CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs
Anne-Christine Merveille
(1)
,
Erica Davis
(2)
,
Anita Becker-Heck
(3, 4, 5)
,
Marie Legendre
(6, 7)
,
Israel Amirav
(8)
,
Géraldine Bataille
(1)
,
John Belmont
(9)
,
Nicole Beydon
(6)
,
Frédéric Billen
(10)
,
Annick Clément
(6)
,
Cécile Clercx
(10)
,
André Coste
(11)
,
Rachelle Crosbie
(12)
,
Jacques de Blic
(13)
,
Stephane Deleuze
(10)
,
Philippe Duquesnoy
(7, 6)
,
Denise Escalier
(7, 6)
,
Estelle Escudier
(7, 6)
,
Manfred Fliegauf
(3)
,
Judith Horvath
(3)
,
Kent Hill
(12)
,
Mark Jorissen
(14)
,
Jocelyne Just
(6)
,
Andreas Kispert
(15)
,
Mark Lathrop
(16)
,
Niki Tomas Loges
(3, 5)
,
June Marthin
(17)
,
Yukihide Momozawa
(1)
,
Guy Montantin
(7, 6)
,
Kim Nielsen
(18)
,
Heike Olbrich
(3, 7)
,
Jean-François Papon
(7, 11)
,
Isabelle Rayet
(17)
,
Gilles Roger
(6)
,
Miriam Schmidts
(3)
,
Henrique Tenreiro
(7, 6)
,
Jeffrey Towbin
(15)
,
Diana Zelenika
(16)
,
Hanswalter Zentgraf
(19)
,
Michel Georges
(1)
,
Anne-Sophie Lequarré
(1)
,
Nicholas Katsanis
(2)
,
Heymut Omran
(3, 5)
,
Serge Amselem
(7, 6)
1
GIGA [Université Liège]
2 Duke University Medical Center
3 University Hospital Freiburg
4 Albert-Ludwigs-Universität Freiburg
5 UKM - University Hospital Münster - Universitaetsklinikum Muenster [Germany]
6 CHU Trousseau [APHP]
7 Physiopathologie des maladies génétiques d'expression pédiatrique
8 Technion - Israel Institute of Technology [Haifa]
9 BCM - Baylor College of Medicine
10 Université de Liège
11 Service d'ORL [Créteil]
12 UCLA - University of California [Los Angeles]
13 Service de Pneumologie Allergologie [CHU Necker]
14 University Hospitals Leuven [Leuven]
15 MHH - Medizinische Hochschule Hannover = Hannover Medical School
16 GENOSCOPE - Genoscope - Centre national de séquençage [Evry]
17 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
18 Copenhagen University Hospital
19 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
2 Duke University Medical Center
3 University Hospital Freiburg
4 Albert-Ludwigs-Universität Freiburg
5 UKM - University Hospital Münster - Universitaetsklinikum Muenster [Germany]
6 CHU Trousseau [APHP]
7 Physiopathologie des maladies génétiques d'expression pédiatrique
8 Technion - Israel Institute of Technology [Haifa]
9 BCM - Baylor College of Medicine
10 Université de Liège
11 Service d'ORL [Créteil]
12 UCLA - University of California [Los Angeles]
13 Service de Pneumologie Allergologie [CHU Necker]
14 University Hospitals Leuven [Leuven]
15 MHH - Medizinische Hochschule Hannover = Hannover Medical School
16 GENOSCOPE - Genoscope - Centre national de séquençage [Evry]
17 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
18 Copenhagen University Hospital
19 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
Marie Legendre
- Fonction : co premier-auteur
- PersonId : 1147534
- IdHAL : marie-legendre
- ORCID : 0000-0003-2178-0846
Annick Clément
- Fonction : Auteur
- PersonId : 1029287
- IdHAL : nadianathan
- ORCID : 0000-0001-5149-7975
Estelle Escudier
- Fonction : Auteur
- PersonId : 1213534
- IdHAL : estelle-escudier
- ORCID : 0000-0002-1569-8072
- IdRef : 033701997
Guy Montantin
- Fonction : Auteur
- PersonId : 1195823
- IdHAL : guy-montantin
- ORCID : 0000-0003-1886-4133
Jean-François Papon
- Fonction : Auteur
- PersonId : 890849
Michel Georges
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 947988
Connectez-vous pour contacter l'auteur
Heymut Omran
- Fonction : co dernier-auteur
Serge Amselem
- Fonction : co dernier-auteur
- PersonId : 936326
- IdHAL : serge-amselem
- ORCID : 0000-0001-9506-3968
- IdRef : 066957761
Résumé
Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex.