Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, Shandong, China.
Reprod Sci. 2020 Dec;27(12):2265-2270. doi: 10.1007/s43032-020-00246-y. Epub 2020 Jul 22.
Human zygote arrest during in vitro culture is rare and the etiology is unclear. The oocyte-specific gene Zar1 plays an essential role in oocyte-embryo transition, and most embryos from Zar1 knockout female mice arrest at the one-cell stage. This study investigates whether maternal ZAR1 gene variations play a role in human zygote arrest. Sequence analysis of ZAR1 was conducted for 47 women with recurrent uncleaved zygotes in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles (≥ 70% zygotes uncleaved in at least 2 cycles), 93 women from IVF/ICSI cycles with normal uncleaved rate and live birth (control subset I) and 188 women with spontaneous pregnancy and live birth (control subset II). One novel synonymous variation (c.516C>T) and one novel intron variation (c.964-55A>T) of ZAR1 were identified in the zygote arrest group but not in any of the 188 controls. However, the bioinformatics analysis revealed that neither of the mutations in ZAR1 has effect on ZAR1 protein function. Compared with control subset I, the allele frequencies of rare SNPs rs117545505 and rs17609740 were significantly different in patients with zygote arrest (P = 0.047, OR = 3.66). Allele frequencies of these two SNPs were also significantly different between the case group and control subset II (P = 0.024, OR = 3.28). In conclusion, two SNPs in ZAR1 are associated with human zygote arrest, although additional proof is needed for validation.
人类体外培养的合子阻滞很少见，病因尚不清楚。卵母细胞特异性基因 Zar1 在卵母细胞-胚胎过渡中起着至关重要的作用，大多数来自 Zar1 基因敲除雌性小鼠的胚胎在一细胞阶段阻滞。本研究探讨了母体 ZAR1 基因变异是否在人类合子阻滞中起作用。对 47 名在体外受精/胞浆内单精子注射（IVF/ICSI）周期中反复出现未分裂合子的女性（至少 2 个周期中≥70%的合子未分裂）、93 名 IVF/ICSI 周期中正常未分裂率和活产的女性（对照组 I）和 188 名自然妊娠和活产的女性（对照组 II）的 ZAR1 进行了序列分析。在合子阻滞组中发现了 ZAR1 的一个新同义变异（c.516C>T）和一个新内含子变异（c.964-55A>T），但在 188 名对照者中均未发现。然而，生物信息学分析表明，ZAR1 中的突变均未影响 ZAR1 蛋白的功能。与对照组 I 相比，rs117545505 和 rs17609740 这两个稀有 SNP 的等位基因频率在合子阻滞患者中差异有统计学意义（P=0.047，OR=3.66）。这两个 SNP 的等位基因频率在病例组和对照组 II 之间也有显著差异（P=0.024，OR=3.28）。总之，ZAR1 中的两个 SNP 与人类合子阻滞有关，尽管还需要进一步的验证。
