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dc.contributor.authorSullivan, Jeremy M.en_US
dc.contributor.authorZimanyi, Christina M.en_US
dc.contributor.authorAisenberg, Williamen_US
dc.contributor.authorBears, Breanneen_US
dc.contributor.authorChen, Dong-Huien_US
dc.contributor.authorDay, John W.en_US
dc.contributor.authorBird, Thomas D.en_US
dc.contributor.authorSiskind, Carly E.en_US
dc.contributor.authorGaudet, Rachelleen_US
dc.contributor.authorSumner, Charlotte J.en_US
dc.date.accessioned2016-05-02T17:01:26Z
dc.date.issued2015en_US
dc.identifier.citationSullivan, Jeremy M., Christina M. Zimanyi, William Aisenberg, Breanne Bears, Dong-Hui Chen, John W. Day, Thomas D. Bird, Carly E. Siskind, Rachelle Gaudet, and Charlotte J. Sumner. 2015. “Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy.” Neurology: Genetics 1 (4): e29. doi:10.1212/NXG.0000000000000029. http://dx.doi.org/10.1212/NXG.0000000000000029.en
dc.identifier.issn2376-7839en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:26860216
dc.description.abstractObjective: To characterize 2 novel TRPV4 mutations in 2 unrelated families exhibiting the Charcot-Marie-Tooth disease type 2C (CMT2C) phenotype. Methods: Direct CMT gene testing was performed on 2 unrelated families with CMT2C. A 4-fold symmetric tetramer model of human TRPV4 was generated to map the locations of novel TRPV4 mutations in these families relative to previously identified disease-causing mutations (neuropathy, skeletal dysplasia, and osteoarthropathy). Effects of the mutations on TRPV4 expression, localization, and channel activity were determined by immunocytochemical, immunoblotting, Ca2+ imaging, and cytotoxicity assays. Results: Previous studies suggest that neuropathy-causing mutations occur primarily at arginine residues on the convex face of the TRPV4 ankyrin repeat domain (ARD). Further highlighting the key role of this domain in TRPV4-mediated hereditary neuropathy, we report 2 novel heterozygous missense mutations in the TRPV4-ARD convex face (p.Arg237Gly and p.Arg237Leu). Generation of a model of the TRPV4 homotetramer revealed that while ARD residues mutated in neuropathy (including Arg237) are likely accessible for intermolecular interactions, skeletal dysplasia–causing TRPV4 mutations occur at sites suggesting disruption of intramolecular and/or intersubunit interactions. Like previously described neuropathy-causing mutations, the p.Arg237Gly and p.Arg237Leu substitutions do not alter TRPV4 subcellular localization in transfected cells but cause elevations of cytosolic Ca2+ levels and marked cytotoxicity. Conclusions: These findings expand the number of ARD residues mutated in TRPV4-mediated neuropathy, providing further evidence of the central importance of this domain to TRPV4 function in peripheral nerve.en
dc.language.isoen_USen
dc.publisherWolters Kluweren
dc.relation.isversionofdoi:10.1212/NXG.0000000000000029en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811381/pdf/en
dash.licenseLAAen_US
dc.titleNovel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathyen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalNeurology: Geneticsen
dash.depositing.authorZimanyi, Christina M.en_US
dc.date.available2016-05-02T17:01:26Z
dc.identifier.doi10.1212/NXG.0000000000000029*
dash.contributor.affiliatedZimanyi, Christina M.
dash.contributor.affiliatedGaudet, Rachelle


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