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

Chiara Olcese,Sandra Chantot,Claire Hogg,Estelle Escudier,Mellisa Dixon,Richard D Emes,Thomas J Cahill ,Corinne Gehrig,Gabriella Vera,Michael R Loebinger,Philippe Duquesnoy,Cara K Vaughan,Ludovic Jeanson,Williams Hj ,Antoine Garin,Michel Guipponi,M Legendre ,Lucia Bartoloni,Mahmoud R Fassad ,Aline Tamalet,Alexandros Onoufriadis,Laura A Dyer ,Lucie Thomas,Amelia Shoemark,C R Boustred ,Jane Hayward,Christel Thauvin‐Robinet ,Lucy Jenkins,M Armengot ,Serge Amselem,Thomas Cullup,Mitali Patel ,Paul Aurora,Andrew Bush,Santeri Kiviluoto,Isabelle Pin,Zhaoxia Sun,Alice Goldenberg,Jean‐François Papon ,Eddie M.k Chung ,Stylianos E Antonarakis,Robert Wilson,Bruno Copin,Mustafa M Munye,Jeremy Bevillard,Jean Louis Blouin ,Hannah M Mitchison

doi:10.1038/ncomms14279

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.

Highlights

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
The identification of putative mutations in the X-linked gene PIH1D3 in different patients prompted us to screen this gene by Sanger sequencing in a cohort of 32 independent male patients; this targeted screening identified a high proportion of affected families, with four males from three families carrying PIH1D3 mutations (9.5% (3/32) of independent cases screened)
These studies led to the identification of PIH1D3 molecular defects in affected males from nine independent families, which were all family-unique (Fig. 1a; Supplementary Figs 1 and 2): three nonsense mutations (c.127G4T, p.Glu43* in PCD12 II:[1]; c.266G4A, p.Trp89* in PCD392 II:[1]; c.511C4T, p.Gln171* in DCP1218), two frameshift mutations (c.263_268delinsG, p.Ile88Argfs*12 in DCP894; c.489_492del; p.Ile164Leufs*11 in GVA30 II:1), one missense change (c.397G4T, p.Asp133Tyr in DCP68), as well as genomic deletions containing the PIH1D3 gene (1.93-Mb, 3.27-Mb and 3.73-Mb deletions in DCP603/DCP1747, DCP1337 and DCP855, respectively)

Summary

Introduction

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. 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. Functional and clinical electron tomography data, we propose this might act in a complementary module akin to the DNAAF2–DNAAF4–HSP90 co-chaperone complex

Methods

Results

Conclusion