鞭毛发育受损和精子运动性受损是男性不育的原因。几个基因,包括AKAP的那些,CCDC,CFAP,和DNAH家族,其中,涉及“鞭毛的多种形态异常”(MMAF)表型;这些是男性不育的最常见原因。纤毛和鞭毛相关蛋白(CFAP)家族包括六个据报道引起MMAF表型的成员:CFAP43,CFAP44,CFAP69,CFAP65,CFAP70和CFAP251。这里,我们发现纤毛和鞭毛相关蛋白61(Cfap61)在小鼠睾丸中特异性高表达,并表明Cfap61敲除雄性小鼠表现出MMAF表型,包括短精子,盘绕,和不规则的鞭毛。Cfap61缺失导致精子严重的形态和行为异常,精子总数减少,精子运动受损,导致男性不育.值得注意的是,由于多个鞭毛成分中的许多变形,Cfap61的缺失损害了精子鞭毛的超微结构异常。野生型小鼠和健康成年人的免疫染色实验表明,Cfap61最初位于精子的颈部,它可能在鞭毛形成中起作用,后来定位于精子的中部。因此,我们的研究提供了令人信服的证据,证明Cfap61的失调会影响精子鞭毛的发育并导致小鼠男性不育.对人类CFAP61基因的进一步研究以及显示人类MMAF表型的临床证据应有助于我们对精子鞭毛形成的发育过程和导致男性不育的致病机制的理解。
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.