X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

Chiara Olcese, Mitali P. Patel, Amelia Shoemark, Santeri Kiviluoto, Marie Legendre, Hywel J. Williams, Cara K. Vaughan, Jane Hayward, Alice Goldenberg, Richard D. Emes, Mustafa M. Munye, Laura Dyer, Thomas Cahill, Jeremy Bevillard, Corinne Gehrig, Michel Guipponi, Sandra Chantot, Philippe Duquesnoy, Lucie Thomas, Ludovic Jeanson, Bruno Copin, Aline Tamalet, Christel Thauvin-Robinet, Jean- François Papon, Antoine Garin, Isabelle Pin, Gabriella Vera, Paul Aurora, Mahmoud R. Fassad, Lucy Jenkins, Christopher Boustred, Thomas Cullup, Mellisa Dixon, Alexandros Onoufriadis, Andrew Bush, Eddie M. K. Chung, Stylianos E. Antonarakis, Michael R. Loebinger, Robert Wilson, Miguel Armengot, Estelle Escudier, Claire Hogg, Serge Amselem, Zhaoxia Sun, Lucia Bartoloni, Jean-Louis Blouin and Hannah M. Mitchison ()
Additional contact information
Chiara Olcese: University of Geneva School of Medicine
Mitali P. Patel: Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health
Amelia Shoemark: Royal Brompton Hospital
Santeri Kiviluoto: Yale University School of Medicine
Marie Legendre: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP
Hywel J. Williams: GOSgene, Genetics and Genomic Medicine Programme, University College London (UCL) Great Ormond Street Institute of Child Health
Cara K. Vaughan: Institute of Structural and Molecular Biology, University College London and Birkbeck College, Biological Sciences
Jane Hayward: Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health
Alice Goldenberg: Service de Génétique, CHU de Rouen, INSERM U1079, Université de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée
Richard D. Emes: School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus
Mustafa M. Munye: Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health
Laura Dyer: Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health
Thomas Cahill: Royal Brompton Hospital
Jeremy Bevillard: University of Geneva School of Medicine
Corinne Gehrig: University of Geneva School of Medicine
Michel Guipponi: University of Geneva School of Medicine
Sandra Chantot: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP
Philippe Duquesnoy: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP
Lucie Thomas: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP
Ludovic Jeanson: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP
Bruno Copin: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP
Aline Tamalet: Service de Pneumologie Pédiatrique, Centre National de Référence des Maladies Respiratoires Rares, Hôpital Armand-Trousseau, AP-HP
Christel Thauvin-Robinet: Centre de génétique, CHU Dijon Bourgogne, Équipe EA4271 GAD, Université de Bourgogne, Hôpital François Mitterrand
Jean- François Papon: Service d’Oto-Rhino-Laryngologie et de Chirurgie Cervico-Maxillo-Faciale, Hôpital Bicêtre, AP-HP
Antoine Garin: Service d’Oto-Rhino-Laryngologie et de Chirurgie Cervico-Maxillo-Faciale, Hôpital Bicêtre, AP-HP
Isabelle Pin: Pédiatrie, CHU Grenoble Alpes, INSERM U 1209, Institut for Advanced Biosciences, Université Grenoble Alpes
Gabriella Vera: Service de Génétique, CHU de Rouen, INSERM U1079, Université de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée
Paul Aurora: Great Ormond Street Hospital for Children
Mahmoud R. Fassad: Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health
Lucy Jenkins: North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, Queen Square
Christopher Boustred: North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, Queen Square
Thomas Cullup: North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, Queen Square
Mellisa Dixon: Royal Brompton Hospital
Alexandros Onoufriadis: King's College London School of Medicine, Guy's Hospital
Andrew Bush: Royal Brompton Hospital
Eddie M. K. Chung: Population, Policy and Practice, University College London (UCL) Great Ormond Street Institute of Child Health
Stylianos E. Antonarakis: University of Geneva School of Medicine
Michael R. Loebinger: Host Defence Unit, Respiratory Medicine, Royal Brompton Hospital
Robert Wilson: Host Defence Unit, Respiratory Medicine, Royal Brompton Hospital
Miguel Armengot: Rhinology and Primary Ciliary Dyskinesia Unit, General and University Hospital, Medical School, Valencia University
Estelle Escudier: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP
Claire Hogg: Royal Brompton Hospital
Serge Amselem: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP
Zhaoxia Sun: Yale University School of Medicine
Lucia Bartoloni: University of Geneva School of Medicine
Jean-Louis Blouin: University of Geneva School of Medicine
Hannah M. Mitchison: Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins.

Date: 2017
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DOI: 10.1038/ncomms14279

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