Cryo-electron tomography reveals ciliary defects underlying human RSPH1 primary ciliary dyskinesia

Jianfeng Lin, Weining Yin, Maria C. Smith, Kangkang Song, Margaret W. Leigh, Maimoona A. Zariwala, Michael R. Knowles, Lawrence E. Ostrowski, Daniela Nicastro

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Cilia play essential roles in normal human development and health; cilia dysfunction results in diseases such as primary ciliary dyskinesia (PCD). Despite their importance, the native structure of human cilia is unknown, and structural defects in the cilia of patients are often undetectable or remain elusive because of heterogeneity. Here we develop an approach that enables visualization of human (patient) cilia at high-resolution using cryo-electron tomography of samples obtained noninvasively by nasal scrape biopsy. We present the native 3D structures of normal and PCD-causing RSPH1-mutant human respiratory cilia in unprecedented detail; this allows comparisons of cilia structure across evolutionarily distant species and reveals the previously unknown primary defect and the heterogeneous secondary defects in RSPH1-mutant cilia. Our data provide evidence for structural and functional heterogeneity in radial spokes, suggest a mechanism for the milder RSPH1 PCD phenotype and demonstrate that cryo-electron tomography can be applied to human disease by directly imaging patient samples.

Original languageEnglish (US)
Article number6727
JournalNature Communications
Volume5
DOIs
StatePublished - Jan 1 2015

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Electron Microscope Tomography
Kartagener Syndrome
Cilia
Tomography
tomography
Defects
Electrons
defects
spokes
phenotype
electrons
Biopsy
health
Visualization
Health
Imaging techniques
high resolution
Human Development
Nose
Phenotype

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)
  • Medicine(all)

Cite this

Cryo-electron tomography reveals ciliary defects underlying human RSPH1 primary ciliary dyskinesia. / Lin, Jianfeng; Yin, Weining; Smith, Maria C.; Song, Kangkang; Leigh, Margaret W.; Zariwala, Maimoona A.; Knowles, Michael R.; Ostrowski, Lawrence E.; Nicastro, Daniela.

In: Nature Communications, Vol. 5, 6727, 01.01.2015.

Research output: Contribution to journalArticle

Lin, J, Yin, W, Smith, MC, Song, K, Leigh, MW, Zariwala, MA, Knowles, MR, Ostrowski, LE & Nicastro, D 2015, 'Cryo-electron tomography reveals ciliary defects underlying human RSPH1 primary ciliary dyskinesia', Nature Communications, vol. 5, 6727. https://doi.org/10.1038/ncomms6727
Lin, Jianfeng ; Yin, Weining ; Smith, Maria C. ; Song, Kangkang ; Leigh, Margaret W. ; Zariwala, Maimoona A. ; Knowles, Michael R. ; Ostrowski, Lawrence E. ; Nicastro, Daniela. / Cryo-electron tomography reveals ciliary defects underlying human RSPH1 primary ciliary dyskinesia. In: Nature Communications. 2015 ; Vol. 5.
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AU - Zariwala, Maimoona A.

AU - Knowles, Michael R.

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