X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3
Author(s)
Type
Journal Article
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.
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.
Date Issued
2017-02-08
Date Acceptance
2016-12-15
Citation
Nature Communications, 2017, 8
ISSN
2041-1723
Publisher
Nature Publishing Group
Journal / Book Title
Nature Communications
Volume
8
Copyright Statement
This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
© The Author(s) 2017
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
© The Author(s) 2017
License URL
Sponsor
NIHR
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
OF-FUNCTION MUTATIONS
IDENTIFIES MUTATIONS
R2TP COMPLEX
DEFECTS
OUTER
PROTEIN
ARMS
VARIANTS
MOTILITY
INNER
Publication Status
Published
Article Number
14279