Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities |
| |
| Institution: | 1. Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom;2. Department of General Pediatrics, University Hospital Muenster, Muenster, Germany;3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;4. Department of Pediatrics B and Pediatric Nephrology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel;5. Institute of Molecular Biology, University of Oregon, Eugene, OR;6. MRC Harwell Institute, Harwell Campus, Oxfordshire, Oxford, United Kingdom;7. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark;8. Peninsula Clinical Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom;9. Metabolic Disease Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel;10. Pediatric Heart Institute, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel;11. The Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel;12. Wohl Institute for Translational Medicine, Sheba Medical Center, Ramat Gan, Israel;13. Department of Genetics, Yale School of Medicine, New Haven, CT;14. New Leaf Center Clinic for Special Children, Mt Eaton, OH;15. Department of Ophthalmology and Vision Science, University of Arizona College of Medicine, University of Arizona, Tucson, AZ |
| |
| Abstract: | PurposeThe 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.MethodsClinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants.ResultsIn 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.ConclusionOur 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. |
| |
| Keywords: | DAW1 Heterotaxy Left-right asymmetry Motile cilia Primary ciliary dyskinesia |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
