PDF(Pubmed)
Abstract：
From a cohort of 167 infertile patients suffering from multiple morphological abnormalities of the flagellum (MMAF), pathogenic bi-allelic mutations were identified in the CCDC146 gene. In somatic cells, CCDC146 is located at the centrosome and at multiple microtubule-related organelles during mitotic division, suggesting that it is a microtubule-associated protein (MAP). To decipher the molecular pathogenesis of infertility associated with CCDC146 mutations, a Ccdc146 knock-out (KO) mouse line was created. KO male mice were infertile, and sperm exhibited a phenotype identical to CCDC146 mutated patients. CCDC146 expression starts during late spermiogenesis. In the spermatozoon, the protein is conserved but is not localized to centrioles, unlike in somatic cells, rather it is present in the axoneme at the level of microtubule doublets. Expansion microscopy associated with the use of the detergent sarkosyl to solubilize microtubule doublets suggests that the protein may be a microtubule inner protein (MIP). At the subcellular level, the absence of CCDC146 impacted all microtubule-based organelles such as the manchette, the head-tail coupling apparatus (HTCA), and the axoneme. Through this study, a new genetic cause of infertility and a new factor in the formation and/or structure of the sperm axoneme were characterized.
摘要：
来自167名患有多种鞭毛形态异常（MMAF）的不育患者，在CCDC146基因中鉴定出致病性双等位基因突变.在体细胞中，CCDC146位于有丝分裂过程中的中心体和多个微管相关细胞器，表明它是一种微管相关蛋白（MAP）。为了破译与CCDC146突变相关的不孕症的分子发病机制，产生Ccdc146敲除(KO)小鼠系。KO雄性小鼠不育，精子表现出与CCDC146突变患者相同的表型。CCDC146表达在晚期精子发生期间开始。在精子中，蛋白质是保守的，但不局限于中心粒，与体细胞不同，相反，它以微管双峰的水平存在于轴突中。与使用洗涤剂sarkosyl溶解微管双合蛋白相关的扩展显微镜表明，该蛋白质可能是微管内部蛋白质（MIP）。在亚细胞水平,CCDC146的缺失影响了所有基于微管的细胞器，如Manchette，头尾耦合装置（HTCA），和轴突。通过这项研究,对不育的新遗传原因和精子轴突形成和/或结构的新因素进行了表征。
