TTC12 loss-of-function mutations cause primary ciliary dyskinesia and unveil distinct dynein assembly mechanisms in motile cilia versus flagella - Archive ouverte HAL Access content directly
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TTC12 loss-of-function mutations cause primary ciliary dyskinesia and unveil distinct dynein assembly mechanisms in motile cilia versus flagella

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Khaled Bouhouche
  • Function : Author
  • PersonId : 908712
Guillaume Thouvenin
  • Function : Author
  • PersonId : 930596
Manon Castelli
  • Function : Author
Michel Lemullois
  • Function : Author
Xavier Dhalluin
  • Function : Author
  • PersonId : 1095240
Valérie Drouin-Garraud
  • Function : Author
  • PersonId : 902580
Isabelle Honoré
  • Function : Author
  • PersonId : 1057282
Nicole Beydon
  • Function : Author
  • PersonId : 1096376
Nathalie Rives
  • Function : Author
France Koll
  • Function : Author
Anne-Marie Tassin

Abstract

Cilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs/IDAs). Defects in ODAs/IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. To date PCD mutations in assembly factors cause a combined ODA/IDA defect, affecting both cilia and flagella. We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the sole absence of IDAs in respiratory cilia. We analysed both primary cells from individuals carrying TTC12 mutations and human differentiated airway cells invalidated for TTC12 by a CRISPR-Cas9 approach, as well as TTC12 depletion in the ciliated model, Paramecium tetraureli. Our results revealed an IDA defect restricted to a subset of single-headed IDAs different in flagella and cilia, while TTC12 depletion in Paramecium tetraurelia recapitulated the sperm phenotype. Overall, our study, which identifies TTC12 as a new gene involved in PCD, unveils distinct dynein assembly mechanisms in human motile cilia versus flagella.
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Dates and versions

inserm-03845363 , version 1 (09-11-2022)

Identifiers

  • HAL Id : inserm-03845363 , version 1

Cite

Lucie THOMAS, Khaled Bouhouche, Marjorie Whitfield, Guillaume Thouvenin, André Coste, et al.. TTC12 loss-of-function mutations cause primary ciliary dyskinesia and unveil distinct dynein assembly mechanisms in motile cilia versus flagella. ESHG 2022, Jun 2022, Vienne, Austria. ⟨inserm-03845363⟩
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