The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans

• Type of Material: Article
• Authors: Maureen Wirschell, Emory University; Heike Olbrich, University Hospital Muenster; Claudius Werner, University Hospital Muenster; Douglas Tritschler, University of Minnesota; Raqual Bower, University of Minnesota; Winfield Sale, Emory University; Niki T. Loges, University Hospital Muenster; Petra Pennekamp, University Hospital Muenster; Sven Lindberg, Lund University; Unne Stenram, Lund University; Birgitta Carlen, Lund University; Elisabeth Horak, Medical University of Innsbruck; Gabriele Koehler, University Hospital Muenster; Peter Nuernberg, University of Cologne; Gudrun Nuernberg, University of Cologne; Mary E. Porter, University of Minnesota; Heymut Omran, University Hospital Muenster
• Language: English
• Date: 2013-03-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Nature America, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/ng.2533
• Title of Journal or Parent Work: Nature Genetics
• ISSN: 1061-4036
• Volume: 45
• Issue: 3
• Start Page: 262
• End Page: 268
• Grant/Funding Information: This work was supported by NIH grants to MEP (GM-55667) and WSS (GM-051173); an NRSA postdoctoral fellowship to MW (GM-075446); funding to WSS from the Children’s Healthcare of Atlanta and Emory University School of Medicine Pediatric Research Center; and funding to Heymut Omran (the “Deutsche Forschungsgemeinschaft” DFG Om 6/4, GRK1104, SFB592, IZKF Muenster and the CEDAD graduate school as well as SYSCILIA from the European community).; Technical and software support was also provided by the Minnesota Supercomputing Institutute.; The Center for Mass Spectrometry and Proteomics at the University of Minnesota is supported by multiple grants including NSF Major Research Instrumentation grants 9871237 and NSF-DBI-0215759.
• Keywords: Life Sciences & Biomedicine; Genetics & Heredity; ASYMMETRY; IDENTIFICATION; RADIAL SPOKES; DEFECTS; Science & Technology; ARMS; INNER; MUTATIONS; MUTANTS; DYSKINESIA; CHLAMYDOMONAS-FLAGELLA
• Research Categories: Biology, Cell; Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Primary ciliary dyskinesia (PCD) is characterized by dysfunction of respiratory cilia and sperm flagella and random determination of visceral asymmetry. Here, we identify the DRC1 subunit of the nexin-dynein regulatory complex (N-DRC), an axonemal structure critical for the regulation of dynein motors, and show that mutations in the gene encoding DRC1, CCDC164, are involved in PCD pathogenesis. Loss-of-function mutations disrupting DRC1 result in severe defects in assembly of the N-DRC structure and defective ciliary movement in Chlamydomonas reinhardtii and humans. Our results highlight a role for N-DRC integrity in regulating ciliary beating and provide the first direct evidence that mutations in DRC genes cause human disease.