Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia

Christina Austin-Tse, Jan Halbritter, Maimoona A. Zariwala, Renée M. Gilberti, Heon Yung Gee, Nathan Hellman, Narendra Pathak, Yan Liu, Jennifer R. Panizzi, Ramila S. Patel-King, Douglas Tritschler, Raqual Bower, Eileen O'Toole, Jonathan D. Porath, Toby W. Hurd, Moumita Chaki, Katrina A. Diaz, Stefan Kohl, Svjetlana Lovric, Daw Yang Hwang & 23 others Daniela A. Braun, Markus Schueler, Rannar Airik, Edgar A. Otto, Margaret W. Leigh, Peadar G. Noone, Johnny L. Carson, Stephanie D. Davis, Jessica E. Pittman, Thomas W. Ferkol, Jeffry J. Atkinson, Kenneth N. Olivier, Scott D. Sagel, Sharon D. Dell, Margaret Rosenfeld, Carlos E. Milla, Niki T. Loges, Heymut Omran, Mary E. Porter, Stephen M. King, Michael R. Knowles, Iain A. Drummond, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

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Abstract

Primary ciliary dyskinesia (PCD) is caused when defects of motile cilia lead to chronic airway infections, male infertility, and situs abnormalities. Multiple causative PCD mutations account for only 65% of cases, suggesting that many genes essential for cilia function remain to be discovered. By using zebrafish morpholino knockdown of PCD candidate genes as an in vivo screening platform, we identified c21orf59, ccdc65, and c15orf26 as critical for cilia motility. c21orf59 and c15orf26 knockdown in zebrafish and planaria blocked outer dynein arm assembly, and ccdc65 knockdown altered cilia beat pattern. Biochemical analysis in Chlamydomonas revealed that the C21orf59 ortholog FBB18 is a flagellar matrix protein that accumulates specifically when cilia motility is impaired. The Chlamydomonas ida6 mutant identifies CCDC65/FAP250 as an essential component of the nexin-dynein regulatory complex. Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families. Similar to findings in zebrafish and planaria, mutations in C21orf59 caused loss of both outer and inner dynein arm components. Our results characterize two genes associated with PCD-causing mutations and elucidate two distinct mechanisms critical for motile cilia function: dynein arm assembly for C21orf59 and assembly of the nexin-dynein regulatory complex for CCDC65.

Original languageEnglish (US)
Pages (from-to)672-686
Number of pages15
JournalAmerican Journal of Human Genetics
Volume93
Issue number4
DOIs
StatePublished - Oct 3 2013

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Kartagener Syndrome
Cilia
Dyneins
Zebrafish
Chlamydomonas
Mutation
Morpholinos
Male Infertility
Essential Genes
Genes
Ciliopathies
Infection

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia. / Austin-Tse, Christina; Halbritter, Jan; Zariwala, Maimoona A.; Gilberti, Renée M.; Gee, Heon Yung; Hellman, Nathan; Pathak, Narendra; Liu, Yan; Panizzi, Jennifer R.; Patel-King, Ramila S.; Tritschler, Douglas; Bower, Raqual; O'Toole, Eileen; Porath, Jonathan D.; Hurd, Toby W.; Chaki, Moumita; Diaz, Katrina A.; Kohl, Stefan; Lovric, Svjetlana; Hwang, Daw Yang; Braun, Daniela A.; Schueler, Markus; Airik, Rannar; Otto, Edgar A.; Leigh, Margaret W.; Noone, Peadar G.; Carson, Johnny L.; Davis, Stephanie D.; Pittman, Jessica E.; Ferkol, Thomas W.; Atkinson, Jeffry J.; Olivier, Kenneth N.; Sagel, Scott D.; Dell, Sharon D.; Rosenfeld, Margaret; Milla, Carlos E.; Loges, Niki T.; Omran, Heymut; Porter, Mary E.; King, Stephen M.; Knowles, Michael R.; Drummond, Iain A.; Hildebrandt, Friedhelm.

In: American Journal of Human Genetics, Vol. 93, No. 4, 03.10.2013, p. 672-686.

