De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry

Julia Wallmeier, Diana Frank, Amelia Shoemark, Tabea Nöthe-Menchen, Sandra Cindric, Heike Olbrich, Niki T. Loges, Isabella Aprea, Gerard W. Dougherty, Petra Pennekamp, Thomas Kaiser, Hannah M. Mitchison, Claire Hogg, Siobhán B. Carr, Maimoona A. Zariwala, Thomas Ferkol, Margaret W. Leigh, Stephanie D. Davis, Jeffrey Atkinson, Susan K. DutcherMichael R. Knowles, Holger Thiele, Janine Altmüller, Henrike Krenz, Marius Wöste, Angela Brentrup, Frank Ahrens, Christian Vogelberg, Deborah J. Morris-Rosendahl, Heymut Omran

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Pages (from-to)1030-1039
Number of pages10
JournalAmerican journal of human genetics
Volume105
Issue number5
DOIs
StatePublished - Nov 7 2019

Keywords

  • FOXJ1
  • cilia
  • ciliogenesis
  • ependyma
  • hydrocephalus
  • lung disease

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