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X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

2017; Nature Portfolio; Volume: 8; Issue: 1 Linguagem: Inglês

10.1038/ncomms14279

2041-1723

Chiara Olcese, Mitali Patel, Amelia Shoemark, Santeri Kiviluoto, Marie Legendre, Hywel Williams, Cara K. Vaughan, Jane Hayward, Alice Goldenberg, Richard D. Emes, Mustafa M. Munye, Laura A. Dyer, Thomas J. Cahill, Jeremy Bevillard, Corinne Gehrig, Michel Guipponi, Sandra Chantot‐Bastaraud, Philippe Duquesnoy, Lucie Thomas, Ludovic Jeanson, Bruno Copin, Aline Tamalet, Christel Thauvin‐Robinet, Jean‐François Papon, Antoine Garin, Isabelle Pin, Gabriella Vera, Paul Aurora, Mahmoud R. Fassad, Lucy Jenkins, C. R. Boustred, Thomas Cullup, Mellisa Dixon, Alexandros Onoufriadis, Andrew Bush, Eddie M.K. Chung, Stylianos E. Antonarakis, Michael R. Loebinger, Robert Wilson, M Armengot, Estelle Escudier, Claire Hogg, Saeed Al-Turki, Carl A. Anderson, Dinu Antony, Inês Barroso, Philip L. Beales, Jamie Bentham, Shoumo Bhattacharya, Keren Carss, Krishna Chatterjee, Sebahattin Çirak, Catherine Cosgrove, D. Allan, Richard Durbin, David Fitzpatrick, Jamie Floyd, A. Reghan Foley, Chris Franklin, Marta Futema, Steve E. Humphries, Matt Hurles, Shane McCarthy, Dawn Muddyman, Francesco Muntoni, Victoria Parker, Felicity Payne, Vincent Plagnol, Lucy Raymond, David B. Savage, Peter Scambler, Miriam Schmidts, Robert K. Semple, Eva Serra, Jim Stalker, Margriet van Kogelenberg, Parthiban Vijayarangakannan, Klaudia Walter, Serge Amselem, Zhaoxia Sun, Lucia Bartoloni, Jean-Louis Blouin, Hannah M. Mitchison,

Cystic Fibrosis Research Advances

Abstract By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins.