Zhang Honghui, Su Wei, Jiang Xiaohong, Wang Yang, Yang Bohan, Wan Xian, Li Cheng, Zhao Shuai, Zhang Changlong, Zhao Shigang, Bian Yuehong, Li Mei, Wu Keliang, Gong Fei, Lin Ge, Zheng Wei, Zhao Han, Chen Zi-Jiang
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, China.
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, China.
Sci China Life Sci. 2025 May 29. doi: 10.1007/s11427-024-2837-9.
Preimplantation embryo arrest is a common cause of female infertility and recurrent failure of assisted reproductive technology. However, its genetic basis is largely unrevealed. Geminin, encoded by the GMNN gene, plays an important role in preventing DNA re-replication by inhibiting CDT1. Here, using whole-exome sequencing and Sanger sequencing, we identified three rare missense mutations of GMNN in females with preimplantation arrest, following a dominant inheritance pattern. The RNA sequencing data from both the mouse zygotes and the patient's one-cell embryo demonstrated the altered cell cycle processes. We then found that these mutations decreased the binding with CDT1 and resulted in activation of CHK1 and DNA damage, resulting in cell cycle disturbance. Our findings uncover a mechanistic understanding of the pathogenesis of human preimplantation embryo arrest, which acts by impairing the correct cell cycle and DNA re-replication procedure, and provides a new molecular target for the diagnosis and treatment of infertile patients.
植入前胚胎停滞是女性不孕和辅助生殖技术反复失败的常见原因。然而，其遗传基础在很大程度上尚未揭示。由GMNN基因编码的Geminin通过抑制CDT1在防止DNA重新复制中起重要作用。在这里，我们使用全外显子组测序和桑格测序，在具有植入前停滞的女性中鉴定出GMNN的三个罕见错义突变，遵循显性遗传模式。来自小鼠受精卵和患者单细胞胚胎的RNA测序数据表明细胞周期过程发生了改变。然后我们发现这些突变减少了与CDT1的结合，并导致CHK1激活和DNA损伤，从而导致细胞周期紊乱。我们的研究结果揭示了对人类植入前胚胎停滞发病机制的机制性理解，其通过损害正确的细胞周期和DNA重新复制过程起作用，并为不孕患者的诊断和治疗提供了新的分子靶点。
