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Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms

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  3. The Controversies and Difficulties of Diagnosing Primary Ciliary Dyskinesia

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  • Inga M Höben
  • Rim Hjeij
  • Heike Olbrich
  • Gerard W Dougherty
  • Tabea Nöthe-Menchen
  • Isabella Aprea
  • Diana Frank
  • Petra Pennekamp
  • Bernd Dworniczak
  • Julia Wallmeier
  • Johanna Raidt
  • Kim G Nielsen
  • Maria C Philipsen
  • Francesca Santamaria
  • Laura Venditto
  • Israel Amirav
  • Huda Mussaffi
  • Freerk Prenzel
  • Kaman Wu
  • Zeineb Bakey
  • Miriam Schmidts
  • Niki T Loges
  • Heymut Omran
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Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11orf70 showed that C11orf70 is expressed in ciliated respiratory cells and that the expression of C11orf70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein-arm assembly factors. Furthermore, C11orf70 shows an interaction with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11orf70 is a preassembly factor involved in the pathogenesis of PCD. The identification of additional genetic defects that cause PCD and male infertility is of great importance for the clinic as well as for genetic counselling.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume102
Issue number5
Pages (from-to)973-984
Number of pages12
ISSN0002-9297
DOIs
Publication statusPublished - 2018

    Research areas

  • Body Patterning, Cilia/metabolism, Dyneins/genetics, Female, Genes, Recessive, Humans, Kartagener Syndrome/genetics, Loss of Function Mutation/genetics, Male, Mutation/genetics, Nuclear Proteins/genetics, Sperm Tail/metabolism

ID: 59080972