泡（考虑非整倍体，如果他们错过了任何的40个染色单体或有额外的副本）被发现携带更高的突变负担在细胞骨架和微管途径的基因功能。Cep 120内的非同义变体rs 2303720对小鼠卵母细胞减数分裂成熟的功能意义的验证表明，CEP 120：p.Arg947His的异位表达导致纺锤体微管成核效率降低和非整倍体的发生率增加。由于小鼠和人类卵母细胞之间的纺锤体构建途径不同，我们观察到的Cep 120变异体异位表达的缺陷可能会改变小鼠卵母细胞减数分裂不同于人类卵母细胞减数分裂。将我们的发现转化到人类系统中，还需要使用敲入“人源化”小鼠模型和人类卵母细胞进行进一步研究。种族之间的变异可能的功能差异也需要调查。更广泛的影响的发现中心体基因的变异似乎是重要的贡献者的风险，母体非整倍体。这些变体的功能验证最终将允许预筛选以选择有更好机会从植入前基因检测中受益的患者。研究资金/竞争兴趣本研究通过R 01-HD 091331向K. S.和J. X。和EMD Serono Grant for Fertility Innovation to N.R.T. N.R. T是基因组预测的股东和雇员。试验注册号N/A。
STUDY QUESTION What are the genetic factors that increase the risk of aneuploid egg production?SUMMARY ANSWER A non-synonymous variant rs2303720 within centrosomal protein 120 (CEP120) disrupts female meiosis in vitro in mouse.WHAT IS KNOWN ALREADY The production of aneuploid eggs, with an advanced maternal age as an established contributing factor, is the major cause of IVF failure, early miscarriage and developmental anomalies. The identity of maternal genetic variants contributing to egg aneuploidy irrespective of age is missing.STUDY DESIGN, SIZE, DURATION Patients undergoing fertility treatment (n=166) were deidentified and selected for whole-exome sequencing.PARTICIPANTS/MATERIALS, SETTING, METHODS Patients self-identified their ethnic groups and their ages ranged from 22 to 49 years old. The study was performed using genomes from White, non-Hispanic patients divided into controls (97) and cases (69) according to the number of aneuploid blastocysts derived during each IVF procedure. Following a gene prioritization strategy, a mouse oocyte system was used to validate the functional significance of the discovered associated genetic variants.MAIN RESULTS AND THE ROLE OF CHANCE Patients producing a high proportion of aneuploid blastocysts (considered aneuploid if they missed any of the 40 chromatids or had extra copies) were found to carry a higher mutational burden in genes functioning in cytoskeleton and microtubule pathways. Validation of the functional significance of a non-synonymous variant rs2303720 within Cep120 on mouse oocyte meiotic maturation revealed that ectopic expression of CEP120:p.Arg947His caused decreased spindle microtubule nucleation efficiency and increased incidence of aneuploidy.LIMITATIONS, REASONS FOR CAUTION Functional validation was performed using the mouse oocyte system. Because spindle building pathways differ between mouse and human oocytes, the defects we observed upon ectopic expression of the Cep120 variant may alter mouse oocyte meiosis differently than human oocyte meiosis. Further studies using knock-in 'humanized' mouse models and in human oocytes will be needed to translate our findings to human system. Possible functional differences of the variant between ethnic groups also need to be investigated.WIDER IMPLICATIONS OF THE FINDINGS Variants in centrosomal genes appear to be important contributors to the risk of maternal aneuploidy. Functional validation of these variants will eventually allow prescreening to select patients that have better chances to benefit from preimplantation genetic testing.STUDY FUNDING/COMPETING INTEREST(S) This study was funded through R01-HD091331 to K.S. and J.X. and EMD Serono Grant for Fertility Innovation to N.R.T. N.R.T. is a shareholder and an employee of Genomic Prediction.TRIAL REGISTRATION NUMBER N/A.