Deletions and Point Mutations of LRRC50 Cause Primary Ciliary Dyskinesia Due to Dynein Arm Defects |
| |
| Authors: | Niki Tomas Loges Heike Olbrich Anita Becker-Heck Karsten Häffner Angelina Heer Christina Reinhard Miriam Schmidts Andreas Kispert Maimoona A. Zariwala Margaret W. Leigh Michael R. Knowles Hanswalter Zentgraf Horst Seithe Gudrun Nürnberg Peter Nürnberg Richard Reinhardt Heymut Omran |
| |
| Affiliation: | 1. Department of Paediatrics and Adolescent Medicine, University Hospital 79106 Freiburg, Germany;2. Faculty of Biology, Albert-Ludwigs-University, 79104 Freiburg, Germany;3. Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hanover, Germany;4. Department of Pathology, University of North Carolina, Chapel Hill, NC 27599-3380, USA;5. Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599-3380, USA;6. Department of Medicine, University of North Carolina, Chapel Hill, NC 27599-3380, USA;7. Department of Tumor Virology, German Cancer Research Center, 69120 Heidelberg, Germany;8. Zentrum für Neugeborene, Kinder und Jugendliche, Klinikum Nürnberg Süd, 90471 Nürnberg, Germany;9. Cologne Center for Genomics and Institute for Genetics, 50674 Cologne, Germany;10. Center for Molecular Medicine Cologne, 50931 Cologne, Germany;11. Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany;12. Max-Planck Institute for Molecular Genetics, 14195 Berlin, Germany;13. Klinik und Poliklinik für Kinder- und Jugendmedizin - Allgemeine Pädiatrie - Universitätsklinikum Münster, Albert-Schweitzer-Strasse 33; 48149 Münster, Germany |
| |
| Abstract: | Genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility in primary ciliary dyskinesia (PCD). The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein complexes responsible for cilia-beat generation and regulation, respectively. Here, we demonstrate that large genomic deletions, as well as point mutations involving LRRC50, are responsible for a distinct PCD variant that is characterized by a combined defect involving assembly of the ODAs and IDAs. Functional analyses showed that LRRC50 deficiency disrupts assembly of distally and proximally DNAH5- and DNAI2-containing ODA complexes, as well as DNALI1-containing IDA complexes, resulting in immotile cilia. On the basis of these findings, we assume that LRRC50 plays a role in assembly of distinct dynein-arm complexes. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
