Charcot-Marie-Tooth disease type 2C (CMT2C) is an autosomal dominant motor neuron disease affecting limbs, diaphragm, and vocal fold muscles. The gene was linked to 12q24.11 in two unrelated families. The coding sequence of all genes in this region were sequenced and two missense mutations in the TRPV gene were identified at positions c.805C>T and c.806G>A, causing the amino acid substitutions R269C and R269H. We confirmed that TrpV4, a well known member of the TRP superfamily of calcium permeable cation channels, is expressed in motor and sensory neurons. In overexpressing oocytes and transfected cells, the R269C and R269H mutations caused increased constitutive and activated channel currents and cell death, blocked by the TRP channel inhibitor ruthenium red. Activating mutations in TrpV4 had previously been associated with skeletal dysplasia. However, our mutations map to a different region of the ankyrin repeat domains. We hypothesize that tissue-specific interactions with other proteins are differentially affected by this phenotypically divergent group of mutations in TrpV4.
University of Manchester (2010) Proc Physiol Soc 19, PC130
Poster Communications: Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2c
A. A. Zdebik1, G. Landoure2, T. L. Martinez3, B. G. Burnett2, H. C. Stanescu1, H. Inada4, C. H. Munns3, M. J. Caterina3, R. Gaudet4, R. Kleta1, K. H. Fischbeck2, C. J. Sumner3
1. Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. 2. NINDS (Neurogenetics), NIH, Bethesda, Maryland, United States. 3. Neurology, Johns Hopkins University, Baltimore, Maryland, United States. 4. Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, United States.
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