@article{85166,
  keywords = {Animals, Humans, Zebrafish, Mutation, Phenotype, Mice, Female, Male, Cells, Cultured, Immunoblotting, Mice, Knockout, In Situ Hybridization, Embryo, Mammalian, Fluorescent Antibody Technique, Immunoprecipitation, Two-Hybrid System Techniques, Cilia, Axonemal Dyneins, Axoneme, Exome, Kartagener Syndrome, Microtubule-Associated Proteins, Pedigree},
  author = {Rim Hjeij and Alexandros Onoufriadis and Christopher Watson and Christopher Slagle and Nikolai Klena and Gerard Dougherty and Ma{\l}gorzata Kurkowiak and Niki Loges and Christine Diggle and Nicholas Morante and George Gabriel and Kristi Lemke and You Li and Petra Pennekamp and Tabea Menchen and Franziska Konert and June Kehlet Marthin and Dorus Mans and Stef Letteboer and Claudius Werner and Thomas Burgoyne and Cordula Westermann and Andrew Rutman and Ian Carr and Christopher O{\textquoteright}Callaghan and Eduardo Moya and Eddie Chung and UK10K Consortium and Eamonn Sheridan and Kim Nielsen and Ronald Roepman and Kerstin Bartscherer and Rebecca Burdine and Cecilia Lo and Heymut Omran and Hannah Mitchison},
  title = {CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation.},
  abstract = { 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. },
  year = {2014},
  journal = {Am J Hum Genet},
  volume = {95},
  pages = {257-74},
  month = {09/2014},
  issn = {1537-6605},
  doi = {10.1016/j.ajhg.2014.08.005},
  language = {eng},
}