2. Academic Validation
  3. 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

  • Am J Hum Genet. 2019 Nov 7;105(5):1030-1039. doi: 10.1016/j.ajhg.2019.09.022.
Julia Wallmeier 1,  Diana Frank 1,  Amelia Shoemark 2,  Tabea Nöthe-Menchen 1,  Sandra Cindric 1,  Heike Olbrich 1,  Niki T Loges 1,  Isabella Aprea 1,  Gerard W Dougherty 1,  Petra Pennekamp 1,  Thomas Kaiser 1,  Hannah M Mitchison 3,  Claire Hogg 4,  Siobhán B Carr 4,  Maimoona A Zariwala 5,  Thomas Ferkol 6,  Margaret W Leigh 7,  Stephanie D Davis 8,  Jeffrey Atkinson 9,  Susan K Dutcher 10,  Michael R Knowles 11,  Holger Thiele 12,  Janine Altmüller 12,  Henrike Krenz 13,  Marius Wöste 13,  Angela Brentrup 14,  Frank Ahrens 15,  Christian Vogelberg 16,  Deborah J Morris-Rosendahl 17,  Heymut Omran 18
Affiliations

Affiliations

  • 1 Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
  • 2 Molecular & Clinical Medicine, University of Dundee, Dundee DD1 4HN, UK; Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, London SW3 6NP, UK.
  • 3 Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
  • 4 Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, London SW3 6NP, UK.
  • 5 Department of Pathology and Laboratory Medicine, Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6 Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.
  • 7 Department of Pediatrics, Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 8 Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 9 Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
  • 10 McDonnell Genome Institute, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA.
  • 11 Department of Medicine, Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 12 Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
  • 13 Institute of Medical Informatics, University of Muenster, 48149 Muenster, Germany.
  • 14 Department of Neurosurgery, University Hospital Muenster, 48149 Muenster, Germany.
  • 15 Children's Hospital "Altona," 22763 Hamburg, Germany.
  • 16 Paediatric Department, University Hospital Carl Gustav Carus Dresden, TU Dresden, 01307 Dresden, Germany.
  • 17 Clinical Genetics and Genomics, Royal Brompton and Harefield NHS Foundation Trust, SW3 6NP London, UK; National Heart and Lung Institute, Imperial College London, SW3 6LY London, UK.
  • 18 Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany. Electronic address: heymut.omran@ukmuenster.de.
PMID: 31630787 DOI: 10.1016/j.ajhg.2019.09.022
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

FOXJ1; cilia; ciliogenesis; ependyma; hydrocephalus; lung disease.

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