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.
Clinical genetics. 2023 Dec 26 [Epub ahead of print]
Shuai Xu, Jingpeng Zhao, Feng Gao, Yuxiang Zhang, Jiaqiang Luo, Chenwang Zhang, Ruhui Tian, Erlei Zhi, Jianxiong Zhang, Furong Bai, Hongfang Sun, Fujun Zhao, Yuhua Huang, Peng Li, Liren Jiang, Zheng Li, Chencheng Yao, Zhi Zhou
School of Life Science and Technology, ShanghaiTech University, Shanghai, China., State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China., Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 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.