Department of Andrology, Center for Men's Health, Department of ART, Institute of Urology, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
J Hum Genet. 2023 Jun;68(6):383-392. doi: 10.1038/s10038-023-01119-3. Epub 2023 Feb 10.
Non-obstructive azoospermia (NOA) is characterized by the failure of sperm production due to testicular disorders and represents the most severe form of male infertility. Growing evidences have indicated that gene defects could be the potential cause of NOA via genome-wide sequencing approaches. Here, bi-allelic deleterious variants in meiosis inhibitor protein 1 (MEI1) were identified by whole-exome sequencing in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro. Furthermore, the missense variant (c.T1585A) was assumed to affect the interaction between MEI1 and its partners via bioinformatic analysis. Collectively, our findings provide direct genetic and functional evidences that bi-allelic variants in MEI1 could cause defective DSBs homoeostasis and meiotic chromosome synapsis, which subsequently lead to meiosis arrest and male infertility. Thus, our study deepens our knowledge of the role of MEI1 in male fertility and provides a novel insight to understand the genetic aetiology of NOA.
非阻塞性无精子症（NOA）的特征是由于睾丸疾病导致精子生成失败，代表了男性不育症最严重的形式。越来越多的证据表明，通过全基因组测序方法，基因缺陷可能是 NOA 的潜在原因。在这里，通过全外显子组测序在四名患有 NOA 的中国患者中鉴定出减数分裂抑制剂蛋白 1（MEI1）的双等位基因有害变异。睾丸病理分析和免疫组织化学染色显示，携带变异的患者的精子发生在精母细胞阶段停滞，存在缺陷的程序性 DNA 双链断裂（DSBs）稳态和减数分裂染色体联会。此外，我们的结果表明，一个错义变异（c.G186C）降低了 MEI1 的表达，一个移码变异（c.251delT）导致 MEI1 的截短蛋白在体外。此外，通过生物信息学分析假设错义变异（c.T1585A）会影响 MEI1 与其伴侣之间的相互作用。总之，我们的研究结果提供了直接的遗传和功能证据，证明 MEI1 的双等位基因变异可导致 DSBs 稳态和减数分裂染色体联会缺陷，进而导致减数分裂停滞和男性不育。因此，我们的研究加深了我们对 MEI1 在男性生育中的作用的认识，并为理解 NOA 的遗传病因提供了新的见解。
