Charcot-Marie-Tooth disease type 2C (CMT2C) is an autosomal dominant neuropathy characterized by limb, diaphragm and laryngeal muscle weakness. Two unrelated families with CMT2C showed significant linkage to chromosome 12q24.11. We sequenced all genes in this region and identified two heterozygous missense mutations in the TRPV4 gene, C805T and G806A, resulting in the amino acid substitutions R269C and R269H. TRPV4 is a well-known member of the TRP superfamily of cation channels. In TRPV4-transfected cells, the CMT2C mutations caused marked cellular toxicity and increased constitutive and activated channel currents. Mutations in TRPV4 were previously associated with skeletal dysplasias. Our findings indicate that TRPV4 mutations can also cause a degenerative disorder of the peripheral nerves. The CMT2C-associated mutations lie in a distinct region of the TRPV4 ankyrin repeats, suggesting that this phenotypic variability may be due to differential effects on regulatory protein-protein interactions.

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We are grateful to the subjects and their families for participating in this study. We thank J. Kissel for discussions regarding clinical evaluation of family 1, A. LaPean for aid in subject characterization, M. K. Floeter and T. Lehky for performing neurophysiological studies, R. R. Wang for crystallization and X-ray data collection, J. Hardy for helpful discussion regarding genetic analysis, A. Singleton and D. Hernandez for help with SNP array analysis, the NINDS DNA sequencing facility for help with sequencing, the Maryland Brain and Tissue Bank for providing human spinal cord and tracheal tissues, M. Suzuki for Trpv4 knockout mice, R. Tsien for providing the fluorescent protein mCherry, A. Hoke for providing DRG cells, J. Griffin for aid in nerve pathology evaluation, S. Heller for providing antibody to TRPV4, T. Jentsch for cells and instruments, C. Rojas and J. Alt for help with FLIPR, S. Minogue for assistance in confocal imaging, M.A. Valverde for providing human TRPV4 expression constructs and M. Plomann for providing PACSIN expression constructs and antibodies. This work was supported by intramural funds from the NINDS at NIH, funds from the Johns Hopkins Department of Neurology and the David and Elaine Potter Charitable Foundation, and NIH grant R01GM081340 and a McKnight Scholar Award to R.G.

Author information

Author notes

    • Guida Landouré
    •  & Anselm A Zdebik

    These authors contributed equally to this work.

    • Robert Kleta
    • , Kenneth H Fischbeck
    •  & Charlotte J Sumner

    These authors jointly directed the project.


  1. Department of Medicine, University College London, London, UK.

    • Guida Landouré
    • , Anselm A Zdebik
    • , Horia C Stanescu
    •  & Robert Kleta
  2. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

    • Guida Landouré
    • , Anselm A Zdebik
    • , Horia C Stanescu
    •  & Robert Kleta
  3. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Guida Landouré
    • , Barrington G Burnett
    • , Yijun Shi
    • , Addis A Taye
    •  & Kenneth H Fischbeck
  4. Service de Neurologie, Centre Hospitalo-Universitaire du Point 'G', Université de Bamako, Bamako, Mali.

    • Guida Landouré
  5. Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Tara L Martinez
    • , Lingling Kong
    •  & Charlotte J Sumner
  6. W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

    • Tara L Martinez
  7. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.

    • Hitoshi Inada
    • , Shelly S Choo
    • , Christopher B Phelps
    •  & Rachelle Gaudet
  8. Department of Biological Chemistry, Center of Sensory Biology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Clare H Munns
    •  & Michael J Caterina
  9. Department of Neuroscience, Center of Sensory Biology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Clare H Munns
    •  & Michael J Caterina
  10. University College London, Institute of Neurology, London, UK.

    • Reema Paudel
    •  & Henry Houlden
  11. Laboratory of Neural Bases of Communication and Swallowing, James Madison University, Harrisonburg, Virginia, USA.

    • Christy L Ludlow


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C.J.S., K.H.F. and R.K. directed the study, and C.J.S wrote the paper. C.J.S., K.H.F., C.L.L., H.H. and G.L. evaluated subjects. R.K., H.C.S., K.H.F. and G.L. did the genetic analysis, and Y.S., A.A.T., R.P., R.K., K.H.F and G.L. carried out the gene sequencing. B.G.B., T.L.M., L.K. and C.J.S. performed qRT-PCR, IHC, cell death assays and co-IP experiments. A.A.Z. completed cell surface biotinylation and electrophysiology in Xenopus oocytes. H.I. and R.G. did electrophysiology in HEK cells and protein-binding assays. Protein structure determination was done by R.G., S.S.C. and C.B.P. Cell calcium imaging was completed by C.H.M. and M.J.C.

Corresponding author

Correspondence to Charlotte J Sumner.

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