X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3.
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.
Department of Genetic Medicine and Development, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland.|Department of Life Sciences and Biotechnologies, University of Ferrara, 46-44121 Ferrara, Italy.
Chiara
C
Olcese
Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.
Mitali P
MP
Patel
Paediatric Department, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
Amelia
A
Shoemark
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
Santeri
S
Kiviluoto
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
Marie
M
Legendre
GOSgene, Genetics and Genomic Medicine Programme, University College London (UCL) Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Hywel J
HJ
Williams
Institute of Structural and Molecular Biology, University College London and Birkbeck College, Biological Sciences, Malet Street, London, WC1E 7HX, UK.
Cara K
CK
Vaughan
Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.
Jane
J
Hayward
Service de Génétique, CHU de Rouen, INSERM U1079, Université de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France.
Alice
A
Goldenberg
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Leicestershire LE12 5RD, UK.|Advanced Data Analysis Centre, University of Nottingham, Sutton Bonington Campus, Leicestershire LE12 5RD, UK.
Richard D
RD
Emes
Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.
Mustafa M
MM
Munye
Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.
Laura
L
Dyer
Paediatric Department, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
Thomas
T
Cahill
Department of Genetic Medicine and Development, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland.
Jeremy
J
Bevillard
Department of Genetic Medicine and Development, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland.
Corinne
C
Gehrig
Department of Genetic Medicine and Development, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland.|Department of Genetic Medicine and Laboratory, University Hospitals of Geneva, CH-1211 Geneva, Switzerland.
Michel
M
Guipponi
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
Sandra
S
Chantot
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
Philippe
P
Duquesnoy
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
Lucie
L
Thomas
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
Ludovic
L
Jeanson
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
Bruno
B
Copin
Service de Pneumologie Pédiatrique, Centre National de Référence des Maladies Respiratoires Rares, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
Aline
A
Tamalet
Centre de génétique, CHU Dijon Bourgogne, Équipe EA4271 GAD, Université de Bourgogne, Hôpital François Mitterrand, 21000 Dijon, France.
Christel
C
Thauvin-Robinet
Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Maxillo-Faciale, Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre 94275, France.
Jean-François
JF
Papon
Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Maxillo-Faciale, Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre 94275, France.
Antoine
A
Garin
Pédiatrie, CHU Grenoble Alpes, INSERM U 1209, Institut for Advanced Biosciences, Université Grenoble Alpes, Grenoble, France.
Isabelle
I
Pin
Service de Génétique, CHU de Rouen, INSERM U1079, Université de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France.
Gabriella
G
Vera
Department of Paediatric Respiratory Medicine, Great Ormond Street Hospital for Children, London WC1N 3JH, 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.
Paul
P
Aurora
Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.|Human Genetics Department, Medical Research Institute, Alexandria University, El-Hadra Alexandria 21561, Egypt.
Mahmoud R
MR
Fassad
North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, Queen Square, London WC1N 3BH, UK.
Lucy
L
Jenkins
North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, Queen Square, London WC1N 3BH, UK.
Christopher
C
Boustred
North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, Queen Square, London WC1N 3BH, UK.
Thomas
T
Cullup
Paediatric Department, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
Mellisa
M
Dixon
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.
Alexandros
A
Onoufriadis
Paediatric Department, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.|Department of Paediatric Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London SW3 6LR, UK.
Andrew
A
Bush
Population, Policy and Practice, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.
Eddie M K
EM
Chung
Department of Genetic Medicine and Development, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland.|Department of Genetic Medicine and Laboratory, University Hospitals of Geneva, CH-1211 Geneva, Switzerland.|Institute of Genetics and Genomics in Geneva, iGE3, CH-1211 Geneva, Switzerland.
Stylianos E
SE
Antonarakis
Host Defence Unit, Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UK.
Michael R
MR
Loebinger
Host Defence Unit, Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UK.
Robert
R
Wilson
Rhinology and Primary Ciliary Dyskinesia Unit, General and University Hospital, Medical School, Valencia University, Valencia E-46014, Spain.
Miguel
M
Armengot
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
Estelle
E
Escudier
Paediatric Department, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
Claire
C
Hogg
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S933 and Service de Génétique et Embryologie Médicales, Hôpital Armand-Trousseau, AP-HP, Paris 75012, France.
Serge
S
Amselem
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
Zhaoxia
Z
Sun
Department of Genetic Medicine and Development, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland.|UOSD Laboratorio Analisi Venezia, ULSS12 Veneziana, 30121 Venezia, Italy.
Lucia
L
Bartoloni
Department of Genetic Medicine and Development, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland.|Department of Genetic Medicine and Laboratory, University Hospitals of Geneva, CH-1211 Geneva, Switzerland.
Jean-Louis
JL
Blouin
Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, Guilford Street, London WC1N 1EH, UK.
Hannah M
HM
Mitchison
D000293:Adolescent; D000328:Adult; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D056444:Axonemal Dyneins / Q000378:metabolism*; D054468:Axoneme / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000473:pathology / Q000648:ultrastructure; D003593:Cytoplasm / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D007619:Kartagener Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D008868:Microtubule Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D010375:Pedigree; D010802:Phylogeny; D017354:Point Mutation; D017510:Protein Folding; D016415:Sequence Alignment; D017384:Sequence Deletion; D013081:Sperm Motility / Q000235:genetics; D000073359:Exome Sequencing; D015027:Zebrafish
D051017:Apoptosis Regulatory Proteins; C000628989:DNAAF6 protein, human; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008868:Microtubule Proteins; D018832:Molecular Chaperones; D056444:Axonemal Dyneins