Abstract

Cilia are evolutionarily conserved microtubule-based organelles that are crucial for diverse biological functions, including motility, cell signaling and sensory perception1. In humans, alterations in the formation and function of cilia manifest clinically as ciliopathies, a growing class of pleiotropic genetic disorders2,3,4. Despite the substantial progress that has been made in identifying genes that cause ciliopathies, therapies for these disorders are not yet available to patients. Although mice with a hypomorphic mutation in the intraflagellar transport protein IFT88 (Ift88Tg737Rpw mice, also known as ORPK mice)5 have been well studied, the relevance of IFT88 mutations to human pathology is unknown. We show that a mutation in IFT88 causes a hitherto unknown human ciliopathy. In vivo complementation assays in zebrafish and mIMCD3 cells show the pathogenicity of this newly discovered allele. We further show that ORPK mice are functionally anosmic as a result of the loss of cilia on their olfactory sensory neurons (OSNs). Notably, adenoviral-mediated expression of IFT88 in mature, fully differentiated OSNs of ORPK mice is sufficient to restore ciliary structures and rescue olfactory function. These studies are the first to use in vivo therapeutic treatment to reestablish cilia in a mammalian ciliopathy. More broadly, our studies indicate that gene therapy is a viable option for cellular and functional rescue of the complex ciliary organelle in established differentiated cells.

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Acknowledgements

This work was support by US National Institutes of Health grants R01DC009606 (J.R.M.), F32DC011990 (J.C.M.), R01DC004553, R01DC008295 (R.R.R.), R01DK75996 (B.K.Y.), R01EY021872 (E.E.D.), R01HD04260, R01DK072301 and R01DK075972 (N.K.), by l'Agence National pour la Recherche (ANR) 2010 FOETOCILPATH 1122 01 (T.A.-B.) and by the University of Alabama at Birmingham Hepatorenal Fibrocystic Disease Core Center (DK074083). E.E.D., C.A.J., P.L.B. and N.K. are supported by the European Community's Seventh Framework Programme FP7/2009 under grant agreement 241955, SYSCILIA. N.K. is a Distinguished Jean and George W. Brumley Professor. We thank P. Loget for referring the family for this study, S. Dugan-Rocha, U. Nagaswamy and A. Hawes for assistance with mutational screening and R. Margolskee (Mount Sinai School of Medicine of New York University) for providing antibodies.

Author information

Affiliations

  1. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.

    • Jeremy C McIntyre
    • , Ariell Joiner
    • , Corey L Williams
    • , Paul M Jenkins
    • , Dyke P McEwen
    • , Lian Zhang
    • , John Escobado
    •  & Jeffrey R Martens
  2. Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.

    • Erica E Davis
    • , I-Chun Tsai
    •  & Nicholas Katsanis
  3. Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.

    • Erica E Davis
    •  & Nicholas Katsanis
  4. Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA.

    • Erica E Davis
    • , I-Chun Tsai
    •  & Nicholas Katsanis
  5. Département de Génétique et INSERM U-781, Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France.

    • Sophie Thomas
    •  & Tania Attié-Bitach
  6. Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK.

    • Katarzyna Szymanska
    •  & Colin A Johnson
  7. Molecular Medicine Unit, Institute of Child Health, University College London, London, UK.

    • Philip L Beales
  8. US National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Eric D Green
    • , James C Mullikin
    •  & NISC Comparative Sequencing Program
  9. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

    • Aniko Sabo
    • , Donna M Muzny
    •  & Richard A Gibbs
  10. Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Bradley K Yoder
  11. Department of Molecular Biology and Genetics, Johns Hopkins University, Baltimore, Maryland, USA.

    • Randall R Reed

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Contributions

J.C.M., E.E.D., A.J., I.-C.T., S.T., K.S., P.M.J., D.P.M., L.Z. and J.E. performed experiments. T.A.-B., P.L.B. and C.A.J. provided patients for mutational analysis. E.D.G., J.C.M., the NISC Comparative Sequencing Program, A.S., D.M.M. and R.A.G. performed the mutational analysis. J.C.M., P.M.J., D.P.M., E.E.D., N.K., R.R.R., C.L.W., B.K.Y. and J.R.M. designed experiments. All authors contributed insight towards shaping the aims of the project. J.C.M. and J.R.M. wrote the manuscript with the help of comments and suggestions from all other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeffrey R Martens.

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    Supplementary Table 1

    Ciliopathy samples with IFT88Met383Lys mutations

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DOI

https://doi.org/10.1038/nm.2860

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