TY - JOUR
T1 - CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation
AU - UK 10K
AU - Hjeij, Rim
AU - Onoufriadis, Alexandros
AU - Watson, Christopher M.
AU - Slagle, Christopher E.
AU - Klena, Nikolai T.
AU - Dougherty, Gerard W.
AU - Kurkowiak, Magorzata
AU - Loges, Niki T.
AU - Diggle, Christine P.
AU - Morante, Nicholas F.C.
AU - Gabriel, George C.
AU - Lemke, Kristi L.
AU - Li, You
AU - Pennekamp, Petra
AU - Menchen, Tabea
AU - Konert, Franziska
AU - Marthin, June Kehlet
AU - Mans, Dorus A.
AU - Letteboer, Stef J.F.
AU - Werner, Claudius
AU - Burgoyne, Thomas
AU - Westermann, Cordula
AU - Rutman, Andrew
AU - Carr, Ian M.
AU - O'Callaghan, Christopher
AU - Moya, Eduardo
AU - Chung, Eddie M.K.
AU - Sheridan, Eamonn
AU - Nielsen, Kim G.
AU - Roepman, Ronald
AU - Bartscherer, Kerstin
AU - Burdine, Rebecca D.
AU - Lo, Cecilia W.
AU - Omran, Heymut
AU - Mitchison, Hannah M.
N1 - Publisher Copyright:
© 2014 by The American Society of Human Genetics. All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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..
AB - 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..
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U2 - 10.1016/j.ajhg.2014.08.005
DO - 10.1016/j.ajhg.2014.08.005
M3 - Article
C2 - 25192045
AN - SCOPUS:84908250713
SN - 0002-9297
VL - 95
SP - 257
EP - 274
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -