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      Mice with a Deletion of Rsph1 Exhibit a Low Level of Mucociliary Clearance and Develop a Primary Ciliary Dyskinesia Phenotype

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          Abstract

          Primary ciliary dyskinesia (PCD) is a genetically and phenotypically heterogeneous disease caused by mutations in over 40 different genes. Individuals with PCD caused by mutations in RSPH1 (radial spoke head 1 homolog) have been reported to have a milder phenotype than other individuals with PCD, as evidenced by a lower incidence of neonatal respiratory distress, higher nasal nitric oxide concentrations, and better lung function. To better understand genotype–phenotype relationships in PCD, we have characterized a mutant mouse model with a deletion of Rsph1. Approximately 50% of cilia from Rsph1 −/− cells appeared normal by transmission EM, whereas the remaining cilia revealed a range of defects, primarily transpositions or a missing central pair. Ciliary beat frequency in Rsph1 −/− cells was significantly lower than in control cells (20.2 ± 0.8 vs. 25.0 ± 0.9 Hz), and the cilia exhibited an aberrant rotational waveform. Young Rsph1 −/− animals demonstrated a low rate of mucociliary clearance in the nasopharynx that was reduced to zero by about 1 month of age. Rsph1 −/− animals accumulated mucus in the nasal cavity but had a lower bacterial burden than animals with a deletion of dynein axonemal intermediate chain 1 ( Dnaic1 −/−). Thus, Rsph1 −/− mice display a PCD phenotype similar to but less severe than that observed in Dnaic1 −/− mice, similar to what has been observed in humans. The results suggest that some individuals with PCD may not have a complete loss of mucociliary clearance and further suggest that early diagnosis and intervention may be important to maintain this low amount of clearance.

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          Author and article information

          Journal
          Am J Respir Cell Mol Biol
          Am. J. Respir. Cell Mol. Biol
          ajrcmb
          American Journal of Respiratory Cell and Molecular Biology
          American Thoracic Society
          1044-1549
          1535-4989
          September 2019
          September 2019
          : 61
          : 3
          : 312-321
          Affiliations
          Marsico Lung Institute/Cystic Fibrosis Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
          Author notes
          Correspondence and requests for reprints should be addressed to Lawrence E. Ostrowski, Ph.D., Marsico Lung Institute/Cystic Fibrosis Center, University of North Carolina at Chapel Hill, 6021A Thurston Bowles Building, CB#7248, Chapel Hill, NC 27599. E-mail: ostro@ 123456med.unc.edu .
          Article
          PMC6839924 PMC6839924 6839924 2017-0387OC
          10.1165/rcmb.2017-0387OC
          6839924
          30896965
          c1ed0907-4fea-4099-a615-1d104698c626
          Copyright © 2019 by the American Thoracic Society
          History
          : 01 November 2017
          : 20 March 2019
          Page count
          Figures: 6, Tables: 0, Pages: 10
          Categories
          Original Research
          Cystic Fibrosis

          bronchiectasis,radial spokes,cilia,mucociliary clearance,primary ciliary dyskinesia

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