Journal Article

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

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

2010

Overview

Charlotte Sumner and colleagues report that mutations in the ankyrin repeat region of TRPV4 cause Charcot-Marie-Tooth disease type 2C. Their functional studies indicate that the mutations result in increased channel activity. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adolescent / Adult / Aged / Agriculture / Amino Acid Sequence / Amino Acid Substitution - genetics / Amino acids / Animal Genetics and Genomics / Ankyrin Repeat / Apoptosis / Base Sequence / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Membrane - metabolism / Cerebrospinal fluid. Meninges. Spinal cord / Charcot-Marie-Tooth disease / Charcot-Marie-Tooth Disease - genetics / Charcot-Marie-Tooth Disease - physiopathology / Charitable foundations / Data collection / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Disease / DNA Mutational Analysis / Female / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genes / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Health aspects / Human Genetics / Humans / Ion Channel Gating / letter / Male / Medical sciences / Middle Aged / Models, Molecular / Molecular Sequence Data / Mutant Proteins - metabolism / Mutation / Mutation - genetics / Nervous system (semeiology, syndromes) / Neurology / Neurotoxins / Pedigree / Phenotype / Risk factors / Studies / Tissues / TRPV Cation Channels - chemistry / TRPV Cation Channels - genetics / Young Adult