Structural insights into the cause of human RSPH4A primary ciliary dyskinesia

Yanhe Zhao, Justine Pinskey, Jianfeng Lin, Weining Yin, Patrick R. Sears, Leigh A. Daniels, Maimoona A. Zariwala, Michael R. Knowles, Lawrence E. Ostrowski, Daniela Nicastro

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Cilia and flagella are evolutionarily conserved eukaryotic organelles involved in cell motility and signaling. In humans, mutations in Radial Spoke Head Component 4A (RSPH4A) can lead to primary ciliary dyskinesia (PCD), a life-shortening disease characterized by chronic respiratory tract infections, abnormal organ positioning, and infertility. Despite its importance for human health, the location of RSPH4A in human cilia has not been resolved, and the structural basis of RSPH4A-/- PCD remains elusive. Here, we present the native three-dimensional structure of RSPH4A-/- human respiratory cilia using samples collected noninvasively from a PCD patient. Using cryo-electron tomography (cryo-ET) and subtomogram averaging, we compared the structures of control and RSPH4A-/- cilia, revealing primary defects in two of the three radial spokes (RSs) within the axonemal repeat and secondary (heterogeneous) defects in the central pair complex. Similar to RSPH1-/- cilia, the radial spoke heads of RS1 and RS2, but not RS3, were missing in RSPH4A-/- cilia. However, RSPH4A-/- cilia also exhibited defects within the arch domains adjacent to the RS1 and RS2 heads, which were not observed with RSPH1 loss. Our results provide insight into the underlying structural basis for RSPH4A-/- PCD and highlight the benefits of applying cryo-ET directly to patient samples for molecular structure determination.

Original languageEnglish (US)
Pages (from-to)1202-1209
Number of pages8
JournalMolecular biology of the cell
Issue number12
StatePublished - May 27 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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