ZFIN ID: ZDB-PUB-181115-16
X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3
Olcese, C., Patel, M.P., Shoemark, A., Kiviluoto, S., Legendre, M., Williams, H.J., Vaughan, C.K., Hayward, J., Goldenberg, A., Emes, R.D., Munye, M.M., Dyer, L., Cahill, T., Bevillard, J., Gehrig, C., Guipponi, M., Chantot, S., Duquesnoy, P., Thomas, L., Jeanson, L., Copin, B., Tamalet, A., Thauvin-Robinet, C., Papon, J.F., Garin, A., Pin, I., Vera, G., Aurora, P., Fassad, M.R., Jenkins, L., Boustred, C., Cullup, T., Dixon, M., Onoufriadis, A., Bush, A., Chung, E.M., Antonarakis, S.E., Loebinger, M.R., Wilson, R., Armengot, M., Escudier, E., Hogg, C., UK10K Rare Group, Amselem, S., Sun, Z., Bartoloni, L., Blouin, J.L., Mitchison, H.M.
Date: 2017
Source: Nature communications   8: 14279 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Adolescent
  • Adult
  • Animals
  • Apoptosis Regulatory Proteins/genetics*
  • Apoptosis Regulatory Proteins/metabolism
  • Axonemal Dyneins/metabolism*
  • Axoneme/pathology
  • Child
  • Child, Preschool
  • Cilia/pathology
  • Cilia/ultrastructure
  • Cytoplasm/pathology
  • Disease Models, Animal
  • Female
  • Genes, X-Linked/genetics*
  • Genetic Diseases, X-Linked/genetics*
  • Genetic Diseases, X-Linked/pathology
  • HEK293 Cells
  • HSP90 Heat-Shock Proteins/metabolism
  • Humans
  • Infant, Newborn
  • Kartagener Syndrome/genetics*
  • Kartagener Syndrome/pathology
  • Male
  • Microscopy, Electron, Transmission
  • Microtubule Proteins/genetics*
  • Molecular Chaperones/genetics*
  • Pedigree
  • Phylogeny
  • Point Mutation
  • Protein Folding
  • Sequence Alignment
  • Sequence Deletion
  • Sperm Motility/genetics
  • Whole Exome Sequencing
  • Zebrafish
PubMed: 28176794 Full text @ Nat. Commun.
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.