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

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

doi:10.1038/ng.512

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

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

School of Medicine

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217 Scopus citations

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.

Original language	English (US)
Pages (from-to)	170-174
Number of pages	5
Journal	Nature genetics
Volume	42
Issue number	2
DOIs	https://doi.org/10.1038/ng.512
State	Published - Feb 2010

ASJC Scopus subject areas

Genetics

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Landouré, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., Paudel, R., Houlden, H., Ludlow, C. L., Caterina, M. J., Gaudet, R., Kleta, R., Fischbeck, K. H., & Sumner, C. J. (2010). Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nature genetics, 42(2), 170-174. https://doi.org/10.1038/ng.512

Landouré, G, Zdebik, AA, Martinez, 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 2010, 'Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C', Nature genetics, vol. 42, no. 2, pp. 170-174. https://doi.org/10.1038/ng.512

@article{53313f9a77a94f1996b2a29842513034,

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.",

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

note = "Funding Information: We are grateful to the subjects and their families for participating in this study. We thank J. Kissel for discussions regarding clinical evaluation of family 1, A. LaPean for aid in subject characterization, M. K. Floeter and T. Lehky for performing neurophysiological studies, R. R. Wang for crystallization and X-ray data collection, J. Hardy for helpful discussion regarding genetic analysis, A. Singleton and D. Hernandez for help with SNP array analysis, the NINDS DNA sequencing facility for help with sequencing, the Maryland Brain and Tissue Bank for providing human spinal cord and tracheal tissues, M. Suzuki for Trpv4 knockout mice, R. Tsien for providing the fluorescent protein mCherry, A. Hoke for providing DRG cells, J. Griffin for aid in nerve pathology evaluation, S. Heller for providing antibody to TRPV4, T. Jentsch for cells and instruments, C. Rojas and J. Alt for help with FLIPR, S. Minogue for assistance in confocal imaging, M.A. Valverde for providing human TRPV4 expression constructs and M. Plomann for providing PACSIN expression constructs and antibodies. This work was supported by intramural funds from the NINDS at NIH, funds from the Johns Hopkins Department of Neurology and the David and Elaine Potter Charitable Foundation, and NIH grant R01GM081340 and a McKnight Scholar Award to R.G.",

year = "2010",

month = feb,

doi = "10.1038/ng.512",

language = "English (US)",

volume = "42",

pages = "170--174",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

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T1 - Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C

AU - Landouré, Guida

AU - Zdebik, Anselm A.

AU - Martinez, Tara L.

AU - Burnett, Barrington G.

AU - Stanescu, Horia C.

AU - Inada, Hitoshi

AU - Shi, Yijun

AU - Taye, Addis A.

AU - Kong, Lingling

AU - Munns, Clare H.

AU - Choo, Shelly S.

AU - Phelps, Christopher B.

AU - Paudel, Reema

AU - Houlden, Henry

AU - Ludlow, Christy L.

AU - Caterina, Michael J.

AU - Gaudet, Rachelle

AU - Kleta, Robert

AU - Fischbeck, Kenneth H.

AU - Sumner, Charlotte J.

N1 - Funding Information: We are grateful to the subjects and their families for participating in this study. We thank J. Kissel for discussions regarding clinical evaluation of family 1, A. LaPean for aid in subject characterization, M. K. Floeter and T. Lehky for performing neurophysiological studies, R. R. Wang for crystallization and X-ray data collection, J. Hardy for helpful discussion regarding genetic analysis, A. Singleton and D. Hernandez for help with SNP array analysis, the NINDS DNA sequencing facility for help with sequencing, the Maryland Brain and Tissue Bank for providing human spinal cord and tracheal tissues, M. Suzuki for Trpv4 knockout mice, R. Tsien for providing the fluorescent protein mCherry, A. Hoke for providing DRG cells, J. Griffin for aid in nerve pathology evaluation, S. Heller for providing antibody to TRPV4, T. Jentsch for cells and instruments, C. Rojas and J. Alt for help with FLIPR, S. Minogue for assistance in confocal imaging, M.A. Valverde for providing human TRPV4 expression constructs and M. Plomann for providing PACSIN expression constructs and antibodies. This work was supported by intramural funds from the NINDS at NIH, funds from the Johns Hopkins Department of Neurology and the David and Elaine Potter Charitable Foundation, and NIH grant R01GM081340 and a McKnight Scholar Award to R.G.

PY - 2010/2

Y1 - 2010/2

N2 - 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.

AB - 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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JO - Nature genetics

JF - Nature genetics

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ER -

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

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