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

Joseph S. Leslie, Rim Hjeij, Asaf Vivante, Elizabeth A. Bearce, Laura Dyer, Jiaolong Wang, Lettie Rawlins, Joanna Kennedy, Nishanka Ubeyratna, James Fasham, Zoe H. Irons, Samuel B. Craig, Julia Koenig, Sebastian George, Ben Pode-Shakked, Yoav Bolkier, Ortal Barel, Shrikant Mane, Kathrine K. Frederiksen, Olivia WengerEthan Scott, Harold E. Cross, Esben Lorentzen, Dominic P. Norris, Yair Anikster, Heymut Omran, Daniel T. Grimes*, Andrew H. Crosby*, Emma L. Baple*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2249-2261
Number of pages13
JournalGenetics in Medicine
Volume24
Issue number11
DOIs
StatePublished - Nov 2022

Funding

FundersFunder number
Akron Children's Hospital986876
Aquatics Facility
Das Deutsche Clinic
Delia B. Baxter Foundation
GC3F Imaging Facility
Hadassah Medical Center, Israel
Institutional Review Board of Sheba Medical Center7786-10
Knight Campus Undergraduate Scholarship
MRC Harwell Institute
Mary Lyon Centre
Medical Research Council MRC Harwell Ethics Committee
National Institute of Mental Health Amish Program
Riisfort-Fonden and Toyota-Fonden
University of Exeter Medical School
National Institutes of HealthR00AR70905, T32HD007348, 1HG006504, F32AR070082
National Human Genome Research Institute
National Institute of General Medical SciencesR35GM142949
University of ArizonaIRB – 1000000050
University of Oregon
Newlife the Charity for Disabled Children
Center for Mendelian Genomics, University of Washington
Medical Research CouncilMC_PC_15047, MC_PC_15054, G1001931, MC-PC-18047, MC_U142670370
University of Exeter
National Heart and Lung InstituteU24 HG008956
Deutsche ForschungsgemeinschaftHJ7/1-1
Israel Science Foundation2773/19

    Keywords

    • DAW1
    • Heterotaxy
    • Left-right asymmetry
    • Motile cilia
    • Primary ciliary dyskinesia

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