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 Horvath; Kent 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

doi:10.1038/ng.726

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

Department of Paediatrics and Adolescent Medicine

300 Citations (Scopus)

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 language	English
Journal	Nature Genetics
Volume	43
Issue number	1
Pages (from-to)	72-8
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.726
Publication status	Published - 2011

Keywords

Animals
Base Sequence
Cells, Cultured
Cilia
Ciliary Motility Disorders
Dogs
Dyneins
Humans
Microscopy, Electron, Transmission
Molecular Sequence Data
Mutation
Proteins

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Merveille, A.-C., Davis, E. E., Becker-Heck, A., Legendre, M., Amirav, I., Bataille, G., Belmont, J., Beydon, N., Billen, F., Clément, A., Clercx, C., Coste, A., Crosbie, R., de Blic, J., Deleuze, S., Duquesnoy, P., Escalier, D., Escudier, E., Fliegauf, M., ... Amselem, S. (2011). CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nature Genetics, 43(1), 72-8. https://doi.org/10.1038/ng.726

Merveille, A-C, Davis, EE, Becker-Heck, A, Legendre, M, Amirav, I, Bataille, G, Belmont, J, Beydon, N, Billen, F, Clément, A, Clercx, C, Coste, A, Crosbie, R, de Blic, J, Deleuze, S, Duquesnoy, P, Escalier, D, Escudier, E, Fliegauf, M, Horvath, J, Hill, K, Jorissen, M, Just, J, Kispert, A, Lathrop, M, Loges, NT, Marthin, JK, Momozawa, Y, Montantin, G, Nielsen, KG, Olbrich, H, Papon, J-F, Rayet, I, Roger, G, Schmidts, M, Tenreiro, H, Towbin, JA, Zelenika, D, Zentgraf, H, Georges, M, Lequarré, A-S, Katsanis, N, Omran, H & Amselem, S 2011, 'CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs', Nature Genetics, vol. 43, no. 1, pp. 72-8. https://doi.org/10.1038/ng.726

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title = "CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs",

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.",

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AU - Merveille, Anne-Christine

AU - Davis, Erica E

AU - Becker-Heck, Anita

AU - Legendre, Marie

AU - Amirav, Israel

AU - Bataille, Géraldine

AU - Belmont, John

AU - Beydon, Nicole

AU - Billen, Frédéric

AU - Clément, Annick

AU - Clercx, Cécile

AU - Coste, André

AU - Crosbie, Rachelle

AU - de Blic, Jacques

AU - Deleuze, Stephane

AU - Duquesnoy, Philippe

AU - Escalier, Denise

AU - Escudier, Estelle

AU - Fliegauf, Manfred

AU - Horvath, Judith

AU - Hill, Kent

AU - Jorissen, Mark

AU - Just, Jocelyne

AU - Kispert, Andreas

AU - Lathrop, Mark

AU - Loges, Niki Tomas

AU - Marthin, June K

AU - Momozawa, Yukihide

AU - Montantin, Guy

AU - Nielsen, Kim G

AU - Olbrich, Heike

AU - Papon, Jean-François

AU - Rayet, Isabelle

AU - Roger, Gilles

AU - Schmidts, Miriam

AU - Tenreiro, Henrique

AU - Towbin, Jeffrey A

AU - Zelenika, Diana

AU - Zentgraf, Hanswalter

AU - Georges, Michel

AU - Lequarré, Anne-Sophie

AU - Katsanis, Nicholas

AU - Omran, Heymut

AU - Amselem, Serge

PY - 2011

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N2 - 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.

AB - 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.

KW - Animals

KW - Base Sequence

KW - Cells, Cultured

KW - Cilia

KW - Ciliary Motility Disorders

KW - Dogs

KW - Dyneins

KW - Humans

KW - Microscopy, Electron, Transmission

KW - Molecular Sequence Data

KW - Mutation

KW - Proteins

UR - https://www.scopus.com/pages/publications/78651260210

U2 - 10.1038/ng.726

DO - 10.1038/ng.726

M3 - Journal article

C2 - 21131972

SN - 1061-4036

VL - 43

SP - 72

EP - 78

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs

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Keywords

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