Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile men and cynomolgus monkey and tree shrew models.
Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile men and cynomolgus monkey and tree shrew models.
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DOI：
10.1016/j.ajhg.2023.01.016
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发表时间：
2023-02
影响因子：
9.8
通讯作者：
Chunyu Liu;W. Si;C. Tu;Shixiong Tian;Xiaojin He;Shengnan Wang;Xiaoyu Yang;C. Yao;Cong Li;Z. Kherraf;Maosen Ye;Zixue Zhou;Yuhua Ma;Yang Gao;Y. Li;Qiwei Liu;Shuyan Tang;Jiaxiong Wang;H. Saiyin;Liangyu Zhao;Liqun Yang;L. Meng;Bingbing Chen;D. Tang;Yiling Zhou;Huan Wu;Mingrong Lv;C. Tan;G. Lin;Qingpeng Kong;Hong Shi;Zhixi Su;Zheng Li;Yong-Gang Yao;L. Jin;Ping Zheng;P. Ray;Y. Tan;Yunxia Cao;Feng Zhang
中科院分区：
文献类型：
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作者：
Chunyu Liu;W. Si;C. Tu;Shixiong Tian;Xiaojin He;Shengnan Wang;Xiaoyu Yang;C. Yao;Cong Li;Z. Kherraf;Maosen Ye;Zixue Zhou;Yuhua Ma;Yang Gao;Y. Li;Qiwei Liu;Shuyan Tang;Jiaxiong Wang;H. Saiyin;Liangyu Zhao;Liqun Yang;L. Meng;Bingbing Chen;D. Tang;Yiling Zhou;Huan Wu;Mingrong Lv;C. Tan;G. Lin;Qingpeng Kong;Hong Shi;Zhixi Su;Zheng Li;Yong-Gang Yao;L. Jin;Ping Zheng;P. Ray;Y. Tan;Yunxia Cao;Feng Zhang
灵长类动物特异性基因（PSG）往往在大脑和睾丸中表达。这种现象与灵长类动物的大脑进化一致，但似乎与哺乳动物精子发生的相似性相矛盾。在这里，我们使用全外显子组测序，在六名无关的弱精子症男性中鉴定出了 X 连锁 SSX1 的有害变异。SSX1 是一种主要在睾丸中表达的 PSG，SSX 家族在啮齿类动物和灵长类动物中独立进化扩展。由于小鼠模型不能用于研究SSX1，我们使用非人类灵长类动物模型和树鼩（在系统发育上与灵长类动物相似）来敲低睾丸中的（KD）Ssx1表达。与在人类中观察到的表型一致，两种 Ssx1-KD 模型均表现出精子活力降低和精子形态异常。此外，RNA测序表明Ssx1缺陷影响精子发生过程中的多个生物过程。总的来说，我们在人类、食蟹猴和树鼩模型中的实验观察强调了SSX1在精子发生中的关键作用。值得注意的是，接受胞浆内单精子注射治疗的五对夫妇中，有三对成功怀孕。这项研究为遗传咨询和临床诊断提供了重要的指导，并且重要的是描述了阐明富含睾丸的 PSG 在精子发生中的功能的方法。
Primate-specific genes (PSGs) tend to be expressed in the brain and testis. This phenomenon is consistent with brain evolution in primates but is seemingly contradictory to the similarity of spermatogenesis among mammals. Here, using whole-exome sequencing, we identified deleterious variants of X-linkedSSX1in six unrelated men with asthenoteratozoospermia.SSX1is a PSG expressed predominantly in the testis, and theSSXfamily evolutionarily expanded independently in rodents and primates. As the mouse model could not be used for studyingSSX1, we used a non-human primate model and tree shrews, which are phylogenetically similar to primates, to knock down (KD)Ssx1expression in the testes. Consistent with the phenotype observed in humans, bothSsx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology. Further, RNA sequencing indicated thatSsx1deficiency influenced multiple biological processes during spermatogenesis. Collectively, our experimental observations in humans and cynomolgus monkey and tree shrew models highlight the crucial role ofSSX1in spermatogenesis. Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy. This study provides important guidance for genetic counseling and clinical diagnosis and, significantly, describes the approaches for elucidating the functions of testis-enriched PSGs in spermatogenesis.