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Sullivan JM, Zimanyi CM, Aisenberg W, et al. Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy. Neurol Genet. 2015;1(4):e29doi: 10.1212/NXG.0000000000000029.
Sullivan, J. M., Zimanyi, C. M., Aisenberg, W., Bears, B., Chen, D. H., Day, J. W., Bird, T. D., Siskind, C. E., Gaudet, R., & Sumner, C. J. (2015). Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy. Neurology. Genetics, 1(4), e29. https://doi.org/10.1212/NXG.0000000000000029
Sullivan, Jeremy M, et al. "Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy." Neurology. Genetics vol. 1,4 (2015): e29. doi: https://doi.org/10.1212/NXG.0000000000000029
Sullivan JM, Zimanyi CM, Aisenberg W, Bears B, Chen DH, Day JW, Bird TD, Siskind CE, Gaudet R, Sumner CJ. Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy. Neurol Genet. 2015 Oct 22;1(4):e29. doi: 10.1212/NXG.0000000000000029. eCollection 2015 Dec. PMID: 27066566; PMCID: PMC4811381.
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Neurol Genet. 2015 Oct 22;1(4):e29. doi: 10.1212/NXG.0000000000000029. eCollection 2015 Dec.

Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy.

Neurology. Genetics

Jeremy M Sullivan, Christina M Zimanyi, William Aisenberg, Breanne Bears, Dong-Hui Chen, John W Day, Thomas D Bird, Carly E Siskind, Rachelle Gaudet, Charlotte J Sumner

Affiliations

  1. Department of Neurology (J.M.S., W.A., B.B., C.J.S.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Molecular and Cellular Biology (C.M.Z., R.G.), Harvard University, Cambridge, MA; Department of Neurology (D.-H.C., T.D.B.), University of Washington School of Medicine, Seattle, WA; Department of Neurology (J.W.D., C.E.S.), Stanford Health Care, Stanford, CA; and Department of Neuroscience (C.J.S.), Johns Hopkins University, Baltimore, MD.

PMID: 27066566 PMCID: PMC4811381 DOI: 10.1212/NXG.0000000000000029

Abstract

OBJECTIVE: 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, Ca(2+) 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 Ca(2+) 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.

References

  1. J Biol Chem. 2011 May 13;286(19):17281-91 - PubMed
  2. Neurology. 2014 May 27;82(21):1919-26 - PubMed
  3. Science. 2001 Oct 5;294(5540):93-6 - PubMed
  4. Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501 - PubMed
  5. J Biol Chem. 2010 Jan 1;285(1):731-40 - PubMed
  6. J Invest Dermatol. 2013 Apr;133(4):1043-51 - PubMed
  7. Bioinformatics. 2006 Jan 15;22(2):195-201 - PubMed
  8. Neurogenetics. 2012 Aug;13(3):195-203 - PubMed
  9. Handb Exp Pharmacol. 2014;222:293-319 - PubMed
  10. Neurology. 2010 Nov 30;75(22):1968-75 - PubMed
  11. Nat Genet. 2010 Feb;42(2):160-4 - PubMed
  12. J Clin Neurosci. 2012 Jul;19(7):927-33 - PubMed
  13. Brain. 2010 Jun;133(Pt 6):1798-809 - PubMed
  14. Nat Genet. 2010 Feb;42(2):165-9 - PubMed
  15. Nat Genet. 2007 Jan;39(1):25-7 - PubMed
  16. Mol Cell Biol. 2001 Aug;21(16):5566-76 - PubMed
  17. J Biol Chem. 2013 Sep 13;288(37):26697-708 - PubMed
  18. J Med Genet. 2014 Jun;51(6):388-94 - PubMed
  19. Nat Genet. 2010 Feb;42(2):170-4 - PubMed
  20. FASEB J. 2014 Jun;28(6):2525-37 - PubMed
  21. EMBO Rep. 2013 Feb;14(2):152-63 - PubMed
  22. Mol Biosyst. 2008 May;4(5):372-9 - PubMed
  23. Neurology. 2012 Jul 10;79(2):192-4 - PubMed
  24. Am J Med Genet A. 2011 Nov;155A(11):2860-4 - PubMed
  25. Neurology. 2011 Mar 8;76(10):887-94 - PubMed
  26. Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21 - PubMed
  27. Nat Commun. 2014 Sep 26;5:4994 - PubMed
  28. Nature. 2013 Dec 5;504(7478):107-12 - PubMed
  29. Biochemistry. 2012 Aug 7;51(31):6195-206 - PubMed
  30. PLoS One. 2011 May 05;6(5):e19533 - PubMed
  31. Am J Med Genet A. 2012 Apr;158A(4):795-802 - PubMed
  32. Nat Genet. 2011 Oct 02;43(11):1142-6 - PubMed
  33. J Cell Sci. 2005 Mar 1;118(Pt 5):917-28 - PubMed
  34. Pflugers Arch. 2015 Oct;467(10):2107-19 - PubMed

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