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NIH Public Access Author Manuscript Nat Genet NIH Public Access Author Manuscript Nat Genet. Author manuscript; available in PMC 2014 April 26. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Nat Genet. 2013 September ; 45(9): 995–1003. doi:10.1038/ng.2707. DYX1C1 is required for axonemal dynein assembly and ciliary motility Aarti Tarkar1,*, Niki T. Loges2,*, Christopher E. Slagle3,*, Richard Francis4, Gerard W. Dougherty2, Joel V. Tamayo3, Brett Shook1, Marie Cantino1, Daniel Schwartz1, Charlotte Jahnke2, Heike Olbrich2, Claudius Werner2, Johanna Raidt2, Petra Pennekamp2, Marouan Abouhamed2, Rim Hjeij2, Gabriele Köhler5, Matthias Griese6, You Li4, Kristi Lemke4, Nikolas Klena4, Xiaoqin Liu4, George Gabriel4, Kimimasa Tobita4, Martine Jaspers7, Lucy C. Morgan8, Adam J. Shapiro9, Stef J.F. Letteboer10,11, Dorus A. Mans10,11, Johnny L. Carson9, Margaret W. Leigh9, Whitney E. Wolf12, Serafine Chen3, Jane S. Lucas13, Alexandros Onoufriadis14, Vincent Plagnol15, Miriam Schmidts14, Karsten Boldt16, UK10K17, Ronald Roepman10,11,18, Maimoona Zariwala19, Cecilia W. Lo4, Hannah M. Mitchison14, Michael R. Knowles12, Rebecca D. Burdine3, Joseph J. LoTurco1,+, and Heymut Omran2,+ 1Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269-3156, USA 2Department of Pediatrics, University Hospital Muenster, 48149 Muenster; Germany 3Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA 4Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201 5Department of Pathology, University Hospital Muenster, 48149 Muenster, Germany 6Dr. von Haunersches Children‘s Hospital, Ludwig Maximilian University, 80337 Munich, Germany 7University Hospital Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium 8Department of +Corresponding and lead authors: Joseph J. LoTurco; Department of Physiology and Neurobiology; University of Connecticut; Storrs, CT 06269-3156, USA; Phone: +1-860-486-3271; [email protected], Heymut Omran; Department of Pediatrics; University Hospital Muenster; 48149, Muenster; Germany; Phone: +49-251-8347731; [email protected]. *Shared first author contribution. 17A list of members appears in the Supplementary Note URLs ZFIN Direct Data Submission: http://zfin.org (2004); For further information about the UK10K group: http://uk10k.org.uk; Complex congenital heart disease (CCHD) database: http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=alleleDetail&id=MGI:531 1375 Database accession numbers All cDNA clones were confirmed by sequence analysis and matched the following gene accession numbers: NM_130810.3 (DYX1C1), NM_178452.4 (DNAAF1/LRRC50), BC016843 (DNAAF3/C19orf51), NM_213607.1 (CCDC103), and NM_018139.2 (DNAAF2/KTU). Authors Contributions J.L. and H.O. designed the study. Authors contributing to human DYX1C1: N.T.L., C.J., H.Ol., R.H., G.W.D., P.P., M.A., D.A.M., S.J.F.L., R.R., K.B. and J.R. performed the experiments and analysed the human data, G.K., C.W., J.R., M.G., M.J., H.O. provided clinical OP patient data; M.Z., L.C.M., A.J. S., J.L.C., M.W.L., W.E.W. and M.R.K. performed mutational analyses and provided the clinical data from UNC patients; UCL patient clinical ascertainment: J.S.L.; UCL mutation analysis: A.O., M.S., H.M.M.; deletion algorithm for UCL patients: V.P., UK’s exome sequencing: UK10K. Authors contributing to mouse Dyx1c1: A.T., B.S., M.C., N.T.L., P.P., M.A. performed the experiments and analysed the mouse data. Authors contributing to mouse Sharpei: R.F., Y.L., K.L., N.K., X.L., G.G., K.T. performed the experiments and analysed the mouse data. Authors contributing to zebrafish Dyx1c1: C.E.S., J.V.T., S.C., R.D.B. performed the experiments and analysed the zebrafish data. Authors contributing to Y2H experiments: D.A.M., S.J.F.L., R.R. Author information The authors have no competing interests as defined by Nature Publishing Group, or other interests that might be perceived to influence the results and/or discussion reported in this article. Tarkar et al. Page 2 Respiratory Medicine, Concord Hospital, Concord 2139, Australia 9Department of Pediatrics, NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript UNC School of Medicine, Chapel Hill, NC 27599, USA 10Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands 11Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands 12Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA 13Primary Ciliary Dyskinesia Centre, NIHR Southampton Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, SO17 1BJ, UK 14Molecular