Karyopherin α deficiency contributes to human preimplantation embryo arrest.
Karyopherin α deficiency contributes to human preimplantation embryo arrest.
复制标题
DOI：
10.1172/jci159951
复制
发表时间：
2023-01-17
影响因子：
15.9
通讯作者：
Sang, Qing
中科院分区：
文献类型：
--
作者：
Wang, Wenjing;Miyamoto, Yoichi;Chen, Biaobang;Shi, Juanzi;Diao, Feiyang;Zheng, Wei;Li, Qun;Yu, Lan;Li, Lin;Xu, Yao;Wu, Ling;Mao, Xiaoyan;Fu, Jing;Li, Bin;Yan, Zheng;Shi, Rong;Xue, Xia;Mu, Jian;Zhang, Zhihua;Wu, Tianyu;Zhao, Lin;Wang, Weijie;Zhou, Zhou;Dong, Jie;Li, Qiaoli;Jin, Li;He, Lin;Sun, Xiaoxi;Lin, Ge;Kuang, Yanping;Wang, Lei;Sang, Qing
胚胎着床前骤停（PREMBA）是女性不育和辅助生殖技术反复失败的常见原因。然而，PREMBA的遗传基础在很大程度上是未知的。在这里，我们使用606名患有PREMBA的女性的全外显子组测序数据，与2,813名对照组进行比较，我们进行了基于群体和基因的负担测试，并确定了一个候选基因，核细胞蛋白亚基α7 （KPNA7）。体外研究表明，鉴定的序列变异降低了KPNA7蛋白水平，损害了KPNA7与其底物核糖体L1结构域蛋白1 （RSL1D1）的结合能力，并影响了KPNA7核转运活性。人和小鼠的比较表明，小鼠的KPNA2而不是小鼠的KPNA7在胚胎发育中起重要的核细胞蛋白作用。Kpna2 - / -雌性小鼠由于合子基因组激活缺陷而出现胚胎停滞，再现了人类PREMBA的表型。此外，卵母细胞特异性敲除Rsl1d1的雌性小鼠再现了Kpna2 - / -小鼠的表型，证明了底物Rsl1d1的重要作用。最后，补充RNA （cRNA）显微注射人类KPNA7，而不是小鼠KPNA7，能够挽救Kpna2 - / -小鼠的胚胎停滞表型，这表明小鼠Kpna2可能是人类KPNA7的同源物。我们的发现揭示了PREMBA的发病机制，它通过损害核蛋白转运而起作用，并为PREMBA患者提供了一个诊断标志。
Preimplantation embryo arrest (PREMBA) is a common cause of female infertility and recurrent failure of assisted reproductive technology. However, the genetic basis of PREMBA is largely unrevealed. Here, using whole-exome sequencing data from 606 women experiencing PREMBA compared with 2,813 controls, we performed a population and gene–based burden test and identified a candidate gene, karyopherin subunit α7 (KPNA7). In vitro studies showed that identified sequence variants reduced KPNA7 protein levels, impaired KPNA7 capacity for binding to its substrate ribosomal L1 domain-containing protein 1 (RSL1D1), and affected KPNA7 nuclear transport activity. Comparison between humans and mice suggested that mouse KPNA2, rather than mouse KPNA7, acts as an essential karyopherin in embryonic development. Kpna2–/– female mice showed embryo arrest due to zygotic genome activation defects, recapitulating the phenotype of human PREMBA. In addition, female mice with an oocyte-specific knockout of Rsl1d1 recapitulated the phenotype of Kpna2–/– mice, demonstrating the vital role of substrate RSL1D1. Finally, complementary RNA (cRNA) microinjection of human KPNA7, but not mouse Kpna7, was able to rescue the embryo arrest phenotype in Kpna2–/– mice, suggesting mouse KPNA2 might be a homologue of human KPNA7. Our findings uncovered a mechanistic understanding for the pathogenesis of PREMBA, which acts by impairing nuclear protein transport, and provide a diagnostic marker for PREMBA patients.
影响因子：
--
作者：
Bogolyubova IO;Bogolyubov DS
通讯作者：
Bogolyubov DS