title: Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.
abstract: 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.
authors.affiliation: Department of Medicine, University College London, UK.
authors.forename: Guida
authors.initials: G
authors.lastname: Landouré
authors.forename: Anselm A
authors.initials: AA
authors.lastname: Zdebik
authors.forename: Tara L
authors.initials: TL
authors.lastname: Martinez
authors.forename: Barrington G
authors.initials: BG
authors.lastname: Burnett
authors.forename: Horia C
authors.initials: HC
authors.lastname: Stanescu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Inada
authors.forename: Yijun
authors.initials: Y
authors.lastname: Shi
authors.forename: Addis A
authors.initials: AA
authors.lastname: Taye
authors.forename: Lingling
authors.initials: L
authors.lastname: Kong
authors.forename: Clare H
authors.initials: CH
authors.lastname: Munns
authors.forename: Shelly S
authors.initials: SS
authors.lastname: Choo
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Phelps
authors.forename: Reema
authors.initials: R
authors.lastname: Paudel
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Christy L
authors.initials: CL
authors.lastname: Ludlow
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caterina
authors.forename: Rachelle
authors.initials: R
authors.lastname: Gaudet
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Sumner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D017089:Ankyrin Repeat; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D015640:Ion Channel Gating; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009498:Neurotoxins; D010375:Pedigree; D010641:Phenotype; D050916:TRPV Cation Channels / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
chemical_list: D050505:Mutant Proteins; D009498:Neurotoxins; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human