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 ccdc151ts272a and mouse Ccdc151Snbl 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.
Highlights
Ciliary motility plays a number of essential roles in the body.[1]
Identification of CCDC151 Mutations through High-Throughput Autozygosity Mapping and Sequencing We used a high-throughput next-generation sequencing (NGS) approach to identify primary ciliary dyskinesia (PCD)-causing mutations in affected individuals that were clinically diagnosed with PCD caused by deficiency of the axonemal outer dynein arm (ODA)
266 The American Journal of Human Genetics 95, 257–274, September 4, 2014 ultrastructural ciliary phenotype of ccdc151ts272a mutants, ccdc[151] RNAi planarians, and Ccdc151Snbl mice (Figures 2H, S4E, and 3C). We further examined this defect at the molecular level by immunofluorescence staining of the respiratory cells of individuals OP-675 and OP-1255 using antibodies directed against two established markers of human dynein arm integrity, the ODA marker DNAH5 and inner dynein arms (IDAs) marker DNALI1
Summary
Ciliary motility plays a number of essential roles in the body.[1]. Notably, coordinated cilia-based fluid movement across the multiciliated epithelial cell surface of respiratory airways forms the major host-defense mechanism of mucociliary clearance. PCD Centre and Pediatrics Pulmonary Service, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark; 11Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands; 12Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands; 13UCL Institute of Ophthalmology, 11–43 Bath Street, London EC1V 9EL, UK; 14Gerhard-Domagk-Institut for Pathology, University Children’s Hospital Muenster, 48149 Muenster, Germany; 15Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK; 16Respiratory, Critical Care & Anaesthesia, Institute of Child Health, University College London & Great Ormond Street Children’s Hospital, 30 Guilford Street, London WC1N 1EH, UK; 17Bradford Royal Infirmary, Bradford, West Yorkshire BD9 6R, UK; 18General and Adolescent Paediatrics Section, Population, Policy and Practice Programme, University College London (UCL) Institute of Child Health, London WC1N 1EH, UK 19These authors contributed to this work 20These authors contributed to this work in a supervisory role 21Present address: Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King’s College London School of Medicine, Guy’s Hospital, London SE1 9RT, UK.
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