Zheng Rui, Wang Yan, Li Yaqian, Guo Juncen, Wen Yuting, Jiang Chuan, Yang Yihong, Shen Ying
Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, China.
Reproduction Medical Center of West China Second University Hospital, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan, China.
J Med Genet. 2023 Mar;60(3):254-264. doi: 10.1136/jmedgenet-2021-108406. Epub 2022 Jun 2.
Loss-of-function mutations in result in multiple morphological abnormalities of the flagella in humans and mice. Intriguingly, a recent study found that FSIP2 might regulate the expression of acrosomal proteins, indicating that might be involved in acrosome development in mice. However, whether also function in acrosome biogenesis in humans is largely unknown, and the underlying mechanism of which is unexplored.
Our objective was to reveal potential function of FSIP2 in regulating sperm acrosome formation.
We performed whole exome sequencing on four asthenoteratozoospermic patients. Western blot analysis and immunofluorescence staining were conducted to assess the protein expression of FSIP2. Proteomics approach, liquid chromatography-tandem mass spectrometry and co-immunoprecipitation were implemented to clarify the molecules in acrosome biogenesis regulated by FSIP2.
Biallelic variants were identified in four asthenoteratozoospermic individuals. The protein expression of MUT- was sharply decreased or absent in vitro or in vivo. Interestingly, aside from the sperm flagellar defects, the acrosomal hypoplasia was detected in numerous sperm from the four patients. FSIP2 co-localised with peanut agglutinin in the acrosome during spermatogenesis. Moreover, FSIP2 interacted with proteins (DPY19L2, SPACA1, HSP90B1, KIAA1210, HSPA2 and CLTC) involved in acrosome biogenesis. In addition, spermatozoa from patients carrying mutations showed downregulated expression of DPY19L2, ZPBP, SPACA1, CCDC62, CCIN, SPINK2 and CSNK2A2.
Our findings unveil that might involve in sperm acrosome development, and consequently, its mutations might contribute to globozoospermia or acrosomal aplasia. We meanwhile first uncover the potential molecular mechanism of FSIP2 regulating acrosome biogenesis.
[基因名称]功能丧失突变会导致人类和小鼠鞭毛出现多种形态异常。有趣的是，最近一项研究发现FSIP2可能调节顶体蛋白的表达，这表明[基因名称]可能参与小鼠顶体发育。然而，[基因名称]在人类顶体生物发生中是否也发挥作用很大程度上未知，其潜在机制也未被探索。
我们的目的是揭示FSIP2在调节精子顶体形成中的潜在功能。
我们对4例弱畸精子症患者进行了全外显子组测序。进行蛋白质印迹分析和免疫荧光染色以评估FSIP2的蛋白表达。采用蛋白质组学方法、液相色谱-串联质谱和免疫共沉淀来阐明受FSIP2调节的顶体生物发生中的分子。
在4例弱畸精子症个体中鉴定出双等位基因[基因名称]变异。MUT-[基因名称]的蛋白表达在体外或体内急剧下降或缺失。有趣的是，除了精子鞭毛缺陷外，在这4例患者的大量精子中还检测到顶体发育不全。在精子发生过程中，FSIP2与花生凝集素在顶体中共定位。此外，FSIP2与参与顶体生物发生的蛋白质（DPY19L2、SPACA1、HSP90B1、KIAA1210、HSPA2和CLTC）相互作用。此外，携带[基因名称]突变的患者的精子显示DPY19L2、ZPBP、SPACA1、CCDC62、CCIN、SPINK2和CSNK2A2的表达下调。
我们的研究结果揭示[基因名称]可能参与精子顶体发育，因此，其突变可能导致圆头精子症或顶体发育不全。我们同时首次揭示了FSIP2调节顶体生物发生的潜在分子机制。
