钙通道基因CATSPER2纯合移码突变（c.834delC）导致受精障碍和男性不育

受精障碍是不明原因男性不育的重要原因，目前尚无方法准确预测精子是否存在受精障碍。CatSper钙通道在受精中起重要作用，研究发现包含CATSPER2等多个基因的染色体片段缺失可能与男性不育有关，但尚未见CATSPER2单基因突变导致不育的报道。本课题组在不明原因男性不育家系中发现CATSPER2纯合移码突变(c.834delC)，其精子超活化、顶体反应和钙内流消失。据此，我们认为该突变可影响CatSper钙通道的组装，阻断精子钙内流，抑制超活化和顶体反应，导致受精障碍和男性不育。本项目将研究该家系不育男性精子的受精能力，以及钙离子载体和ICSI对受精能力的补救作用；建立基因敲入小鼠模型明确突变的功能；通过蛋白分子互作研究阐明其发挥作用的分子机制；并在IVF受精障碍散发病例中对CATSPER2及其家族基因进行突变筛查。以期发现精子受精障碍的原因和机制，为相关男性不育的诊治提供新靶点和新思路。

Fertilization failure is one of the common reasons causing male infertility. No assay can accurately predict the fertilization capability of a given sperm sample till now. CatSper calcium channel plays an important role in the process of fertilization. Previous studies showed that chromosome deletion involving several genes including CATSPER2 was associated with fertilization failure. However, However, a single mutation in CATSPER2 gene leading to human fertilization failure has not been reported yet. In our previous study, we found a homozygous frameshift mutation of CATSPER2(c.834delC) in a male infertile family. Furthermore, we found the disruption of sperm hyperactivation, acrosome reaction and calcium influx in the family. Combined with the literature, we suggest that this mutation can disrupt the assembly of CatSper channel, then inhibit sperm calcium influx, hyperactivation and acrosome reaction, leading to fertilization failures and male infertility. This project will analyze the fertilization capability and the remedial effect of calcium ionophoreon and ICSI on fertilization capability in sperm of male infertile members of this family, The knock-in mouse model of CATSPER2 frameshift mutation (c.834delC) will be established to verify the phenotype and mechanism of the mutant. Gene mutation screening and analysis of CATSPER2 and CATSPER2 family will also be carried out for sporadic cases of IVF fertilization failure. This study will help to elucidate the causes and mechanisms of fertilization failures and provide new targets and ideas for the diagnosis and treatment of asscociated male infertility.