Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C

Guida Landouré, Anselm A. Zdebik, Tara L. Martinez, Barrington G. Burnett, Horia C. Stanescu, Hitoshi Inada, Yijun Shi, Addis A. Taye, Lingling Kong, Clare H. Munns, Shelly S. Choo, Christopher B. Phelps, Reema Paudel, Henry Houlden, Christy L. Ludlow, Michael J. Caterina, Rachelle Gaudet, Robert Kleta, Kenneth H. Fischbeck, Charlotte J. Sumner

Research output: Contribution to journalArticlepeer-review

217 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)170-174
Number of pages5
JournalNature genetics
Issue number2
StatePublished - Feb 2010

ASJC Scopus subject areas

  • Genetics


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