De novo mutations in FOXJ1 result in a motile ciliopathy with hydrocephalus and randomization of left/right body asymmetry

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Item Type:	Article
Title:	De novo mutations in FOXJ1 result in a motile ciliopathy with hydrocephalus and randomization of left/right body asymmetry
Creators Name:	Wallmeier, J., Frank, D., Shoemark, A., Nöthe-Menchen, T., Cindric, S., Olbrich, H., Loges, N.T., Aprea, I., Dougherty, G.W., Pennekamp, P., Kaiser, T., Mitchison, H.M., Hogg, C., Carr, S.B., Zariwala, M.A., Ferkol, T., Leigh, M.W., Davis, S.D., Atkinson, J., Dutcher, S.K., Knowles, M.R., Thiele, H., Altmüller, J., Krenz, H., Wöste, M., Brentrup, A., Ahrens, F., Vogelberg, C., Morris-Rosendahl, D.J. and Omran, H.
Abstract:	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.
Keywords:	Hydrocephalus, Lung Disease, Cilia, Ciliogenesis, Ependyma, FOXJ1
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	105
Number:	5
Page Range:	1030-1039
Date:	7 November 2019
Official Publication:	https://doi.org/10.1016/j.ajhg.2019.09.022
PubMed:	View item in PubMed

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