TY - JOUR
T1 - CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms
AU - Panizzi, Jennifer R.
AU - Becker-Heck, Anita
AU - Castleman, Victoria H.
AU - Al-Mutairi, Dalal A.
AU - Liu, Yan
AU - Loges, Niki T.
AU - Pathak, Narendra
AU - Austin-Tse, Christina
AU - Sheridan, Eamonn
AU - Schmidts, Miriam
AU - Olbrich, Heike
AU - Werner, Claudius
AU - Häffner, Karsten
AU - Hellman, Nathan
AU - Chodhari, Rahul
AU - Gupta, Amar
AU - Kramer-Zucker, Albrecht
AU - Olale, Felix
AU - Burdine, Rebecca D.
AU - Schier, Alexander F.
AU - O'Callaghan, Christopher
AU - Chung, Eddie M.K.
AU - Reinhardt, Richard
AU - Mitchison, Hannah M.
AU - King, Stephen M.
AU - Omran, Heymut
AU - Drummond, Iain A.
N1 - Funding Information:
We thank the patients and their families for their participation and acknowledge support from the PCD Family Support Group (UK) and the German patient support group ‘Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.’ . We thank R. Mark Gardiner and E. Moya for their help and involvement in the study. We thank R. Hirst and A. Rutman for electron microscopy. We thank A. Heer, C. Warmt, D. Nergenau, R.S. Patel-King and L. Luo for excellent technical assistance. This work was funded by US National Institutes of Health grants DK053093 (I.A.D.) and GM051293 (S.M.K.), National Research Service Award fellowship grant F32DK083868 (J.R.P.), an American Heart Association Established Investigator Award (A.F.S.), Deutsche Forschungsgemeinschaft (DFG) grants (DFG Om 6/4, GRK1109 and SFB592), EU grant SYSCILIA, IZKF-project (Om2/009/12), and Kindness for Kids grant (H. Omran), the Medical Research Council UK, the Wellcome Trust and the Fondation Milena Carvajal–ProKartagener.
PY - 2012/6
Y1 - 2012/6
N2 - Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation and establishing laterality. Cilia motility defects cause primary ciliary dyskinesia (PCD, MIM244400), a disorder affecting 1:15,000-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive ciliary bending. Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD-linked loci. Here we show that the zebrafish cilia paralysis mutant schmalhans (smh tn222) encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a-regulated gene product. Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated.
AB - Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation and establishing laterality. Cilia motility defects cause primary ciliary dyskinesia (PCD, MIM244400), a disorder affecting 1:15,000-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive ciliary bending. Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD-linked loci. Here we show that the zebrafish cilia paralysis mutant schmalhans (smh tn222) encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a-regulated gene product. Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated.
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U2 - 10.1038/ng.2277
DO - 10.1038/ng.2277
M3 - Article
C2 - 22581229
AN - SCOPUS:84861640948
SN - 1061-4036
VL - 44
SP - 714
EP - 719
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -