CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation.

TitleCCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation.
Publication TypeJournal Article
Year of Publication2014
AuthorsHjeij, R, Onoufriadis, A, Watson, CM, Slagle, CE, Klena, NT, Dougherty, GW, Kurkowiak, M, Loges, NT, Diggle, CP, Morante, NFC, Gabriel, GC, Lemke, KL, Li, Y, Pennekamp, P, Menchen, T, Konert, F, Marthin, JKehlet, Mans, DA, Letteboer, SJF, Werner, C, Burgoyne, T, Westermann, C, Rutman, A, Carr, IM, O'Callaghan, C, Moya, E, Chung, EMK, Sheridan, E, Nielsen, KG, Roepman, R, Bartscherer, K, Burdine, RD, Lo, CW, Omran, H, Mitchison, HM
Corporate Authors
JournalAm J Hum Genet
Volume95
Issue3
Pagination257-74
Date Published2014 Sep 4
ISSN1537-6605
KeywordsAnimals, Axonemal Dyneins, Axoneme, Cells, Cultured, Cilia, Embryo, Mammalian, Exome, Female, Fluorescent Antibody Technique, Humans, Immunoblotting, Immunoprecipitation, In Situ Hybridization, Kartagener Syndrome, Male, Mice, Mice, Knockout, Microtubule-Associated Proteins, Mutation, Pedigree, Phenotype, Two-Hybrid System Techniques, Zebrafish
Abstract

<p>A diverse family of cytoskeletal dynein motors powers various cellular transport systems, including axonemal dyneins generating the force for ciliary and flagellar beating essential to movement of extracellular fluids and of cells through fluid. Multisubunit outer dynein arm (ODA) motor complexes, produced and preassembled in the cytosol, are transported to the ciliary or flagellar compartment and anchored into the axonemal microtubular scaffold via the ODA docking complex (ODA-DC) system. In humans, defects in ODA assembly are the major cause of primary ciliary dyskinesia (PCD), an inherited disorder of ciliary and flagellar dysmotility characterized by chronic upper and lower respiratory infections and defects in laterality. Here, by combined high-throughput mapping and sequencing, we identified CCDC151 loss-of-function mutations in five affected individuals from three independent families whose cilia showed a complete loss of ODAs and severely impaired ciliary beating. Consistent with the laterality defects observed in these individuals, we found Ccdc151 expressed in vertebrate left-right organizers. Homozygous zebrafish ccdc151(ts272a) and mouse Ccdc151(Snbl) mutants display a spectrum of situs defects associated with complex heart defects. We demonstrate that CCDC151 encodes an axonemal coiled coil protein, mutations in which abolish assembly of CCDC151 into respiratory cilia and cause a failure in axonemal assembly of the ODA component DNAH5 and the ODA-DC-associated components CCDC114 and ARMC4. CCDC151-deficient zebrafish, planaria, and mice also display ciliary dysmotility accompanied by ODA loss. Furthermore, CCDC151 coimmunoprecipitates CCDC114 and thus appears to be a highly evolutionarily conserved ODA-DC-related protein involved in mediating assembly of both ODAs and their axonemal docking machinery onto ciliary microtubules.</p>

DOI10.1016/j.ajhg.2014.08.005
Alternate JournalAm. J. Hum. Genet.
PubMed ID25192045
PubMed Central IDPMC4157146
Grant List100140 / / Wellcome Trust / United Kingdom
2R01HD048584 / HD / NICHD NIH HHS / United States
MR/L01629X/1 / / Medical Research Council / United Kingdom
R01 HD048584 / HD / NICHD NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
U01-HL098180 / HL / NHLBI NIH HHS / United States