Biallelic variants in MAD2L1BP (p31(comet)) cause female infertility characterized by oocyte maturation arrest.
Biallelic variants in MAD2L1BP (p31(comet)) cause female infertility characterized by oocyte maturation arrest.
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作者：
Huang L;Li W;Dai X;Zhao S;Xu B;Wang F;Jin RT;Luo L;Wu L;Jiang X;Cheng Y;Zou J;Xu C;Tong X;Fan HY;Zhao H;Bao J
人类卵母细胞成熟停滞是原发性不孕症女性患者的严重情况之一。然而，这种人类疾病背后的遗传因素在很大程度上仍然未知。纺锤体组装检查点（SAC）是一种复杂的监视机制，可确保染色体在整个细胞周期中准确分离。一旦染色体的动粒正确地连接到双极纺锤体并且SAC得到满足，MAD 2L 1BP（最著名的是p31 comet）结合有丝分裂阻滞缺陷2（MAD 2）并募集AAA+-ATP酶TRIP 13以分解有丝分裂检查点复合物（MCC），导致细胞周期进展。在这项研究中，通过全外显子组测序（WES），我们确定了纯合子和复合杂合子MAD 2L 1BP变异体在三个家庭的女性患者诊断为原发性不孕症，由于卵母细胞中期I（MI）逮捕。功能研究表明，由MAD 2L 1BP的C-末端截短产生的蛋白变体失去了与MAD 2的结合能力。cRNA显微注射全长或截短的MAD 2L 1BP揭示了它们在驱动小鼠卵母细胞中极体1（PB 1）挤出中的不协调作用。此外，当通过显微注射全长MAD 2L 1 BP cRNA拯救时，携带突变的MAD 2L 1 BP的患者卵母细胞恢复了极体排出（PBE）。总之，我们的研究确定并表征了MAD 2L 1BP中负责MI时人类卵母细胞成熟停滞的新型双等位基因变体，从而提示了治疗女性原发性不孕症的新治疗途径。
Human oocyte maturation arrest represents one of the severe conditions for female patients with primary infertility. However, the genetic factors underlying this human disease remain largely unknown. The spindle assembly checkpoint (SAC) is an intricate surveillance mechanism that ensures accurate segregation of chromosomes throughout cell cycles. Once the kinetochores of chromosomes are correctly attached to bipolar spindles and the SAC is satisfied, the MAD2L1BP, best known as p31comet, binds mitosis arrest deficient 2 (MAD2) and recruits the AAA+-ATPase TRIP13 to disassemble the mitotic checkpoint complex (MCC), leading to the cell-cycle progression. In this study, by whole-exome sequencing (WES), we identified homozygous and compound heterozygous MAD2L1BP variants in three families with female patients diagnosed with primary infertility owing to oocyte metaphase I (MI) arrest. Functional studies revealed that the protein variants resulting from the C-terminal truncation of MAD2L1BP lost their binding ability to MAD2. cRNA microinjection of full-length or truncated MAD2L1BP uncovered their discordant roles in driving the extrusion of polar body 1 (PB1) in mouse oocytes. Furthermore, the patient’s oocytes carrying the mutated MAD2L1BP resumed polar body extrusion (PBE) when rescued by microinjection of full-length MAD2L1BP cRNAs. Together, our studies identified and characterized novel biallelic variants in MAD2L1BP responsible for human oocyte maturation arrest at MI, and thus prompted new therapeutic avenues for curing female primary infertility.
DOI：
10.3791/64459
发表时间：
2022-09-13
期刊：
Journal of visualized experiments : JoVE
影响因子：
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作者：
Aboelenain M;Schindler K;Blengini CS
通讯作者：
Blengini CS
DOI：
10.1083/jcb.145.7.1395
发表时间：
1999-06-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Woods LM;Hodges CA;Baart E;Baker SM;Liskay M;Hunt PA
通讯作者：
Hunt PA