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DYX1C1 is required for axonemal dynein assembly and ciliary motility

Nature Genetics volume 45, pages 995–1003 (2013)Cite this article

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Abstract

DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2–4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4).

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Figure 1: Deficiency of Dyx1c1 in mouse causes phenotypes consistent with motile cilia defects.
Figure 2: Knockdown of dyx1c1 in zebrafish.
Figure 3: Motile cilia are dysfunctional in Dyx1c1-mutant mice.
Figure 4: DYX1C1 mutations in humans cause defective ODA and IDA assembly.
Figure 5: DYX1C1 is localized in the cytoplasm of respiratory epithelial cells and interacts with DNAAF2.

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NCBI Reference Sequence

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NCBI Reference Sequence

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Acknowledgements

We thank the individuals with PCD and their families for participating in this study, the German patient support group Kartagener Syndrom und Primaere Ciliaere Dyskinesie and the US PCD foundation. We thank S. King (University of Connecticut Health Center) for providing antibodies and for helpful discussions. This work was funded by the Deutsche Forschungsgemeinschaft (DFG Om 6/4), by the Interdisziplinaeres Zentrum für Klinische Forschung (IZKF) Münster (H. Omran), by the European Community's Seventh Framework Programme FP7/2009, under grant agreement 241955, SYSCILIA (R.R. and H. Omran), and BESTCILIA, under grant agreement 305404 (H. Omran), by the Netherlands Organization for Scientific Research (NWO; Vidi-91786396 and Vici-016.130.664) (R.R.) and by grants from the US National Institutes of Health (NIH; R01 HD055655, R01 MH056524 and P01 HD057853 (J.J.L.): research grant 5 U54 HL096458-06 (M.R.K., M.W.L., J.L.C. and M.A.Z.); NHLBI grant 5 R01HL071798 (M.R.K. and M.A.Z.); National Institute of Child Health and Human Development (NICHD) grant 2 R01HD048584 (C.E.S., J.V.T., S.C. and R.D.B.); NIH grant U01HL098180 (C.W.L.); and American Heart Association fellowship (Y.L.). The work was also supported by Newlife Foundation grant 10/11/15 (H.M.M.) and Action Medical Research grant RTF1411 (M.S.). UK10K was funded by the Wellcome Trust (award WT091310). This work was supported in part by US NIH grant UL1 TR000083 from the National Center for Advancing Translational Sciences (NCATS).

Author information

Author notes

  1. Aarti Tarkar, Niki T Loges, Christopher E Slagle and Maimoona A Zariwala: These authors contributed equally to this work.

  2. Joseph J LoTurco and Heymut Omran: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA

    Aarti Tarkar, Brett Shook, Marie Cantino, Daniel Schwartz & Joseph J LoTurco

  2. Department of Pediatrics, University Hospital Münster, Münster, Germany

    Niki T Loges, Gerard W Dougherty, Charlotte Jahnke, Heike Olbrich, Claudius Werner, Johanna Raidt, Petra Pennekamp, Marouan Abouhamed, Rim Hjeij & Heymut Omran

  3. Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA

    Christopher E Slagle, Joel V Tamayo, Serafine Chen & Rebecca D Burdine

  4. Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Richard Francis, You Li, Kristi Lemke, Nikolas Klena, Xiaoqin Liu, George Gabriel, Kimimasa Tobita & Cecilia W Lo

  5. Department of Pathology, University Hospital Münster, Münster, Germany

    Gabriele Köhler

  6. Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany

    Matthias Griese

  7. Department of Otorhinolaryngology, University Hospital Leuven, Leuven, Belgium

    Martine Jaspers

  8. Department of Respiratory Medicine, Concord Hospital, Concord, New South Wales, Australia

    Lucy C Morgan

  9. Department of Pediatrics, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina, USA

    Adam J Shapiro, Johnny L Carson & Margaret W Leigh

  10. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands

    Stef J F Letteboer, Dorus A Mans & Ronald Roepman

  11. Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands

    Stef J F Letteboer, Dorus A Mans & Ronald Roepman

  12. Department of Medicine, UNC School of Medicine, Chapel Hill, North Carolina, USA

    Whitney E Wolf & Michael R Knowles

  13. Primary Ciliary Dyskinesia Centre, National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton, UK

    Jane S Lucas

  14. Molecular Medicine Unit, Institute of Child Health, University College London, London, UK

    Alexandros Onoufriadis, Miriam Schmidts & Hannah M Mitchison

  15. Genetics Institute, University College London, London, UK

    Vincent Plagnol

  16. Division of Experimental Ophthalmology and Medical Proteome Center, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany

    Karsten Boldt

  17. Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands

    Ronald Roepman

  18. Department of Pathology & Laboratory Medicine, UNC School of Medicine, Chapel Hill, North Carolina, USA

    Maimoona A Zariwala

Authors
  1. Aarti Tarkar
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  2. Niki T Loges
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  3. Christopher E Slagle
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  4. Richard Francis
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  5. Gerard W Dougherty
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  6. Joel V Tamayo
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  7. Brett Shook
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  8. Marie Cantino
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  9. Daniel Schwartz
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  16. Rim Hjeij
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  17. Gabriele Köhler
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  18. Matthias Griese
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  19. You Li
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  24. Kimimasa Tobita
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  25. Martine Jaspers
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  26. Lucy C Morgan
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  27. Adam J Shapiro
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  28. Stef J F Letteboer
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  29. Dorus A Mans
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  30. Johnny L Carson
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  31. Margaret W Leigh
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  32. Whitney E Wolf
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  33. Serafine Chen
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  34. Jane S Lucas
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  36. Vincent Plagnol
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  37. Miriam Schmidts
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  38. Karsten Boldt
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  39. Ronald Roepman
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  40. Maimoona A Zariwala
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  41. Cecilia W Lo
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  42. Hannah M Mitchison
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  43. Michael R Knowles
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  44. Rebecca D Burdine
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  45. Joseph J LoTurco
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  46. Heymut Omran
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Consortia

