title: TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport.
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.
authors.affiliation: 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.
authors.forename: Miriam
authors.identifier: 0000000217146749
authors.initials: M
authors.lastname: Schmidts
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Claudio R
authors.initials: CR
authors.lastname: Cortés
authors.affiliation: 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.
authors.forename: Dorus A
authors.identifier: 0000000209091717
authors.initials: DA
authors.lastname: Mans
authors.affiliation: 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.
authors.forename: Celine
authors.initials: C
authors.lastname: Huber
authors.affiliation: Division of Experimental Ophthalmology and Medical Proteome Center, Center of Ophthalmology, University of Tübingen, Tübingen 72074, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Boldt
authors.affiliation: Genetics and Genomic Medicine Programme, University College London (UCL), Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Mitali
authors.initials: M
authors.lastname: Patel
authors.affiliation: 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.
authors.forename: Jeroen
authors.identifier: 0000000206584399
authors.initials: J
authors.lastname: van Reeuwijk
authors.affiliation: Plateforme de Bioinformatique, Institut Imagine, Université Paris Descartes, Paris 75015, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Plaza
authors.affiliation: 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.
authors.forename: Sylvia E C
authors.initials: SE
authors.lastname: van Beersum
authors.affiliation: Genetics and Genomic Medicine Programme, University College London (UCL), Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Zhi Min
authors.initials: ZM
authors.lastname: Yap
authors.affiliation: 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.
authors.forename: Stef J F
authors.initials: SJ
authors.lastname: Letteboer
authors.affiliation: Departments of Orthopaedic Surgery and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles 90095, California, USA.
authors.forename: S Paige
authors.initials: SP
authors.lastname: Taylor
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Warren
authors.initials: W
authors.lastname: Herridge
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Developmental Biology and Cancer Programme, University College London (UCL), Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.affiliation: Division of Experimental Ophthalmology and Medical Proteome Center, Center of Ophthalmology, University of Tübingen, Tübingen 72074, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.affiliation: 1] Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey [2] Medical Genetics Department, Koc University School of Medicine, 34010 Istanbul, Turkey.
authors.forename: Hulya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Departments of Orthopaedic Surgery and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles 90095, California, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.affiliation: Department of Molecular Biology and Biophysics and Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: King
authors.affiliation: 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.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.affiliation: Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates.
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Carol
authors.initials: C
authors.lastname: Wicking
authors.affiliation: 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.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: 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.
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.affiliation: Genetics and Genomic Medicine Programme, University College London (UCL), Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: George B
authors.initials: GB
authors.lastname: Witman
mesh_terms: D000818:Animals; D016825:Chlamydomonas reinhardtii; D003598:Cytoskeletal Proteins; D004398:Dyneins / Q000235:genetics*; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics*; D005407:Flagella / Q000502:physiology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D019683:Penetrance; D015027:Zebrafish
chemical_list: D003598:Cytoskeletal Proteins; D004398:Dyneins; C000593114:DYNLT2B protein, human