Department of Genetics, Rutgers University, Piscataway, NJ, USA.
Human Genetics Institute of New Jersey, Piscataway, NJ, USA.
Adv Anat Embryol Cell Biol. 2024;238:1-22. doi: 10.1007/978-3-031-55163-5_1.
Successful reproduction relies on the union of a single chromosomally normal egg and sperm. Chromosomally normal eggs develop from precursor cells, called oocytes, that have undergone accurate chromosome segregation. The process of chromosome segregation is governed by the oocyte spindle, a unique cytoskeletal machine that splits chromatin content of the meiotically dividing oocyte. The oocyte spindle develops and functions in an idiosyncratic process, which is vulnerable to genetic variation in spindle-associated proteins. Human genetic variants in several spindle-associated proteins are associated with poor clinical fertility outcomes, suggesting that heritable etiologies for oocyte dysfunction leading to infertility exist and that the spindle is a crux for female fertility. This chapter examines the mammalian oocyte spindle through the lens of human genetic variation, covering the genes TUBB8, TACC3, CEP120, AURKA, AURKC, AURKB, BUB1B, and CDC20. Specifically, it explores how patient-identified variants perturb spindle development and function, and it links these molecular changes in the oocyte to their cognate clinical consequences, such as oocyte maturation arrest, elevated egg aneuploidy, primary ovarian insufficiency, and recurrent pregnancy loss. This discussion demonstrates that small genetic errors in oocyte meiosis can result in remarkably far-ranging embryonic consequences, and thus reveals the importance of the oocyte's fine machinery in sustaining life.
成功的繁殖依赖于单个染色体正常的卵子和精子的结合。染色体正常的卵子由称为卵母细胞的前体细胞发育而来，这些前体细胞经历了准确的染色体分离。染色体分离的过程受卵母细胞纺锤体的控制，卵母细胞纺锤体是一种独特的细胞骨架机器，可分裂减数分裂卵母细胞的染色质内容。卵母细胞纺锤体在一种特殊的过程中发育和发挥作用，这种过程容易受到纺锤体相关蛋白的遗传变异的影响。几种与纺锤体相关的蛋白质中的人类遗传变异与较差的临床生育结局有关，这表明存在导致不孕的卵母细胞功能障碍的可遗传病因，并且纺锤体是女性生育力的关键。本章通过人类遗传变异的视角来研究哺乳动物卵母细胞纺锤体，涵盖了 TUBB8、TACC3、CEP120、AURKA、AURKC、AURKB、BUB1B 和 CDC20 等基因。具体来说，它探讨了患者鉴定的变异如何扰乱纺锤体的发育和功能，并将卵母细胞中的这些分子变化与其相应的临床后果联系起来，例如卵母细胞成熟阻滞、卵子非整倍体增加、原发性卵巢功能不全和复发性妊娠丢失。这一讨论表明，卵母细胞减数分裂中的微小遗传错误会导致胚胎后果显著扩大，从而揭示了卵母细胞精细机制在维持生命中的重要性。
