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Motile ciliopathies

Abstract

Motile cilia are highly complex hair-like organelles of epithelial cells lining the surface of various organ systems. Genetic mutations (usually with autosomal recessive inheritance) that impair ciliary beating cause a variety of motile ciliopathies, a heterogeneous group of rare disorders. The pathogenetic mechanisms, clinical symptoms and severity of the disease depend on the specific affected genes and the tissues in which they are expressed. Defects in the ependymal cilia can result in hydrocephalus, defects in the cilia in the fallopian tubes or in sperm flagella can cause female and male subfertility, respectively, and malfunctional motile monocilia of the left–right organizer during early embryonic development can lead to laterality defects such as situs inversus and heterotaxy. If mucociliary clearance in the respiratory epithelium is severely impaired, the disorder is referred to as primary ciliary dyskinesia, the most common motile ciliopathy. No single test can confirm a diagnosis of motile ciliopathy, which is based on a combination of tests including nasal nitric oxide measurement, transmission electron microscopy, immunofluorescence and genetic analyses, and high-speed video microscopy. With the exception of azithromycin, there is no evidence-based treatment for primary ciliary dyskinesia; therapies aim at relieving symptoms and reducing the effects of reduced ciliary motility.

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Fig. 1: Clinical manifestations of motile ciliopathies.
Fig. 2: Cilium structure in respiratory epithelial cells.
Fig. 3: Genetic analysis.
Fig. 4: Cilium assembly.
Fig. 5: Transmission electron microscopy and immunofluorescence analysis of healthy cilia.
Fig. 6: Transmission electron microscopy and immunofluorescence analysis of cilia defects.

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Acknowledgements

This work was supported by the Swiss National Science Foundation (SNF grant no. 320030_173044 and grant no. 320030B_192804 to C.E.K.) contributing to the work relating to epidemiology of PCD. The National Institutes of Health (NIH/NHLBI grant R01HL071798 to M.A.Z. and NIH/ORDR/NCATS/NHLBI grant U54HL096458 to M.W.L. and M.A.Z.) contributed to the work relating to diagnosis, screening and prevention. The Genetic Disorders of Mucociliary Clearance Consortium (GDMCC; U54HL096458) is part of the NCATS RDCRN and is supported by the RDCRN Data Management and Coordinating Center (DMCC; U2CTR002818). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR) funded through a collaboration between NCATS and the NHLBI. PCD clinical and research activities in Southampton, UK, are funded or supported by NHS England, NIHR RfPB (200470), NIHR Southampton Clinical Research Facility, AAIR Charity, Wessex Medical Research, BEAT-PCD European Respiratory Society, BEAT-PCD COST Action (BM1407) and the Clinical Research Collaboration European Reference Network for Rare Respiratory Diseases (ERN-LUNG; project ID no. 739546), contributing to the work on quality of life. The Children Lung Foundation (Denmark) contributed to the work relating to disease management. H.O. received funding from the Deutsche Forschungsgemeinschaft (DFG; Om6/7, Om6/8, OM6/10, OM6/14, and DFG clinical research unit 326 subprojekt OM6/11), the Interdisziplinaeres Zentrum für Klinische Forschung (IZKF) Muenster (Om2/015/16, OM2/10/20), and the European Commission (LYSOCIL, Horizon2020 GA ID 811087 and Registry Warehouse, Horizon2020 GA ID 777295). J.W. received funding from the DFG (WA 4283/1-1), “Innovative Medical Research” of the University of Muenster Medical School (WA 1 2 14 18) and “Dekanat der Medizinischen Fakultät der WWU”. J.W., K.G.N., J.S.L., C.E.K. and H.O. are members of the European Reference Network of Rare Respiratory Disease (ERN-LUNG).

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Introduction (H.O. and J.W.); Epidemiology (C.E.K.); Mechanisms/pathophysiology (H.O. and J.W.); Diagnosis, screening and prevention (H.O., J.W., M.W.L., C.E.K. J.S.L and M.A.Z.); Management (K.G.N.); Quality of life (J.S.L.); Outlook (H.O. and J.W.); Overview of Primer (H.O.).

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Nature Reviews Disease Primers thanks A. Bush, R. Hirst, F. Santamaria, A. Shoemark and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

ERN-Lung: https://ern-lung.eu/

European Reference Networks (ERNs): http://ec.europa.eu/health/ern/policy_en

NHLBI primary ciliary dyskinesia: https://www.nhlbi.nih.gov/health-topics/primary-ciliary-dyskinesia

RDCRN primary ciliary dyskinesia: https://rarediseases.info.nih.gov/diseases/4484/primary-ciliary-dyskinesia

US CDC meningococcal vaccine recommendations: https://www.cdc.gov/vaccines/vpd/mening/hcp/recommendations.html

US CDC pneumococcal vaccination: https://www.cdc.gov/pneumococcal/vaccination.html

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Wallmeier, J., Nielsen, K.G., Kuehni, C.E. et al. Motile ciliopathies. Nat Rev Dis Primers 6, 77 (2020). https://doi.org/10.1038/s41572-020-0209-6

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