1. Developmental Biology
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TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

  1. Louise A Stephen
  2. Hasan Tawamie
  3. Gemma M Davis
  4. Lars Tebbe
  5. Peter Nürnberg
  6. Gudrun Nürnberg
  7. Holger Thiele
  8. Michaela Thoenes
  9. Eugen Boltshauser
  10. Steffen Uebe
  11. Oliver Rompel
  12. André Reis
  13. Arif B Ekici
  14. Lynn McTeir
  15. Amy M Fraser
  16. Emma A Hall
  17. Pleasantine Mill
  18. Nicolas Daudet
  19. Courtney Cross
  20. Uwe Wolfrum
  21. Rami Abou Jamra
  22. Megan G Davey
  23. Hanno J Bolz  Is a corresponding author
  1. University of Edinburgh, United Kingdom
  2. Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
  3. Johannes Gutenberg University of Mainz, Germany
  4. University of Cologne, Germany
  5. University Hospital of Cologne, Germany
  6. University Children's Hospital Zurich, Switzerland
  7. University College London, United Kingdom
  8. A.T. Still University, United States
Research Article
  • Cited 36
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Cite this article as: eLife 2015;4:e08077 doi: 10.7554/eLife.08077

Abstract

Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional JBTS patients. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population, and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects.

Article and author information

Author details

  1. Louise A Stephen

    Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Hasan Tawamie

    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Gemma M Davis

    Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Lars Tebbe

    Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Peter Nürnberg

    Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Gudrun Nürnberg

    Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Holger Thiele

    Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Michaela Thoenes

    Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Eugen Boltshauser

    Department of Paediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  10. Steffen Uebe

    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Oliver Rompel

    Institute of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. André Reis

    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Arif B Ekici

    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Lynn McTeir

    Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Amy M Fraser

    Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Emma A Hall

    Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Pleasantine Mill

    Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. Nicolas Daudet

    UCL Ear Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Courtney Cross

    School of Osteopathic Medicine, A.T. Still University, Mesa, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Uwe Wolfrum

    Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  21. Rami Abou Jamra

    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  22. Megan G Davey

    Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  23. Hanno J Bolz

    Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany
    For correspondence
    hanno.bolz@uk-koeln.de
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Talpid3 chicken lines are maintained at the Roslin Institute under UK Home Office license 60/4506 [Dr Paul Hocking], after ethical review.Animal experiments carried out at the JGU Mainz corresponded to the statement by the Association for Research in Vision and Ophthalmology (ARVO) as to care and use of animals in research.

Human subjects: Blood samples for DNA extraction were obtained with written informed consent. All investigations were conducted according to the Declaration of Helsinki, and the study was approved by the institutional review board of the Ethics Committees of the University of Erlangen-N�rnberg, the University of Bonn, and the University Hospital of Cologne.

Reviewing Editor

  1. Harry C Dietz, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: April 13, 2015
  2. Accepted: September 19, 2015
  3. Accepted Manuscript published: September 19, 2015 (version 1)
  4. Accepted Manuscript updated: September 30, 2015 (version 2)
  5. Version of Record published: November 12, 2015 (version 3)

Copyright

© 2015, Stephen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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