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 Ellen 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; Elias 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 Ellen 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, Elias Nicholas Katsanis, Heymut Omran, Serge Amselem

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

272 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 language	English (US)
Pages (from-to)	72-78
Number of pages	7
Journal	Nature Genetics
Volume	43
Issue number	1
DOIs	https://doi.org/10.1038/ng.726
State	Published - Jan 2011

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.

ASJC Scopus subject areas

Genetics

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10.1038/ng.726

Cite this

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), 72-78. https://doi.org/10.1038/ng.726

@article{c1171dc3bd714f15a5b48bfb655e6553,

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.",

author = "Merveille, {Anne Christine} and Davis, {Erica Ellen} and Anita Becker-Heck and Marie Legendre and Israel Amirav and G{\'e}raldine Bataille and John Belmont and Nicole Beydon and Fr{\'e}d{\'e}ric Billen and Annick Cl{\'e}ment and C{\'e}cile Clercx and Andr{\'e} Coste and Rachelle Crosbie and {De Blic}, Jacques and Stephane Deleuze and Philippe Duquesnoy and Denise Escalier and Estelle Escudier and Manfred Fliegauf and Judith Horvath and Kent Hill and Mark Jorissen and Jocelyne Just and Andreas Kispert and Mark Lathrop and Loges, {Niki Tomas} and Marthin, {June K.} and Yukihide Momozawa and Guy Montantin and Nielsen, {Kim G.} and Heike Olbrich and Papon, {Jean Fran{\c c}ois} and Isabelle Rayet and Gilles Roger and Miriam Schmidts and Henrique Tenreiro and Towbin, {Jeffrey A.} and Diana Zelenika and Hanswalter Zentgraf and Michel Georges and Lequarr{\'e}, {Anne Sophie} and Katsanis, {Elias Nicholas} and Heymut Omran and Serge Amselem",

note = "Funding Information: This work was supported by grants from the European Union (LUPA IP) and from the Police Scientifique F{\'e}d{\'e}rale de Belgique (GENFUNC PAI) (to M.G.), from the Legs Poix from the Chancellerie des Universit{\'e}s, the Assistance Publique-H{\^o}pitaux 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 Unit{\'e} de Recherche Clinique (URC) Est (AP-HP, H{\^o}pital 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.",

year = "2011",

month = jan,

doi = "10.1038/ng.726",

language = "English (US)",

volume = "43",

pages = "72--78",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "1",

}

Merveille, AC, 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, JF, Rayet, I, Roger, G, Schmidts, M, Tenreiro, H, Towbin, JA, Zelenika, D, Zentgraf, H, Georges, M, Lequarré, AS, Katsanis, EN, 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. 72-78. https://doi.org/10.1038/ng.726

TY - JOUR

T1 - CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs

AU - Merveille, Anne Christine

AU - Davis, Erica Ellen

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, Elias Nicholas

AU - Omran, Heymut

AU - Amselem, Serge

N1 - Funding Information: 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.

PY - 2011/1

Y1 - 2011/1

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.

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U2 - 10.1038/ng.726

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JO - Nature Genetics

JF - Nature Genetics

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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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