PDF(Pubmed)
Abstract：
Introduction: Primary ciliary dyskinesia (PCD) is caused by the dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. This study aimed to map novel PCD variants and determine their pathogenicity in PCD patients in Kuwait. Methods: Herein, we present five PCD individuals belonging to a cohort of 105 PCD individuals recruited from different hospitals in Kuwait. Genomic DNAs from the family members were analysed to screen for pathogenic PCD variants. Transmission electron microscopy (TEM) and immunofluorescence (IF) analyses were performed on the nasal biopsies to detect specific structural abnormalities within the ciliated cells. Results: Genetic screening and functional analyses confirmed that the five PCD individuals carried novel pathogenic variants of DNAH5 causing PCD in three Arabic families. Of these, one multiplex family with two affected individuals showed two novel homozygous missense variants in DNAH5 causing PCD with situs inversus; another multiplex family with two affected individuals showed two newly identified compound heterozygous variants in DNAH5 causing PCD with situs solitus. In addition, novel heterozygous variants were identified in a child with PCD and situs solitus from a singleton family with unrelated parents. TEM analysis demonstrated the lack of outer dynein arms (ODAs) in all analysed samples, and IF analysis confirmed the absence of the dynein arm component of DNAH5 from the ciliary axoneme. Conclusion: The newly identified pathogenic variants of DNAH5 are associated with PCD as well as variable pulmonary clinical manifestations in Arabic families.
摘要：
简介：原发性纤毛运动障碍（PCD）是由活动纤毛的功能障碍引起的，导致肺部的粘液纤毛清除不足。这项研究旨在绘制新的PCD变体，并确定其在科威特PCD患者中的致病性。方法：这里，我们介绍了5名PCD个体,他们属于从科威特不同医院招募的105名PCD个体.分析来自家族成员的基因组DNA以筛选致病性PCD变体。对鼻活检进行透射电子显微镜（TEM）和免疫荧光（IF）分析，以检测纤毛细胞内的特定结构异常。结果：遗传筛选和功能分析证实，五个PCD个体携带DNAH5的新致病变体，导致三个阿拉伯家族的PCD。其中,一个具有两个受影响个体的多重家族在DNAH5中显示出两个新的纯合错义变体，导致具有反向位点的PCD；另一个具有两个受影响个体的多重家族在DNAH5中显示出两个新鉴定的复合杂合变体，导致具有反向位点的PCD。此外,在患有PCD的儿童中发现了新的杂合变体，并且来自父母无关的单例家庭。TEM分析表明，所有分析样品中缺乏外部动力蛋白臂（ODA），和IF分析证实睫状轴突中不存在DNAH5的动力蛋白臂成分。结论：DNAH5的新发现的致病变异与阿拉伯家族的PCD以及可变的肺部临床表现有关。
