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; UK10K Rare Group; Serge Amselem; Zhaoxia Sun; Lucia Bartoloni; Jean-Louis Blouin; Hannah M Mitchison

doi:10.1038/ncomms14279

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

Nat Commun. 2017 Feb 8:8:14279. doi: 10.1038/ncomms14279.

Authors

Chiara Olcese^{1

2}, Mitali P Patel³, Amelia Shoemark⁴, Santeri Kiviluoto⁵, Marie Legendre⁶, Hywel J Williams⁷, Cara K Vaughan⁸, Jane Hayward³, Alice Goldenberg⁹, Richard D Emes^{10

11}, Mustafa M Munye³, Laura Dyer³, Thomas Cahill⁴, Jeremy Bevillard¹, Corinne Gehrig¹, Michel Guipponi^{1

12}, Sandra Chantot⁶, Philippe Duquesnoy⁶, Lucie Thomas⁶, Ludovic Jeanson⁶, Bruno Copin⁶, Aline Tamalet¹³, Christel Thauvin-Robinet¹⁴, Jean-François Papon¹⁵, Antoine Garin¹⁵, Isabelle Pin¹⁶, Gabriella Vera⁹, Paul Aurora^{17

18}, Mahmoud R Fassad^{3

19}, Lucy Jenkins²⁰, Christopher Boustred²⁰, Thomas Cullup²⁰, Mellisa Dixon⁴, Alexandros Onoufriadis²¹, Andrew Bush^{4

22}, Eddie M K Chung²³, Stylianos E Antonarakis^{1

12

24}, Michael R Loebinger²⁵, Robert Wilson²⁵, Miguel Armengot²⁶, Estelle Escudier⁶, Claire Hogg⁴; UK10K Rare Group; Serge Amselem⁶, Zhaoxia Sun⁵, Lucia Bartoloni^{1

27}, Jean-Louis Blouin^{1

12}, Hannah M Mitchison³

Collaborators

Affiliations

¹ Department of Genetic Medicine and Development, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland.
² Department of Life Sciences and Biotechnologies, University of Ferrara, 46-44121 Ferrara, Italy.
³ Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.
⁴ Paediatric Department, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
⁵ Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
⁶ Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
⁷ GOSgene, Genetics and Genomic Medicine Programme, University College London (UCL) Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
⁸ Institute of Structural and Molecular Biology, University College London and Birkbeck College, Biological Sciences, Malet Street, London, WC1E 7HX, UK.
⁹ Service de Génétique, CHU de Rouen, INSERM U1079, Université de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France.
¹⁰ School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Leicestershire LE12 5RD, UK.
¹¹ Advanced Data Analysis Centre, University of Nottingham, Sutton Bonington Campus, Leicestershire LE12 5RD, UK.
¹² Department of Genetic Medicine and Laboratory, University Hospitals of Geneva, CH-1211 Geneva, Switzerland.
¹³ Service de Pneumologie Pédiatrique, Centre National de Référence des Maladies Respiratoires Rares, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
¹⁴ Centre de génétique, CHU Dijon Bourgogne, Équipe EA4271 GAD, Université de Bourgogne, Hôpital François Mitterrand, 21000 Dijon, France.
¹⁵ Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Maxillo-Faciale, Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre 94275, France.
¹⁶ Pédiatrie, CHU Grenoble Alpes, INSERM U 1209, Institut for Advanced Biosciences, Université Grenoble Alpes, Grenoble, France.
¹⁷ Department of Paediatric Respiratory Medicine, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
¹⁸ 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.
¹⁹ Human Genetics Department, Medical Research Institute, Alexandria University, El-Hadra Alexandria 21561, Egypt.
²⁰ North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, Queen Square, London WC1N 3BH, UK.
²¹ Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
²² Department of Paediatric Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London SW3 6LR, UK.
²³ Population, Policy and Practice, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.
²⁴ Institute of Genetics and Genomics in Geneva, iGE3, CH-1211 Geneva, Switzerland.
²⁵ Host Defence Unit, Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UK.
²⁶ Rhinology and Primary Ciliary Dyskinesia Unit, General and University Hospital, Medical School, Valencia University, Valencia E-46014, Spain.
²⁷ UOSD Laboratorio Analisi Venezia, ULSS12 Veneziana, 30121 Venezia, Italy.

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.

Publication types

Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Adolescent
Adult
Animals
Apoptosis Regulatory Proteins / genetics*
Apoptosis Regulatory Proteins / metabolism
Axonemal Dyneins / metabolism*
Axoneme / pathology
Child
Child, Preschool
Cilia / pathology
Cilia / ultrastructure
Cytoplasm / pathology
Disease Models, Animal
Exome Sequencing
Female
Genes, X-Linked / genetics*
Genetic Diseases, X-Linked / genetics*
Genetic Diseases, X-Linked / pathology
HEK293 Cells
HSP90 Heat-Shock Proteins / metabolism
Humans
Infant, Newborn
Intracellular Signaling Peptides and Proteins
Kartagener Syndrome / genetics*
Kartagener Syndrome / pathology
Male
Microscopy, Electron, Transmission
Microtubule Proteins / genetics*
Molecular Chaperones / genetics*
Pedigree
Phylogeny
Point Mutation
Protein Folding
Sequence Alignment
Sequence Deletion
Sperm Motility / genetics
Zebrafish

Substances

Apoptosis Regulatory Proteins
DNAAF6 protein, human
HSP90 Heat-Shock Proteins
Intracellular Signaling Peptides and Proteins
Microtubule Proteins
Molecular Chaperones
Axonemal Dyneins

Abstract

Publication types

MeSH terms

Substances

Grants and funding