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.
| Original language | English |
|---|---|
| Pages (from-to) | 973-984 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 102 |
| Issue number | 5 |
| DOIs | |
| State | Published - 3 May 2018 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2018 American Society of Human Genetics
Funding
We are grateful to all affected individuals and their family members, whose cooperation made this study possible, and we thank all referring physicians. We thank A. Dorißen, D. Ernst, S. Helms, M. Herting, A. Robbers, L. Schwiddessen, F.J. Seesing, M. Tekaat, K. Wohlgemuth, and C. Westermann for excellent technical work. We would like to thank the Genome Aggregation Database and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/ . This work was supported by the Deutsche Forschungsgemeinschaft (DFG) OM6/7, OM6/8, OM6/9, OM6/10, OM6/11, and DFG KFO326 (H.O.), OL450/1 (H.Ol.), and HJ7/1-1 (R.H.), by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Münster to H.O. (Om2/009/12 and Om/015/16), the European Union seventh framework program under grant agreement 305404, project BESTCILIA (to H.O., K.G.N., and M.C.P.) and “Innovative Medical Research“ of the University of Muenster Medical School (I-LO121517 to N.T.L. and I-WA121418 to J.W.) and the Faculty of Medicine of the Westphalian Wilhelms University (to J.W.). M.S. acknowledges funding from Radboudumc and the Radboud Institute for Molecular Life Sciences Nijmegen (Hypatia tenure track fellowship), DFG (CRC1140 KIDGEM), and the European research Council (ERC StG TREATCilia, grant 716344). I.Am. acknowledges the Chief Office of the Ministry of Health in Israel grant number 3-6176 .
| Funders | Funder number |
|---|---|
| Faculty of Medicine of the Westphalian Wilhelms University | |
| Interdisziplinäres Zentrum für Klinische Forschung | Om/015/16, Om2/009/12 |
| Radboud Institute for Molecular Life Sciences Nijmegen | CRC1140 KIDGEM |
| University of Muenster Medical School | I-WA121418, I-LO121517 |
| Horizon 2020 Framework Programme | 716344 |
| European Commission | |
| Deutsche Forschungsgemeinschaft | OM6/11, OM6/10, OL450/1, KFO326, OM6/8, OM6/7, HJ7/1-1, OM6/9 |
| Seventh Framework Programme | 305404 |
| Ministry of Health, State of Israel | 3-6176 |
Keywords
- C11ORF70
- cilia
- dynein arms
- preassembly
- primary ciliary dyskinesia
- sperm flagella