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Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. 2010
Guida Landouré, and
Anselm A Zdebik, and
Tara L Martinez, and
Barrington G Burnett, and
Horia C Stanescu, and
Hitoshi Inada, and
Yijun Shi, and
Addis A Taye, and
Lingling Kong, and
Clare H Munns, and
Shelly S Choo, and
Christopher B Phelps, and
Reema Paudel, and
Henry Houlden, and
Christy L Ludlow, and
Michael J Caterina, and
Rachelle Gaudet, and
Robert Kleta, and
Kenneth H Fischbeck, and
Charlotte J Sumner
Department of Medicine, University College London, UK.
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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