@article{59f091bf21d44c8292ffe376acba33cd,
title = "Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia",
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.",
author = "Christina Austin-Tse and Jan Halbritter and Zariwala, {Maimoona A.} and Gilberti, {Ren{\'e}e M.} and Gee, {Heon Yung} and Nathan Hellman and Narendra Pathak and Yan Liu and Panizzi, {Jennifer R.} and Patel-King, {Ramila S.} and Douglas Tritschler and Raqual Bower and Eileen O'Toole and Porath, {Jonathan D.} and Hurd, {Toby W.} and Moumita Chaki and Diaz, {Katrina A.} and Stefan Kohl and Svjetlana Lovric and Hwang, {Daw Yang} and Braun, {Daniela A.} and Markus Schueler and Rannar Airik and Otto, {Edgar A.} and Leigh, {Margaret W.} and Noone, {Peadar G.} and Carson, {Johnny L.} and Davis, {Stephanie D.} and Pittman, {Jessica E.} and Ferkol, {Thomas W.} and Atkinson, {Jeffry J.} and Olivier, {Kenneth N.} and Sagel, {Scott D.} and Dell, {Sharon D.} and Margaret Rosenfeld and Milla, {Carlos E.} and Loges, {Niki T.} and Heymut Omran and Porter, {Mary E.} and King, {Stephen M.} and Knowles, {Michael R.} and Drummond, {Iain A.} and Friedhelm Hildebrandt",
note = "Funding Information: We are grateful to all PCD subjects and family members for their participation and thank the US PCD Foundation and to the investigators and the coordinators of the “Genetic Disorders of Mucociliary Clearance Consortium.” We are also grateful to the funding agencies that supported this work; these include the National Institutes of Health, the Howard Hughes Medical Institute, the Deutsche Forschungsgemeinschaft, the IZKF Muenster, and the European Community{\textquoteright}s Seventh Framework Programme. Detailed acknowledgements can be found in the Supplemental Data . ",
year = "2013",
month = oct,
day = "3",
doi = "10.1016/j.ajhg.2013.08.015",
language = "English (US)",
volume = "93",
pages = "672--686",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",
}