Research output: Contribution to journalArticle

Austin-Tse, C, Halbritter, J, Zariwala, MA, Gilberti, RM, Gee, HY, Hellman, N, Pathak, N, Liu, Y, Panizzi, JR, Patel-King, RS, Tritschler, D, Bower, R, O'Toole, E, Porath, JD, Hurd, TW, Chaki, M, Diaz, KA, Kohl, S, Lovric, S, Hwang, DY, Braun, DA, Schueler, M, Airik, R, Otto, EA, Leigh, MW, Noone, PG, Carson, JL, Davis, SD, Pittman, JE, Ferkol, TW, Atkinson, JJ, Olivier, KN, Sagel, SD, Dell, SD, Rosenfeld, M, Milla, CE, Loges, NT, Omran, H, Porter, ME, King, SM, Knowles, MR, Drummond, IA & Hildebrandt, F 2013, 'Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia', American Journal of Human Genetics, vol. 93, no. 4, pp. 672-686. https://doi.org/10.1016/j.ajhg.2013.08.015
Austin-Tse, Christina ; Halbritter, Jan ; Zariwala, Maimoona A. ; Gilberti, Renée M. ; Gee, Heon Yung ; Hellman, Nathan ; Pathak, Narendra ; Liu, Yan ; Panizzi, Jennifer R. ; Patel-King, Ramila S. ; Tritschler, Douglas ; Bower, Raqual ; O'Toole, Eileen ; Porath, Jonathan D. ; Hurd, Toby W. ; Chaki, Moumita ; Diaz, Katrina A. ; Kohl, Stefan ; Lovric, Svjetlana ; Hwang, Daw Yang ; Braun, Daniela A. ; Schueler, Markus ; Airik, Rannar ; Otto, Edgar A. ; Leigh, Margaret W. ; Noone, Peadar G. ; Carson, Johnny L. ; Davis, Stephanie D. ; Pittman, Jessica E. ; Ferkol, Thomas W. ; Atkinson, Jeffry J. ; Olivier, Kenneth N. ; Sagel, Scott D. ; Dell, Sharon D. ; Rosenfeld, Margaret ; Milla, Carlos E. ; Loges, Niki T. ; Omran, Heymut ; Porter, Mary E. ; King, Stephen M. ; Knowles, Michael R. ; Drummond, Iain A. ; Hildebrandt, Friedhelm. / Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 4. pp. 672-686.
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abstract = "Primary ciliary dyskinesia (PCD) is caused when defects of motile cilia lead to chronic airway infections, male infertility, and situs abnormalities. Multiple causative PCD mutations account for only 65{\%} of cases, suggesting that many genes essential for cilia function remain to be discovered. By using zebrafish morpholino knockdown of PCD candidate genes as an in vivo screening platform, we identified c21orf59, ccdc65, and c15orf26 as critical for cilia motility. c21orf59 and c15orf26 knockdown in zebrafish and planaria blocked outer dynein arm assembly, and ccdc65 knockdown altered cilia beat pattern. Biochemical analysis in Chlamydomonas revealed that the C21orf59 ortholog FBB18 is a flagellar matrix protein that accumulates specifically when cilia motility is impaired. The Chlamydomonas ida6 mutant identifies CCDC65/FAP250 as an essential component of the nexin-dynein regulatory complex. Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families. Similar to findings in zebrafish and planaria, mutations in C21orf59 caused loss of both outer and inner dynein arm components. Our results characterize two genes associated with PCD-causing mutations and elucidate two distinct mechanisms critical for motile cilia function: dynein arm assembly for C21orf59 and assembly of the nexin-dynein regulatory complex for CCDC65.",
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T1 - Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia

AU - Austin-Tse, Christina

AU - Halbritter, Jan

AU - Zariwala, Maimoona A.

AU - Gilberti, Renée M.

AU - Gee, Heon Yung

AU - Hellman, Nathan

AU - Pathak, Narendra

AU - Liu, Yan

AU - Panizzi, Jennifer R.

AU - Patel-King, Ramila S.

AU - Tritschler, Douglas

AU - Bower, Raqual

AU - O'Toole, Eileen

AU - Porath, Jonathan D.

AU - Hurd, Toby W.

AU - Chaki, Moumita

AU - Diaz, Katrina A.

AU - Kohl, Stefan

AU - Lovric, Svjetlana

AU - Hwang, Daw Yang

AU - Braun, Daniela A.

AU - Schueler, Markus

AU - Airik, Rannar

AU - Otto, Edgar A.

AU - Leigh, Margaret W.

AU - Noone, Peadar G.

AU - Carson, Johnny L.

AU - Davis, Stephanie D.

AU - Pittman, Jessica E.

AU - Ferkol, Thomas W.

AU - Atkinson, Jeffry J.

AU - Olivier, Kenneth N.

AU - Sagel, Scott D.

AU - Dell, Sharon D.

AU - Rosenfeld, Margaret

AU - Milla, Carlos E.

AU - Loges, Niki T.

AU - Omran, Heymut

AU - Porter, Mary E.

AU - King, Stephen M.

AU - Knowles, Michael R.

AU - Drummond, Iain A.

AU - Hildebrandt, Friedhelm

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N2 - Primary ciliary dyskinesia (PCD) is caused when defects of motile cilia lead to chronic airway infections, male infertility, and situs abnormalities. Multiple causative PCD mutations account for only 65% of cases, suggesting that many genes essential for cilia function remain to be discovered. By using zebrafish morpholino knockdown of PCD candidate genes as an in vivo screening platform, we identified c21orf59, ccdc65, and c15orf26 as critical for cilia motility. c21orf59 and c15orf26 knockdown in zebrafish and planaria blocked outer dynein arm assembly, and ccdc65 knockdown altered cilia beat pattern. Biochemical analysis in Chlamydomonas revealed that the C21orf59 ortholog FBB18 is a flagellar matrix protein that accumulates specifically when cilia motility is impaired. The Chlamydomonas ida6 mutant identifies CCDC65/FAP250 as an essential component of the nexin-dynein regulatory complex. Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families. Similar to findings in zebrafish and planaria, mutations in C21orf59 caused loss of both outer and inner dynein arm components. Our results characterize two genes associated with PCD-causing mutations and elucidate two distinct mechanisms critical for motile cilia function: dynein arm assembly for C21orf59 and assembly of the nexin-dynein regulatory complex for CCDC65.

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