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.
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Rim
authors.initials: R
authors.lastname: Hjeij
authors.affiliation: Genetics and Genomic Medicine Programme, University College London (UCL) Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Onoufriadis
authors.affiliation: Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds LS9 7TF, UK; Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Watson
authors.affiliation: Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Slagle
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15201, USA.
authors.forename: Nikolai T
authors.initials: NT
authors.lastname: Klena
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: Dougherty
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany; International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland; Department of Molecular and Clinical Genetics, Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Kurkowiak
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Diggle
authors.affiliation: Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA.
authors.forename: Nicholas F C
authors.initials: NF
authors.lastname: Morante
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15201, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Gabriel
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15201, USA.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Lemke
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15201, USA.
authors.forename: You
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Pennekamp
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Tabea
authors.initials: T
authors.lastname: Menchen
authors.affiliation: Max Planck Research Group on Stem Cells & Regeneration, Max Planck Institute for Molecular Biomedicine, and Medical Faculty, University of Muenster, 48149 Muenster, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Konert
authors.affiliation: Danish PCD Centre and Pediatrics Pulmonary Service, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: June Kehlet
authors.initials: JK
authors.lastname: Marthin
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
authors.forename: Dorus A
authors.initials: DA
authors.lastname: Mans
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
authors.forename: Stef J F
authors.initials: SJ
authors.lastname: Letteboer
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Burgoyne
authors.affiliation: Gerhard-Domagk-Institut for Pathology, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Westermann
authors.affiliation: Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rutman
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.affiliation: Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK; Respiratory, Critical Care & Anaesthesia, Institute of Child Health, University College London & Great Ormond Street Children's Hospital, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Callaghan
authors.affiliation: Bradford Royal Infirmary, Bradford, West Yorkshire BD9 6R, UK.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Moya
authors.affiliation: General and Adolescent Paediatrics Section, Population, Policy and Practice Programme, University College London (UCL) Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Eddie M K
authors.initials: EM
authors.lastname: Chung
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: Danish PCD Centre and Pediatrics Pulmonary Service, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: Kim G
authors.initials: KG
authors.lastname: Nielsen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.affiliation: Max Planck Research Group on Stem Cells & Regeneration, Max Planck Institute for Molecular Biomedicine, and Medical Faculty, University of Muenster, 48149 Muenster, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bartscherer
authors.affiliation: Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA.
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Burdine
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15201, USA.
authors.forename: Cecilia W
authors.initials: CW
authors.lastname: Lo
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany. Electronic address: heymut.omran@ukmuenster.de.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.affiliation: Genetics and Genomic Medicine Programme, University College London (UCL) Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
mesh_terms: D000818:Animals; D056444:Axonemal Dyneins / Q000235:genetics / Q000378:metabolism*; D054468:Axoneme / Q000235:genetics; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism / Q000473:pathology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D007619:Kartagener Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020798:Two-Hybrid System Techniques; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; C578794:ODAD1 protein, human; D056444:Axonemal Dyneins