2. Academic Validation
  3. Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus

Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus

  • Am J Hum Genet. 2018 Dec 6;103(6):984-994. doi: 10.1016/j.ajhg.2018.10.016.
Mahmoud R Fassad 1,  Amelia Shoemark 2,  Marie Legendre 3,  Robert A Hirst 4,  France Koll 5,  Pierrick le Borgne 5,  Bruno Louis 6,  Farheen Daudvohra 7,  Mitali P Patel 8,  Lucie Thomas 3,  Mellisa Dixon 7,  Thomas Burgoyne 7,  Joseph Hayes 4,  Andrew G Nicholson 9,  Thomas Cullup 10,  Lucy Jenkins 10,  Siobhán B Carr 7,  Paul Aurora 11,  Michel Lemullois 5,  Anne Aubusson-Fleury 5,  Jean-François Papon 12,  Christopher O'Callaghan 13,  Serge Amselem 3,  Claire Hogg 7,  Estelle Escudier 3,  Anne-Marie Tassin 5,  Hannah M Mitchison 14
Affiliations

Affiliations

  • 1 Genetics and Genomic Medicine Programme, University College London, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; Department of Human Genetics, Medical Research Institute, Alexandria University, 165 El-Horreya Avenue El-Hadra, 21561 Alexandria, Egypt.
  • 2 PCD Diagnostic Team and Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, London SW3 6NP, UK; School of Medicine, University of Dundee, Dundee DD2 4BF, UK.
  • 3 Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Département de Génétique Médicale, 75012 Paris, France; Sorbonne Universités, Paris 06, INSERM UMR_S933, 75005 Paris, France.
  • 4 Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK.
  • 5 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris Sud, Université Paris-Saclay, 1 Avenue de la Terrasse, 91198 Gif sur Yvette, France.
  • 6 INSERM U955, Equipe 13, Faculté de Médecine de Créteil, Université Paris Est, 94010 Créteil, France.
  • 7 PCD Diagnostic Team and Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, London SW3 6NP, UK.
  • 8 Genetics and Genomic Medicine Programme, University College London, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
  • 9 Histopathology Department, Royal Brompton and Harefield NHS Trust, London SW3 6NP, UK.
  • 10 Regional Molecular Genetics Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, Queen Square, London WC1N 3BH, UK.
  • 11 Department of Respiratory, Critical Care and Anaesthesia Unit, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK; Department of Paediatric Respiratory Medicine, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
  • 12 Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Maxillo-Faciale, Hôpital Bicêtre, AP-HP, 94275 Le Kremlin-Bicêtre, France.
  • 13 Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK; Department of Respiratory, Critical Care and Anaesthesia Unit, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.
  • 14 Genetics and Genomic Medicine Programme, University College London, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK. Electronic address: [email protected].
PMID: 30471717 DOI: 10.1016/j.ajhg.2018.10.016
Abstract

Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.

Keywords

DNAH9; dynein; motile cilia; mutation; primary ciliary dyskinesia; situs inversus; tomography.

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