2. Academic Validation
  3. TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

  • Nat Commun. 2015 Jun 5;6:7074. doi: 10.1038/ncomms8074.
Miriam Schmidts 1,  Yuqing Hou 2,  Claudio R Cortés 3,  Dorus A Mans 4,  Celine Huber 5,  Karsten Boldt 6,  Mitali Patel 7,  Jeroen van Reeuwijk 4,  Jean-Marc Plaza 8,  Sylvia E C van Beersum 4,  Zhi Min Yap 7,  Stef J F Letteboer 4,  S Paige Taylor 9,  Warren Herridge 10,  Colin A Johnson 10,  Peter J Scambler 11,  Marius Ueffing 6,  Hulya Kayserili 12,  Deborah Krakow 9,  Stephen M King 13,  UK10K,  Philip L Beales 14,  Lihadh Al-Gazali 15,  Carol Wicking 3,  Valerie Cormier-Daire 5,  Ronald Roepman 4,  Hannah M Mitchison 7,  George B Witman 2
Affiliations

Affiliations

  • 1 1] Genetics and Genomic Medicine Programme, University College London (UCL), Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK [2] Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands [3] Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands [4] Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Mathildenstrasse 1, 79112 Freiburg, Germany.
  • 2 Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
  • 3 Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
  • 4 1] Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands [2] Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
  • 5 INSERM UMR_1163, Département de génétique, Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
  • 6 Division of Experimental Ophthalmology and Medical Proteome Center, Center of Ophthalmology, University of Tübingen, Tübingen 72074, Germany.
  • 7 Genetics and Genomic Medicine Programme, University College London (UCL), Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
  • 8 Plateforme de Bioinformatique, Institut Imagine, Université Paris Descartes, Paris 75015, France.
  • 9 Departments of Orthopaedic Surgery and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles 90095, California, USA.
  • 10 Section of Ophthalmology and Neuroscience, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
  • 11 Developmental Biology and Cancer Programme, University College London (UCL), Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
  • 12 1] Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey [2] Medical Genetics Department, Koc University School of Medicine, 34010 Istanbul, Turkey.
  • 13 Department of Molecular Biology and Biophysics and Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
  • 14 1] Genetics and Genomic Medicine Programme, University College London (UCL), Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK [2] Centre for Translational Genomics-GOSgene, UCL Institute of Child Health, London WC1N 1EH, UK.
  • 15 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates.
PMID: 26044572 DOI: 10.1038/ncomms8074
Abstract

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.

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