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

Miriam Schmidts; Yuqing Hou; Claudio R Cortés; Dorus A Mans; Celine Huber; Karsten Boldt; Mitali Patel; Jeroen van Reeuwijk; Jean-Marc Plaza; Sylvia E C van Beersum; Zhi Min Yap; Stef J F Letteboer; S Paige Taylor; Warren Herridge; Colin A Johnson; Peter J Scambler; Marius Ueffing; Hulya Kayserili; Deborah Krakow; Stephen M King; UK10K; Philip L Beales; Lihadh Al-Gazali; Carol Wicking; Valerie Cormier-Daire; Ronald Roepman; Hannah M Mitchison; George B Witman

doi:10.1038/ncomms8074

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

Nat Commun. 2015 Jun 5:6:7074. doi: 10.1038/ncomms8074.

Authors

Miriam Schmidts¹, Yuqing Hou², Claudio R Cortés³, Dorus A Mans⁴, Celine Huber⁵, Karsten Boldt⁶, Mitali Patel⁷, Jeroen van Reeuwijk⁴, Jean-Marc Plaza⁸, Sylvia E C van Beersum⁴, Zhi Min Yap⁷, Stef J F Letteboer⁴, S Paige Taylor⁹, Warren Herridge¹⁰, Colin A Johnson¹⁰, Peter J Scambler¹¹, Marius Ueffing⁶, Hulya Kayserili¹², Deborah Krakow⁹, Stephen M King¹³; UK10K; Philip L Beales¹⁴, Lihadh Al-Gazali¹⁵, Carol Wicking³, Valerie Cormier-Daire⁵, Ronald Roepman⁴, Hannah M Mitchison⁷, George B Witman²

Collaborators

UK10K:
Saeed Al-Turki, Carl Anderson, Richard Anney, Dinu Antony, Jennifer Asimit, Mohammad Ayub, Jeff Barrett, Inês Barroso, Jamie Bentham, Shoumo Bhattacharya, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Chris Boustred, Gerome Breen, Marie-Jo Brion, Andrew Brown, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, Allan Daly, Petr Danecek, George Davey Smith, Aaron Day-Williams, Ian Day, Richard Durbin, Sarah Edkins, Peter Ellis, David Evans, I Sadaf Farooqi, Ghazaleh Fatemifar, David Fitzpatrick, Paul Flicek, Jamie Floyd, A Reghan Foley, Chris Franklin, Marta Futema, Louise Gallagher, Tom Gaunt, Daniel Geschwind, Celia Greenwood, Detelina Grozeva, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Jie Huang, Steve E Humphries, Matt Hurles, Pirro Hysi, David Jackson, Yalda Jamshidi, David Jewell, Joyce Chris, Jane Kaye, Thomas Keane, John Kemp, Karen Kennedy, Alastair Kent, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Irene Lee, Rui Li, Yingrui Li, Liu Ryan, Jouko Lönnqvist, Margarida Lopes, Daniel G MacArthur, Mangino Massimo, Jonathan Marchini, John Maslen, Shane McCarthy, Peter McGuffin, Andrew McIntosh, Andrew McKechanie, Andrew McQuillin, Yasin Memari, Sarah Metrustry, Josine Min, Alireza Moayyeri, James Morris, Dawn Muddyman, Francesco Muntoni, Kate Northstone, Michael O'Donovan, Stephen O'Rahilly, Alexandros Onoufriadis, Karim Oualkacha, Michael Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, John Perry, Olli Pietilainen, Vincent Plagnol, Michael A Quail, Lydia Quaye, Lucy Raymond, Karola Rehnström, J Brent Richards, Sue Ring, Graham R S Ritchie, David B Savage, Nadia Schoenmakers, Robert K Semple, Eva Serra, Hashem Shihab, So-Youn Shin, David Skuse, Kerrin Small, Carol Smee, Artigas María Soler, Nicole Soranzo, Lorraine Southam, Tim Spector, Beate St Pourcain, David St Clair, Jim Stalker, Gabriela Surdulescu, Jaana Suvisaari, Ioanna Tachmazidou, Jing Tian, Nic Timpson, Martin Tobin, Ana Valdes, Margriet van Kogelenberg, Parthiban Vijayarangakannan, Louise Wain, Klaudia Walter, Jun Wang, Kirsten Ward, Ellie Wheeler, Ros Whittall, Hywel Williams, Kathy Williamson, Scott G Wilson, Kim Wong, Tamieka Whyte, Xu ChangJiang, Eleftheria Zeggini, Feng Zhang, Hou-Feng Zheng

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chlamydomonas reinhardtii
Cytoskeletal Proteins
Dyneins / genetics*
Ellis-Van Creveld Syndrome / genetics*
Flagella / physiology*
Gene Knockdown Techniques
HEK293 Cells
Humans
Mice
Mutation
Penetrance
Zebrafish

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

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Abstract

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