School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Department of Andrology, Center for Men's Health, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Clin Genet. 2024 Apr;105(4):440-445. doi: 10.1111/cge.14473. Epub 2023 Dec 26.
Nonobstructive azoospermia (NOA), the most severe manifestation of male infertility, lacks a comprehensive understanding of its genetic etiology. Here, a bi-allelic loss-of-function variant in REC114 (c.568C > T: p.Gln190*) were identified through whole exome sequencing (WES) in a Chinese NOA patient. Testicular histopathological analysis and meiotic chromosomal spread analysis were conducted to assess the stage of spermatogenesis arrested. Co-immunoprecipitation (Co-IP) and Western blot (WB) were used to investigate the influence of variant in vitro. In addition, our results revealed that the variant resulted in truncated REC114 protein and impaired interaction with MEI4, which was essential for meiotic DNA double-strand break (DSB) formation. As far as we know, this study presents the first report that identifies REC114 as the causative gene for male infertility. Furthermore, our study demonstrated indispensability of the REC114-MEI4 complex in maintaining DSB homoeostasis, and highlighted that the disruption of the complex due to the REC114 variant may underline the mechanism of NOA.
非梗阻性无精子症（NOA）是男性不育症最严重的表现形式，其遗传病因尚不完全清楚。在这里，通过对一名中国 NOA 患者进行全外显子组测序（WES），鉴定出 REC114 中的双等位基因功能丧失变异（c.568C>T：p.Gln190*）。通过睾丸组织学分析和减数分裂染色体铺展分析来评估生精阻滞的阶段。通过共免疫沉淀（Co-IP）和 Western blot（WB）实验来研究体外变异的影响。此外，我们的结果表明，该变异导致 REC114 蛋白截短，并损害了其与 MEI4 的相互作用，而 MEI4 对于减数分裂 DNA 双链断裂（DSB）的形成至关重要。据我们所知，这项研究首次报道了 REC114 是男性不育的致病基因。此外，我们的研究表明 REC114-MEI4 复合物在维持 DSB 同源性方面不可或缺，并强调由于 REC114 变异导致复合物的破坏可能是 NOA 的机制之一。
