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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Dokumenter

DOI

  • Joseph S. Leslie, University of Exeter
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  • Rim Hjeij, Universität Münster
    • ,
  • Asaf Vivante, Tel Aviv University, Sheba Medical Center at Tel Hashomer
    • ,
  • Elizabeth A. Bearce, University of Oregon
    • ,
  • Laura Dyer, MRC Harwell Institute
    • ,
  • Jiaolong Wang
  • Lettie Rawlins, University of Exeter
    • ,
  • Joanna Kennedy, University of Exeter
    • ,
  • Nishanka Ubeyratna, University of Exeter
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  • James Fasham, University of Exeter
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  • Zoe H. Irons, University of Oregon
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  • Samuel B. Craig, University of Oregon
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  • Julia Koenig, Universität Münster
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  • Sebastian George, Universität Münster
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  • Ben Pode-Shakked, Tel Aviv University, Sheba Medical Center at Tel Hashomer
    • ,
  • Yoav Bolkier, Tel Aviv University, Sheba Medical Center at Tel Hashomer
    • ,
  • Ortal Barel, Tel Aviv University, Sheba Medical Center at Tel Hashomer
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  • Shrikant Mane, Yale University
    • ,
  • Kathrine K. Frederiksen
  • Olivia Wenger, New Leaf Center Clinic for Special Children
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  • Ethan Scott, New Leaf Center Clinic for Special Children
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  • Harold E. Cross, University of Arizona
    • ,
  • Esben Lorentzen
  • Dominic P. Norris, MRC Harwell Institute
    • ,
  • Yair Anikster, Tel Aviv University, Sheba Medical Center at Tel Hashomer
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  • Heymut Omran, Universität Münster
    • ,
  • Daniel T. Grimes, University of Oregon
    • ,
  • Andrew H. Crosby, University of Exeter
    • ,
  • Emma L. Baple, University of Exeter

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.

OriginalsprogEngelsk
TidsskriftGenetics in Medicine
Vol/bind24
Nummer11
Sider (fra-til)2249-2261
ISSN1098-3600
DOI
StatusUdgivet - nov. 2022

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