Gabriel George C, Lo Cecilia W
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, United States of America.
Prog Pediatr Cardiol. 2019 Sep;54. doi: 10.1016/j.ppedcard.2019.101128. Epub 2019 Jul 10.
We recently conducted a large-scale mouse mutagenesis screen and uncovered a central role for cilia in the pathogenesis of congenital heart disease (CHD). Though our screen was phenotype based, most of the genes recovered were cilia-related, including genes encoding proteins important for ciliogenesis, cilia-transduced cell signaling, and vesicular trafficking. Also unexpected, many of the cilia related genes recovered are known direct protein-protein interactors, even though each gene was recovered independently in unrelated mouse lines. These findings suggest a cilia-based protein-protein interactome network may provide the context for congenital heart disease pathogenesis. This could explain the incomplete penetrance and variable expressivity of human CHD, and account for its complex non-Mendelian etiology. Supporting these findings in mice, a preponderance of cilia and cilia related cell signaling genes were observed among de novo pathogenic variants identified in a CHD patient cohort. Further clinical relevance unfolded with the observation of a high prevalence of respiratory cilia dysfunction in CHD patients. This was associated with increased postsurgical respiratory complications. Together these findings highlight the importance of cilia in CHD pathogenesis and suggest possible clinical translation with instituting pulmonary therapy to improve outcome for CHD patients undergoing congenital cardiac surgeries.
我们最近进行了一项大规模的小鼠诱变筛选，发现纤毛在先天性心脏病（CHD）发病机制中起核心作用。尽管我们的筛选基于表型，但回收的大多数基因都与纤毛相关，包括编码对纤毛发生、纤毛转导的细胞信号传导和囊泡运输重要的蛋白质的基因。同样出乎意料的是，回收的许多与纤毛相关的基因是已知的直接蛋白质-蛋白质相互作用因子，尽管每个基因都是在不相关的小鼠品系中独立回收的。这些发现表明基于纤毛的蛋白质-蛋白质相互作用组网络可能为先天性心脏病发病机制提供背景。这可以解释人类CHD的不完全外显率和可变表达性，并解释其复杂的非孟德尔病因。在小鼠中支持这些发现的是，在一个CHD患者队列中鉴定出的新生致病性变体中，观察到大量纤毛和与纤毛相关的细胞信号基因。随着观察到CHD患者中呼吸纤毛功能障碍的高患病率，进一步揭示了临床相关性。这与术后呼吸并发症增加有关。这些发现共同强调了纤毛在CHD发病机制中的重要性，并表明通过实施肺部治疗可能进行临床转化，以改善接受先天性心脏手术的CHD患者的预后。
