Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and recurrent homozygous nonsense variants and a splicing variant in TRIP13 are reported to cause Wilms tumors in children. In this study, we identified homozygous and compound heterozygous missense pathogenic variants in TRIP13 responsible for female infertility mainly characterized by oocyte meiotic arrest in five individuals from four independent families. Individuals from three families suffered from oocyte maturation arrest, whereas the individual from the fourth family had abnormal zygote cleavage. All displayed only the infertility phenotype without Wilms tumors or any other abnormalities. In vitro and in vivo studies showed that the identified variants reduced the protein abundance of TRIP13 and caused its downstream molecule, HORMAD2, to accumulate in HeLa cells and in proband-derived lymphoblastoid cells. The chromosome mis-segregation assay showed that variants did not have any effects on mitosis. Injecting TRIP13 cRNA into oocytes from one affected individual was able to rescue the phenotype, which has implications for future therapeutic treatments. This study reports pathogenic variants in TRIP13 responsible for oocyte meiotic arrest, and it highlights the pivotal but different roles of TRIP13 in meiosis and mitosis. These findings also indicate that different dosage effects of mutant TRIP13 might result in two distinct human diseases.

正常的卵母细胞减数分裂是人类成功繁殖的先决条件，并且该过程中的异常会导致不育。2016年，我们发现TUBB8中的突变可导致人类卵母细胞减数分裂停滞。但是，大多数受影响个体的潜在遗传因素仍然未知。编码AAA-ATPase的TRIP13是纺锤体装配检查点的关键组成部分，据报道，TRIP13中的纯合子无义变异体和剪接变异体可引起儿童Wilms肿瘤。在这项研究中，我们确定了TRIP13中的纯合和复合杂合错义致病变体造成女性不育的原因主要是来自四个独立家庭的五个个体的卵母细胞减数分裂停滞。来自三个家庭的个体遭受卵母细胞成熟阻滞，而来自第四家庭的个体的合子卵裂异常。全部仅显示不育表型，无威尔姆斯肿瘤或任何其他异常。体外和体内研究表明，鉴定出的变体降低了TRIP13的蛋白质丰度，并导致其下游分子HORMAD2在HeLa细胞和先证者来源的淋巴母细胞中积累。染色体错误分离测定表明，变体对有丝分裂没有任何影响。注入TRIP13来自一个受影响个体的卵母细胞中的cRNA能够挽救该表型，这对未来的治疗方法具有重要意义。这项研究报告了TRIP13中致卵母细胞减数分裂阻滞的致病变异，并着重强调了TRIP13在减数分裂和有丝分裂中的关键但不同的作用。这些发现还表明，突变体TRIP13的不同剂量作用可能导致两种不同的人类疾病。