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

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  • Jianfeng Lin

    (Rosenstiel Basic Medical Sciences Research Center, Brandeis University)

  • Weining Yin

    (Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina)

  • Maria C. Smith

    (Rosenstiel Basic Medical Sciences Research Center, Brandeis University)

  • Kangkang Song

    (Rosenstiel Basic Medical Sciences Research Center, Brandeis University)

  • Margaret W. Leigh

    (University of North Carolina School of Medicine)

  • Maimoona A. Zariwala

    (University of North Carolina School of Medicine)

  • Michael R. Knowles

    (University of North Carolina School of Medicine)

  • Lawrence E. Ostrowski

    (Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina)

  • Daniela Nicastro

    (Rosenstiel Basic Medical Sciences Research Center, Brandeis University)

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.

Suggested Citation

  • Jianfeng Lin & Weining Yin & Maria C. Smith & Kangkang Song & Margaret W. Leigh & Maimoona A. Zariwala & Michael R. Knowles & Lawrence E. Ostrowski & Daniela Nicastro, 2014. "Cryo-electron tomography reveals ciliary defects underlying human RSPH1 primary ciliary dyskinesia," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6727
    DOI: 10.1038/ncomms6727
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    Cited by:

    1. Avrin Ghanaeian & Sumita Majhi & Caitlyn L. McCafferty & Babak Nami & Corbin S. Black & Shun Kai Yang & Thibault Legal & Ophelia Papoulas & Martyna Janowska & Melissa Valente-Paterno & Edward M. Marco, 2023. "Integrated modeling of the Nexin-dynein regulatory complex reveals its regulatory mechanism," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Xueming Meng & Cong Xu & Jiawei Li & Benhua Qiu & Jiajun Luo & Qin Hong & Yujie Tong & Chuyu Fang & Yanyan Feng & Rui Ma & Xiangyi Shi & Cheng Lin & Chen Pan & Xueliang Zhu & Xiumin Yan & Yao Cong, 2024. "Multi-scale structures of the mammalian radial spoke and divergence of axonemal complexes in ependymal cilia," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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