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, Erica E. Davis, Anita Becker-Heck, Marie Legendre, Israel Amirav, Géraldine Bataille, John Belmont, Nicole Beydon, Frédéric Billen, Annick Clément, Cécile Clercx, André Coste, Rachelle Crosbie, Jacques De Blic, Stephane Deleuze, Philippe Duquesnoy, Denise Escalier, Estelle Escudier, Manfred Fliegauf, Judith HorvathKent Hill, Mark Jorissen, Jocelyne Just, Andreas Kispert, Mark Lathrop, Niki Tomas Loges, June K. Marthin, Yukihide Momozawa, Guy Montantin, Kim G. Nielsen, Heike Olbrich, Jean François Papon, Isabelle Rayet, Gilles Roger, Miriam Schmidts, Henrique Tenreiro, Jeffrey A. Towbin, Diana Zelenika, Hanswalter Zentgraf, Michel Georges, Anne Sophie Lequarré, Nicholas Katsanis, Heymut Omran, Serge Amselem

Research output: Contribution to journalArticlepeer-review

270 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)72-78
Number of pages7
JournalNature Genetics
Volume43
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

Funding

This work was supported by grants from the European Union (LUPA IP) and from the Police Scientifique Fédérale de Belgique (GENFUNC PAI) (to M.G.), from the Legs Poix from the Chancellerie des Universités, the Assistance Publique-Hôpitaux de Paris (PHRC AOM06053, P060245) and the Agence Nationale pour la Recherche (ANR-05-MRAR-022-01) (to S.A.), the US National Institutes of Health (HD04260, DK072301 and DK075972 (to N.K.) and DK079541 (to E.E.D.)) and by grants from the “Deutsche Forschungsgemeinschaft” DFG Om 6/4, GRK1104, SFB592, and the European Community (EU-CILIA; SYS-CILIA) (to H.O.). A.C.M. is a fellow from the FRIA. N.K. is the Jean and George W. Brumley Professor. Y.M. benefits from a postdoctoral fellowship to study abroad from the Japanese Society for the Promotion of Science (JSPS). We thank the Bobtail breeders for assistance; patients and their family members whose cooperation made this study possible; all referring physicians; the German patient support group “Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.”; K. Nakamura and the GIGA-R genomics platform for their contribution to sequencing; E. Ostrander for samples from healthy Old English Sheepdogs; the Unité de Recherche Clinique (URC) Est (AP-HP, Hôpital Saint-Antoine, Paris, France) for support; and A. Heer, C. Reinhard, C. Kopp, K. Sutter, M. Petry, C. Tessmer, A.-M. Vojtek and S. Franz for technical assistance.

FundersFunder number
EU-CILIA
European Community
GENFUNC
Japanese Society for the Promotion of Science
LUPA IP
PHRCAOM06053, P060245
Police Scientifique Fédérale de Belgique
National Institutes of HealthDK075972, DK079541, HD04260
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK072301
European Commission
Deutsche ForschungsgemeinschaftSFB592, DFG Om 6/4, GRK1104
Agence Nationale pour le Développement de la Recherche en SantéANR-05-MRAR-022-01
Assistance publique-Hôpitaux de Paris
Chancellerie des Universités de Paris

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