UK10K

Contributions

J.J.L. and H. Omran designed the study. N.T.L., C.J., H. Olbrich, R.H., G.W.D., P.P., M.A., D.A.M., S.J.F.L., R.R., K.B. and J.R. performed experiments with human DYX1C1 and analyzed the data. G.K., C.W., J.R., M.G., M.J. and H. Omran provided clinical data on OP cases. M.A.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 clinical data from UNC cases. J.S.L. performed clinical ascertainment of UCL cases. A.O., M.S. and H.M.M. performed mutation analysis of UCL cases. V.P. developed the deletion algorithm for UCL cases. UK10K performed exome sequencing of UK samples. A.T., B.S., M.C., N.T.L., D.S., P.P. and M.A. performed experiments with mouse Dyx1c1 and analyzed the data. C.W.L., R.F., Y.L., K.L., N.K., X.L., G.G. and K.T. performed experiments with the mouse Sharpei mutant and analyzed the data. C.E.S., J.V.T., S.C. and R.D.B. performed the zebrafish experiments and analyses. D.A.M., S.J.F.L. and R.R. contributed to the yeast two-hybrid experiments.

Corresponding authors

Correspondence to Joseph J LoTurco or Heymut Omran.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Details appear in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 4–6, Supplementary Figures 1–9 and Supplementary Notes (PDF 2280 kb)

Supplementary Table 1

Clinical findings and DYX1C1 mutations in PCD patients with ODA and IDA defects. (XLSX 14 kb)

Supplementary Table 2

Wild-type and knockout MS/MS results. (XLSX 1009 kb)

Supplementary Table 3

Complete list of PANTHER Gene Ontology enrichment terms from Dyx1c1-interacting proteins identified by tandem mass spectrometry. (XLSX 25 kb)

Supplementary Video 1

Sharpei mutants show a spectrum of complex CHD, such as transposition of the great arteries with ventricular septal defect and coronary fistula. (AVI 10661 kb)

Supplementary Video 2

Sharpei mutants show a spectrum of complex CHD, such as double-outlet right ventricle with right atrial isomerism. (AVI 21309 kb)

Supplementary Video 3

Sharpei mutants show a spectrum of complex CHD, such as muscular VSD and atrioventricular septal defects. (AVI 8636 kb)

Supplementary Video 4

Directional ependymal fluid flow visualized by the displacement of a small volume of India ink pressure injected onto the ependymal surface. (AVI 261 kb)

Supplementary Video 5

Directional ependymal fluid flow was completely missing in tissue obtained from all Dyx1c1Δ/Δ. (AVI 238 kb)

Supplementary Video 6

Motility of ependymal cilia in coronal brain slices examined by IR-DIC videomicroscopy. (AVI 316 kb)

Supplementary Video 7

Cilia on ependymal cells from all Dyx1c1Δ/Δ examined (n = 4) lacked ciliary beating. (AVI 313 kb)

Supplementary Video 8

Videomicroscopy of tissue slice from the third brain ventricle in newborn homozygous Sharpei mutants also showed completely immotile cilia. Beads added to the solution above the brain slice exhibited only random motion, whereas in wild-type littermate control, the beads showed ependymal cilia–generated flow (AVI 18924 kb)

Supplementary Video 9

Tracheal airway epithelia in newborn homozygous Sharpei mutants showed completely immotile cilia, consistent with PCD, whereas littermate controls showed normal rapid synchronous ciliary beat. (AVI 18733 kb)

Supplementary Video 10

dyx1c1 morpholino–injected embryos had cilia in Kupffer's vesicle that lacked motility compared to uninjected embryos. The video scans through the Kupffer's vesicle, and non-motile cilia can be observed on the periphery. (AVI 722 kb)

Supplementary Video 11

Motility of cilia in Kupffer's vesicle in a wild-type zebrafish embryo analyzed with high-speed videomicroscopy. The video scans through the Kupffer's vesicle, and motile cilia can be observed on the periphery. (AVI 1815 kb)

Supplementary Video 12

Analysis of the ciliary beating pattern of respiratory cilia from OP-86 II2 by high-speed videomicroscopy. (AVI 2093 kb)

Supplementary Video 13

Analysis of the ciliary beating pattern of respiratory cilia from OP-86 II2 by high-speed videomicroscopy. (AVI 15106 kb)

Supplementary Video 14

Analysis of the ciliary beating pattern of respiratory cilia from F648II1 by high-speed videomicroscopy. (AVI 15106 kb)

Supplementary Video 15

Analysis of the ciliary beating pattern of respiratory cilia from F648II1 by high-speed videomicroscopy. (AVI 15106 kb)

Supplementary Video 16

Analysis of the ciliary beating pattern of respiratory cilia from control respiratory cells by high-speed videomicroscopy. (AVI 15106 kb)

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Tarkar, A., Loges, N., Slagle, C. et al. DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat Genet 45, 995–1003 (2013). https://doi.org/10.1038/ng.2707

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