De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry
De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry
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DOI：
10.1016/j.ajhg.2019.09.022
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发表时间：
2019-11-07
影响因子：
9.8
通讯作者：
Omran, Heymut
中科院分区：
文献类型：
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作者：
Wallmeier, Julia;Frank, Diana;Omran, Heymut
脑积水是发育性中枢神经系统（CNS）畸形最常见的形式之一。脑脊液（CSF）的流动取决于心跳和身体运动。此外，研究表明脑脊液在脑室内和穿过脑室的流动取决于脑室室管膜细胞的纤毛运动，这在小鼠脑形成过程中对维持脑脊液通道狭窄部位的通畅起着至关重要的作用。利用全外显子组和全基因组测序，我们在6个个体中发现了与室管膜纤毛发育缺陷相关的独特运动性纤毛病的常染色体显性原因。FOXJ1编码一个众所周知的叉头转录因子成员，对运动性纤毛的发生很重要。FOXJ1的杂合新生突变导致运动性纤毛病，其特征是脑积水、慢性破坏性气道疾病和左右体不对称的随机化。正如高速视频显微镜（HVMA）、透射电镜（TEM）和免疫荧光分析（IF）所记录的那样，突变的呼吸道上皮细胞不能产生流体流动，并且每个细胞的纤毛数量减少。透射电镜和中频显示基底定位错误。与这一发现一致，局灶黏附蛋白PTK2在突变呼吸道上皮细胞的细胞质中显示异常定位。
Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.