Rao Damerla Rama, Gabriel George C, Li You, Klena Nikolai T, Liu Xiaoqin, Chen Yu, Cui Cheng, Pazour Gregory J, Lo Cecilia W
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Birth Defects Res C Embryo Today. 2014 Jun;102(2):115-25. doi: 10.1002/bdrc.21067.
Structural birth defect (SBD) is a major cause of morbidity and mortality in the newborn period. Although the etiology of SBD is diverse, a wide spectrum of SBD associated with ciliopathies points to the cilium as having a central role in the pathogenesis of SBDs. Ciliopathies are human diseases arising from disruption of cilia structure and/or function. They are associated with developmental anomalies in one or more organ systems and can involve defects in motile cilia, such as those in the airway epithelia or from defects in nonmotile (primary cilia) that have sensory and cell signaling function. Availability of low cost next generation sequencing has allowed for explosion of new knowledge in genetic etiology of ciliopathies. This has led to the appreciation that many genes are shared in common between otherwise clinically distinct ciliopathies. Further insights into the relevance of the cilium in SBD has come from recovery of pathogenic mutations in cilia-related genes from many large-scale mouse forward genetic screens with differing developmental phenotyping focus. Our mouse mutagenesis screen for congenital heart disease (CHD) using noninvasive fetal echocardiography has yielded a marked enrichment for pathogenic mutations in genes required for motile or primary cilia function. These novel mutant mouse models will be invaluable for modeling human ciliopathies and further interrogating the role of the cilium in the pathogenesis of SBD and CHD. Overall, these findings suggest a central role for the cilium in the pathogenesis of a wide spectrum of developmental anomalies associated with CHD and SBDs.
结构性出生缺陷（SBD）是新生儿发病和死亡的主要原因。尽管SBD的病因多种多样，但与纤毛病相关的广泛SBD表明纤毛在SBD的发病机制中起核心作用。纤毛病是由纤毛结构和/或功能破坏引起的人类疾病。它们与一个或多个器官系统的发育异常有关，可能涉及运动性纤毛的缺陷，如气道上皮中的纤毛，或具有感觉和细胞信号功能的非运动性（原发性）纤毛的缺陷。低成本下一代测序技术的出现，使得纤毛病遗传病因学的新知识激增。这使得人们认识到，在临床上不同的纤毛病之间，许多基因是共有的。对纤毛在SBD中的相关性的进一步认识，来自于许多大规模小鼠正向遗传筛选中，从具有不同发育表型重点的纤毛相关基因中发现的致病突变。我们使用无创胎儿超声心动图对先天性心脏病（CHD）进行的小鼠诱变筛选，显著富集了运动性或原发性纤毛功能所需基因中的致病突变。这些新型突变小鼠模型对于模拟人类纤毛病，以及进一步探究纤毛在SBD和CHD发病机制中的作用将具有重要价值。总体而言，这些发现表明纤毛在与CHD和SBD相关的广泛发育异常的发病机制中起核心作用。
