【摘要】 不育症困扰世界范围内约10%～15%的育龄夫妇.男性不育常由少精、弱精、畸形精子症等引起,表现为精子数量减少、精子运动能力降低、精子鞭毛多发性形态异常(MMAF)以及这些多重缺陷的组合.研究发现AKAP、CCDC、CFAP和DNAH等基因家族与精子鞭毛多发性形态异常相关.然而已知的MMAF基因只能解释大约60%的MMAF病例,因此MMAF存在遗传异质性,仍有未知的MMAF致病相关基因需要挖掘.本文通过构建睾丸中特异表达的CFAP61基因的敲除小鼠,发现雄鼠不育、精子活力下降和MMAF,提示CFAP61基因可能参与人类男性少弱畸精子症或其他纤毛疾病导致男性不育.更多还原

【Abstract】 Impaired flagellar development and impaired motility of sperm is a cause of infertility in males. Several genes, including those of the AKAP, CCDC, CFAP, and DNAH families, among others, are involved in the‘‘multiple morphological abnormalities of the flagella"(MMAF) phenotype; these are the most common causes of male infertility. The Cilia-and flagella-associated protein(CFAP) family includes six members reported to cause MMAF phenotypes: CFAP43, CFAP44, CFAP69, CFAP65, CFAP70, and CFAP251. Here, we found that cilia-and flagella-associated protein 61(Cfap61) is highly expressed specifically in murine testes and show that the Cfap61-knockout male mice demonstrate MMAF phenotype, including sperm with short, coiled, and irregular flagella. Deletion of Cfap61 resulted in severe morphological and behavior abnormalities in sperm, reduced total sperm counts, impaired sperm motility, and led to male infertility.Notably, absence of Cfap61 impaired sperm flagella ultrastructural abnormalities on account of numerous distortions in multiple flagellum components. Immunostaining experiments in wild-type mice and healthy adult humans indicated that Cfap61 is initially localized at the neck of sperm, where it potentially functions in flagellum formation, and is later localized to the midpiece of the sperm. Thus, our study provides compelling evidence that dysregulation of Cfap61 affects sperm flagellum development and induces male infertility in mice. Further investigations of the CFAP61 gene in humans alongside clinical evidence showing MMAF phenotype in humans should contribute to our understanding of developmental processes underlying sperm flagellum formation and the pathogenic mechanisms that cause male infertility.更多还原