CFAP300: Mutations in Slavic Patients with Primary Ciliary Dyskinesia and a Role in Ciliary Dynein Arms Trafficking
CFAP300: Mutations in Slavic Patients with Primary Ciliary Dyskinesia and a Role in Ciliary Dynein Arms Trafficking
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DOI：
10.1165/rcmb.2018-0260oc
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发表时间：
2019-10-01
影响因子：
6.4
通讯作者：
Witt, Michel
中科院分区：
文献类型：
--
作者：
Zietkiewicz, Ewa;Bukowy-Bieryllo, Zuzanna;Witt, Michel
原发性纤毛运动障碍（PCD）是一种罕见的，遗传异质性遗传性疾病的一类纤毛病变。尽管最近取得了进展，但三分之一患者的PCD遗传基础仍然未知。为了寻找新的基因和/或突变，在120名不相关的波兰PCD患者中进行了全外显子组测序，这些患者早期没有发现PCD的遗传原因。在PCD基因的许多致病性变体中，检测到CFAP 300（别名C11 orf 70）的突变。在整个波兰PCD队列中的扩展筛选显示了相对较高的频率（3.6%），否则罕见的c。[198_200 del_insCC]变异，表明它应该包括在人群特异性遗传测试的PCD在斯拉夫人的群体。CFAP 300突变患者的呼吸道上皮细胞的免疫荧光分析显示，外部和内部动力蛋白臂标记物的缺失或异常定位，与透射电子显微镜图像一致，表明缺乏两个动力蛋白臂。有趣的是，CFAP 300突变患者中DNAH 5和DNALI 1蛋白的不同定位表明，预先组装的外部和内部动力蛋白臂向轴丝运输的不同机制。CFAP 300在悬浮培养中纤毛发生过程中的表达谱与其在纤毛组装中的作用一致。在模式生物中进行的基因沉默实验，Schmidtea mediterranea（扁形虫），指出CFAP 300在纤毛功能中的保守作用。
Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous hereditary disease from a class of ciliopathies. In spite of the recent progress, the genetic basis of PCD in one-third of patients remains unknown. In search for new genes and/or mutations, whole-exome sequencing was performed in 120 unrelated Polish patients with PCD, in whom no genetic cause of PCD was earlier identified. Among a number of pathogenic variants in PCD genes, mutations in CFAP300 (alias C11orf70) were detected. Extended screening in the whole Polish PCD cohort revealed the relatively high frequency (3.6%) of otherwise rare c.[198_200 del_insCC] variant, indicating that it should be included in population-specific genetic tests for PCD in Slavic populations. Immunofluorescence analysis of the respiratory epithelial cells from patients with CFAP300 mutations revealed the absence or aberrant localization of outer and inner dynein arm markers, consistent with transmission electron microscope images indicating the lack of both dynein arms. Interestingly, the disparate localization of DNAH5 and DNALI1 proteins in patients with CFAP300 mutations suggested differential mechanisms for the trafficking of preassembled outer and inner dynein arms to the axoneme. The profile of CFAP300 expression during ciliogenesis in suspension culture was consistent with its role in cilia assembly. Gene silencing experiments, performed in a model organism, Schmidtea mediterranea (flatworm), pointed to the conserved role of CFAP300 in ciliary function.