Medicine Unit, Institute of Child Health, University College London, London WC1N 1EH, UK 15University College London, Genetics Institute, London, WC1E 6BT, UK 16Institute for Ophthalmic Research, Division of Experimental Ophthalmology and Medical Proteome Center, University of Tuebingen, D-72076 Tuebingen, Germany 18Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands 19Department of Pathology & Laboratory Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA SUMMARY Dyx1c1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deletion of Dyx1c1 exons 2–4 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a genetically heterogeneous disorder characterized by chronic airway disease, laterality defects, and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1c.T2A start codon mutation recovered from an ENU mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also created laterality and ciliary motility defects. In humans, recessive loss-of-function DYX1C1 mutations were identified in twelve PCD individuals. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans revealed disruptions of outer and inner dynein arms (ODA/IDA). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA/IDA assembly factor DNAAF2/ KTU. Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4). Cilia, hair-like organelles projecting from the surface of nearly all polarized cell types, serve essential roles in cellular signalling and motility1. The basic structure of motile cilia, and the related organelle flagellum is remarkably conserved throughout evolution. In most motile cilia, a ring of nine peripheral microtubule doublets surrounds a central pair apparatus of single microtubules that connect to the nine peripheral doublets by radial spokes (9+2 structure). Motile monocilia present at the mouse node during early embryogenesis are an exception, lacking the central pair apparatus (9+0 structure). Distinct multi-protein dynein complexes attached at regular intervals to the peripheral microtubule doublets contain molecular motors that drive and regulate ciliary motility. Specifically, outer dynein arms (ODA) are responsible for beat generation, while both the inner dynein arms (IDA) and the nexin link-dynein regulatory complexes (N-DRCs) regulate ciliary and flagellar beating pattern and frequency. Identifying the proteins responsible for correct assembly of this molecular machinery is critical to understanding the causes of motile cilia-related diseases. Nat Genet. Author manuscript; available in PMC 2014 April 26. Tarkar et al. Page 3 Primary ciliary dyskinesia (PCD) (MIM 242650), a rare genetic disorder affecting approximately 1 in 20,000 individuals, is caused by immotile or dyskinetic cilia. Loss of NIH-PA Author Manuscript NIH-PA Author Manuscriptciliary NIH-PA Author Manuscript function in upper and lower airways causes defective mucociliary airway clearance and subsequently, chronic inflammation that regularly progresses to destructive airway disease (bronchiectasis). Organ laterality defects are also observed with approximately half of PCD patients exhibiting situs inversus, and more rarely situs ambiguus, which can associate with complex congenital heart disease2. Dysfunctional sperm tails (flagella) frequently cause male infertility in PCD individuals, warranting assisted reproductive technologies. Another consequence of ciliary dysfunction, particularly evident in mouse models, is hydrocephalus caused by disrupted flow of cerebrospinal fluid through the cerebral aqueduct connecting the third and fourth brain ventricles3. Although ciliary dysmotility is not sufficient for hydrocephalus formation in humans due to morphological differences between the mouse and human brain, the incidence of hydrocephalus, secondary to aqueduct closure, is increased in PCD individuals3. Genetic analyses of PCD patients have now revealed several autosomal recessive mutations in genes encoding axonemal subunits of the ODA complexes and related components4–12. In addition, recessive mutations in CCDC39 (MIM 613798) and CCDC40 (MIM 613799) have been linked to PCD with severe tubular disorganisation and defective nexin links13,14. Mutations in the radial spoke head genes RSPH4A and RSPH9 as well as in HYDIN can cause intermittent or complete loss of the central apparatus microtubules15–17. Two X-linked PCD variants associated with syndromic cognitive dysfunction and retinal degeneration are caused by mutations
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