Liu Wenjing, Sun Xiya, Li Fubing, Jiang Qiuyun, An Jianting, Wu Yingying, Yang Jingyi, Qin Meng, Zhao Yuxin, Tang Yongjia, Wu Tingyue, Yan Zhiqiang, Jiang Dewei, Liu Rong, Li Wenhui, Zhi Xu, Chen Ceshi
The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China; Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China.
State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China.
J Adv Res. 2025 Jul;73:231-245. doi: 10.1016/j.jare.2024.08.011. Epub 2024 Aug 12.
Homologous recombination repair during meiosis is essential for the exchange of genetic information between sister chromosomes, underpinning spermatogenesis and, consequently, fertility. The disruption of this process can lead to infertility, highlighting the importance of identifying the molecular actors involved.
This study aims to elucidate the role of the E3 ubiquitin ligase Rnf126 in spermatogenesis and its impact on fertility, particularly through its involvement in meiotic homologous recombination repair.
We used heterozygous and homozygous Rnf126 deletion models in mouse testes to examine the consequences on testicular health, sperm count, and the process of spermatogenesis. Additionally, we explored the association between RNF126 gene missense variants and nonobstructive male infertility in patients, with a focus on their functional impact on the protein's ubiquitin ligase activity.
Rnf126 deletion led to testicular atrophy, disrupted seminiferous tubule structure, reduced sperm count, and spermatogenesis arrest at meiotic prophase I. Furthermore, male mice exhibited impaired homologous recombination repair and increased apoptosis within the seminiferous tubules. We identified four missense variants of the RNF126 (V68M, R241H, E261A, D253N) associated with male infertility. Specifically, the E261A and D253N variants, located in the RING domain, directly compromised the E3 ubiquitin ligase activity of RNF126.
Our findings demonstrate the pivotal role of RNF126 in maintaining spermatogenesis and fertility, offering insights into the molecular mechanisms underlying male infertility. The identified RNF126 variants present novel targets for diagnostic and therapeutic strategies in treating nonobstructive male infertility.
减数分裂期间的同源重组修复对于姐妹染色体之间的遗传信息交换至关重要，它是精子发生以及生育能力的基础。这一过程的破坏会导致不育，凸显了识别其中涉及的分子因素的重要性。
本研究旨在阐明E3泛素连接酶Rnf126在精子发生中的作用及其对生育能力的影响，特别是通过其参与减数分裂同源重组修复的过程。
我们在小鼠睾丸中使用了杂合和纯合Rnf126缺失模型，以研究对睾丸健康、精子数量和精子发生过程的影响。此外，我们探讨了RNF126基因错义变体与男性不育患者非梗阻性男性不育之间的关联，重点关注它们对蛋白质泛素连接酶活性的功能影响。
Rnf126缺失导致睾丸萎缩、生精小管结构破坏、精子数量减少以及精子发生在减数分裂前期I停滞。此外，雄性小鼠表现出同源重组修复受损，生精小管内细胞凋亡增加。我们鉴定出与男性不育相关的RNF126的四个错义变体（V68M、R241H、E261A、D253N）。具体而言，位于RING结构域的E261A和D253N变体直接损害了RNF126的E3泛素连接酶活性。
我们的研究结果表明RNF126在维持精子发生和生育能力方面起着关键作用，为男性不育的分子机制提供了见解。所鉴定的RNF126变体为治疗非梗阻性男性不育的诊断和治疗策略提供了新的靶点。
