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

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Nat Genet. 2009 Dec 27

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

Landouré G, Zdebik AA, ez TL, Burnett BG, Stanescu HC, Inada H, Shi Y,

Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL,

Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ.

[1] Department of Medicine, University College London, London, UK. [2]

Department of Neuroscience, Physiology and Pharmacology, University College

London, London, UK. [3] Neurogenetics Branch, National Institute of Neurological

Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda,

land, USA. [4] Service de Neurologie, Centre Hospitalo-Universitaire du

Point 'G', Université de Bamako, Bamako, Mali. [5] These authors contributed

equally to this work.

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.