Identification of Novel Variants of Thyroid Hormone Receptor Interaction Protein 13 That Cause Female Infertility Characterized by Zygotic Cleavage Failure.
Identification of Novel Variants of Thyroid Hormone Receptor Interaction Protein 13 That Cause Female Infertility Characterized by Zygotic Cleavage Failure.
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甲状腺激素受体相互作用蛋白 13 的新变体的鉴定，该变体导致以合子卵裂失败为特征的女性不孕症
DOI：
10.3389/fphys.2022.899149
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发表时间：
2022
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
合子卵裂失败（ZCF）是一种严重的早期胚胎停滞，其中合子不能完成第一次卵裂。虽然BTG 4和CHEK 1的突变已被确定为ZCF的遗传原因，但这些基因只能解释一小部分ZCF病例。因此，需要确定其他受影响个体的潜在遗传原因。在这里，我们确定了三个TRIP 13错义变异负责ZCF在两名患者，并表明他们遵循隐性遗传模式。所有三种变体都导致氢键的明显变化和DNA损伤的一致增加。此外，转录组测序的卵母细胞和逮捕胚胎含有这些变体建议更多的差异表达的转录本在生发囊泡（GV）卵母细胞比在1-细胞胚胎。在GV期卵母细胞和1-细胞期胚胎中，与能量代谢和细胞周期进程相关的重要基因表达显著下调，而与DNA修复相关的基因表达显著上调。这些发现强调了TRIP 13在减数分裂和有丝分裂中的关键作用，以及扩大了TR 1 P13变体与女性不育，特别是与ZCF相关的遗传和表型谱。
Zygotic cleavage failure (ZCF) is a severe, early type of embryonic arrest in which zygotes cannot complete the first cleavage. Although mutations in BTG4 and CHEK1 have been identified as genetic causes of ZCF, these genes only explain a small population of ZCF cases. Thus, the underlying genetic causes for other affected individuals need to be identified. Here, we identified three TRIP13 missense variants responsible for ZCF in two patients and showed that they followed a recessive inheritance pattern. All three variants resulted in obvious changes in hydrogen bonding and consistent increase in DNA damage. Additionally, transcriptomic sequencing of oocytes and arrested embryos containing these variants suggested a greater number of differentially expressed transcripts in germinal vesicle (GV) oocytes than in 1-cell embryos. Vital genes for energy metabolism and cell cycle procession were widely and markedly downregulated, while DNA repair-related genes were significantly upregulated in both GV oocytes and 1-cell embryos of patients. These findings highlight a critical role of TRIP13 in meiosis and mitosis, as well as expand the genetic and phenotypic spectra of TR1P13 variants with respect to female infertility, especially in relation to ZCF.
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