PUBLICATION

Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities

Authors
Leslie, J.S., Hjeij, R., Vivante, A., Bearce, E.A., Dyer, L., Wang, J., Rawlins, L., Kennedy, J., Ubeyratna, N., Fasham, J., Irons, Z.H., Craig, S.B., Koenig, J., George, S., Pode-Shakked, B., Bolkier, Y., Barel, O., Mane, S., Frederiksen, K.K., Wenger, O., Scott, E., Cross, H.E., Lorentzen, E., Norris, D.P., Anikster, Y., Omran, H., Grimes, D.T., Crosby, A.H., Baple, E.L.
ID
ZDB-PUB-220909-4
Date
2022
Source
Genetics in medicine : official journal of the American College of Medical Genetics   24(11): 2249-2261 (Journal)
Registered Authors
Keywords
DAW1, Heterotaxy, Left-right asymmetry, Motile cilia, Primary ciliary dyskinesia
MeSH Terms
  • Zebrafish/genetics
  • Cilia/metabolism
  • Humans
  • Mutation
  • Ciliopathies*/genetics
  • Ciliopathies*/metabolism
  • Ciliopathies*/pathology
  • Animals
  • Mice
  • Proteins/genetics
  • Ciliary Motility Disorders*/genetics
  • Ciliary Motility Disorders*/metabolism
  • Ciliary Motility Disorders*/pathology
  • Axoneme/genetics
(all 14)
PubMed
36074124 Full text @ Genet. Med.
Abstract
Purpose The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis.
Methods Clinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants.
Results In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments.
Conclusion Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.
Genes / Markers
Figures
Figure Gallery (3 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
dand5daw1b1403/b1403 (AB)standard conditions10-13 somitesISH
dand5WTstandard conditions10-13 somitesISH
1 - 2 of 2
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Phenotype
Fish Conditions Stage Phenotype Figure
daw1b1403/b1403 (AB)standard conditions10-13 somites
daw1b1403/b1403 (AB)standard conditions10-13 somites
daw1b1403/b1403 (AB)standard conditions10-13 somites
1 - 3 of 3
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b1403
    		Small Deletion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    No data available
    Fish
    Fish
    daw1b1403/b1403 (AB)
    WT
    1 - 2 of 2
    Show
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    No data available
    Mapping
    No data available
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    Citation
    Leslie, J.S., Hjeij, R., Vivante, A., Bearce, E.A., Dyer, L., Wang, J., Rawlins, L., Kennedy, J., Ubeyratna, N., Fasham, J., Irons, Z.H., Craig, S.B., Koenig, J., George, S., Pode-Shakked, B., Bolkier, Y., Barel, O., Mane, S., Frederiksen, K.K., Wenger, O., Scott, E., Cross, H.E., Lorentzen, E., Norris, D.P., Anikster, Y., Omran, H., Grimes, D.T., Crosby, A.H., Baple, E.L. (2022) Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities. Genetics in medicine : official journal of the American College of Medical Genetics. 24(11):2249-2261.