1. Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms
- Author
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Gerard W. Dougherty, Petra Pennekamp, Johanna Raidt, Inga M. Höben, Laura Venditto, Julia Wallmeier, Israel Amirav, Tabea Nöthe-Menchen, Heymut Omran, Diana Frank, Huda Mussaffi, Kaman Wu, Kim G. Nielsen, Niki T. Loges, Maria C. Philipsen, Bernd Dworniczak, Zeineb Bakey, Isabella Aprea, Francesca Santamaria, Miriam Schmidts, Freerk Prenzel, Rim Hjeij, Heike Olbrich, Höben, Inga M., Hjeij, Rim, Olbrich, Heike, Dougherty, Gerard W., Nöthe-Menchen, Tabea, Aprea, Isabella, Frank, Diana, Pennekamp, Petra, Dworniczak, Bernd, Wallmeier, Julia, Raidt, Johanna, Nielsen, Kim G., Philipsen, Maria C., Santamaria, Francesca, Venditto, Laura, Amirav, Israel, Mussaffi, Huda, Prenzel, Freerk, Wu, Kaman, Bakey, Zeineb, Schmidts, Miriam, Loges, Niki T., and Omran, Heymut
- Subjects
Male ,0301 basic medicine ,primary ciliary dyskinesia ,Genes, Recessive ,Flagellum ,Biology ,Male infertility ,Pathogenesis ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,dynein arm ,Genetic ,Loss of Function Mutation ,Report ,Ciliogenesis ,preassembly ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Nuclear Protein ,Body Patterning ,Primary ciliary dyskinesia ,Kartagener Syndrome ,Cilium ,cilia ,Dynein ,Dyneins ,Nuclear Proteins ,C11ORF70 ,medicine.disease ,Sperm ,sperm flagella ,3. Good health ,Cell biology ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,030104 developmental biology ,Sperm Tail ,Mutation ,Motile cilium ,Female ,Human - Abstract
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.
- Published
- 2018