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 journalArticle

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
Early online date17 Oct 2019
DOIs
Publication statusPublished - 7 Nov 2019

Fingerprint

Cilia
Hydrocephalus
Random Allocation
Cerebrospinal Fluid
Mutation
Transmission Electron Microscopy
Fluorescent Antibody Technique
Brain
Epithelial Cells
Nervous System Malformations
Basal Bodies
Exome
Forkhead Transcription Factors
Video Microscopy
Focal Adhesions
Cell Movement
Cytoplasm
Central Nervous System
Genome
Ciliopathies

Keywords

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

Cite this

Wallmeier, Julia ; Frank, Diana ; Shoemark, Amelia ; Nöthe-Menchen, Tabea ; Cindric, Sandra ; Olbrich, Heike ; Loges, Niki T ; Aprea, Isabella ; Dougherty, Gerard W ; Pennekamp, Petra ; Kaiser, Thomas ; Mitchison, Hannah M ; Hogg, Claire ; Carr, Siobhán B ; Zariwala, Maimoona A ; Ferkol, Thomas ; Leigh, Margaret W ; Davis, Stephanie D ; Atkinson, Jeffrey ; Dutcher, Susan K ; Knowles, Michael R ; Thiele, Holger ; Altmüller, Janine ; Krenz, Henrike ; Wöste, Marius ; Brentrup, Angela ; Ahrens, Frank ; Vogelberg, Christian ; Morris-Rosendahl, Deborah J ; Omran, Heymut. / De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry. In: American Journal of Human Genetics. 2019 ; Vol. 105, No. 5. pp. 1030-1039.
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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.",
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author = "Julia Wallmeier and Diana Frank and Amelia Shoemark and Tabea N{\"o}the-Menchen and Sandra Cindric and Heike Olbrich and Loges, {Niki T} and Isabella Aprea and Dougherty, {Gerard W} and Petra Pennekamp and Thomas Kaiser and Mitchison, {Hannah M} and Claire Hogg and Carr, {Siobh{\'a}n B} and Zariwala, {Maimoona A} and Thomas Ferkol and Leigh, {Margaret W} and Davis, {Stephanie D} and Jeffrey Atkinson and Dutcher, {Susan K} and Knowles, {Michael R} and Holger Thiele and Janine Altm{\"u}ller and Henrike Krenz and Marius W{\"o}ste and Angela Brentrup and Frank Ahrens and Christian Vogelberg and Morris-Rosendahl, {Deborah J} and Heymut Omran",
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Wallmeier, J, Frank, D, Shoemark, A, Nöthe-Menchen, T, Cindric, S, Olbrich, H, Loges, NT, Aprea, I, Dougherty, GW, Pennekamp, P, Kaiser, T, Mitchison, HM, Hogg, C, Carr, SB, Zariwala, MA, Ferkol, T, Leigh, MW, Davis, SD, Atkinson, J, Dutcher, SK, Knowles, MR, Thiele, H, Altmüller, J, Krenz, H, Wöste, M, Brentrup, A, Ahrens, F, Vogelberg, C, Morris-Rosendahl, DJ & Omran, H 2019, 'De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry', American Journal of Human Genetics, vol. 105, no. 5, pp. 1030-1039. https://doi.org/10.1016/j.ajhg.2019.09.022

De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry. / Wallmeier, Julia; Frank, Diana; Shoemark, Amelia; Nöthe-Menchen, Tabea; Cindric, Sandra; Olbrich, Heike; Loges, Niki T; Aprea, Isabella; Dougherty, Gerard W; Pennekamp, Petra; Kaiser, Thomas; Mitchison, Hannah M; Hogg, Claire; Carr, Siobhán B; Zariwala, Maimoona A; Ferkol, Thomas; Leigh, Margaret W; Davis, Stephanie D; Atkinson, Jeffrey; Dutcher, Susan K; Knowles, Michael R; Thiele, Holger; Altmüller, Janine; Krenz, Henrike; Wöste, Marius; Brentrup, Angela; Ahrens, Frank; Vogelberg, Christian; Morris-Rosendahl, Deborah J; Omran, Heymut (Lead / Corresponding author).

In: American Journal of Human Genetics, Vol. 105, No. 5, 07.11.2019, p. 1030-1039.

Research output: Contribution to journalArticle

TY - JOUR

T1 - De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry

AU - Wallmeier, Julia

AU - Frank, Diana

AU - Shoemark, Amelia

AU - Nöthe-Menchen, Tabea

AU - Cindric, Sandra

AU - Olbrich, Heike

AU - Loges, Niki T

AU - Aprea, Isabella

AU - Dougherty, Gerard W

AU - Pennekamp, Petra

AU - Kaiser, Thomas

AU - Mitchison, Hannah M

AU - Hogg, Claire

AU - Carr, Siobhán B

AU - Zariwala, Maimoona A

AU - Ferkol, Thomas

AU - Leigh, Margaret W

AU - Davis, Stephanie D

AU - Atkinson, Jeffrey

AU - Dutcher, Susan K

AU - Knowles, Michael R

AU - Thiele, Holger

AU - Altmüller, Janine

AU - Krenz, Henrike

AU - Wöste, Marius

AU - Brentrup, Angela

AU - Ahrens, Frank

AU - Vogelberg, Christian

AU - Morris-Rosendahl, Deborah J

AU - Omran, Heymut

N1 - Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2019/11/7

Y1 - 2019/11/7

N2 - 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.

AB - 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.

KW - FOXJ1

KW - cilia

KW - ciliogenesis

KW - ependyma

KW - hydrocephalus

KW - lung disease

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U2 - 10.1016/j.ajhg.2019.09.022

DO - 10.1016/j.ajhg.2019.09.022

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JO - American Journal of Human Genetics

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