TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies
March 8, 2011 issue
76 (10) 887-894
Abstract
Objective:
To improve understanding of TRPV4-associated axonal Charcot-Marie-Tooth (CMT) neuropathy phenotypes and their debated pathologic mechanism.
Methods:
A total of 17 CMT2C phenotypic families with vocal cord and diaphragmatic involvement and 36 clinically undifferentiated CMT2 subjects underwent sequencing analysis of the coding region of TRPV4. Functional studies of mutant proteins were performed using transiently transfected cells for TRPV4 subcellular localization, basal and stimulated Ca2+ channel analysis, and cell viability assay with or without channel blockade.
Results:
Two TRPV4 mutations R232C and R316H from 17 CMT2C families were identified in the ankyrin repeat domains. The R316H is a novel de novo mutation found in a patient with CMT2C phenotype. The family with R232C mutation had individuals with and without vocal cord and diaphragm involvement. Both mutant TRPV4 proteins had normal subcellular localization in HEK293 and HeLa cells. Cells transfected with R232C and R316H displayed increased intracellular Ca2+ levels and reversible cell death by the TRPV channel antagonist, ruthenium red.
Conclusion:
TRPV4 ankyrin domain alterations including a novel de novo mutation cause axonal CMT2. Individuals with the same mutation may have nondistinct CMT2 or have phenotypic CMT2C with vocal cord paresis. Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of loss-of-function appears to be pathologically important. The reversibility of cell death by channel blockade provides an attractive area of investigation in consideration of treatable axonal degeneration.
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Supplementary Material
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Information & Authors
Information
Published In
Neurology®
Volume 76 • Number 10 • March 8, 2011
Pages: 887-894
Copyright
Copyright © 2011 by AAN Enterprises, Inc.
Publication History
Received: July 7, 2010
Accepted: September 22, 2010
Published online: February 2, 2011
Published in print: March 8, 2011
Authors
Author Contributions
C.J.K., P.J.D., T.S., and H.-X.D. conceived this project. C.J.K., Y.W., and L.H. performed sequencing analysis. Y.S., F.F., and H.X.D. performed functional analysis. C.J.K., M.D., G.N., M.E.M., A.C., and K.M.M. examined and collected family information and samples. C.J.K., H.-X.D., T.S., and P.J.D. analyzed the data and wrote the article.
Disclosure
Dr. Klein, Dr. Shi, Dr. Fecto, Dr. Donaghy, Dr. Nicholson, Dr. McEntagart, Dr. Crosby, Dr. Wu, Dr. Lou, and Dr. McEvoy report no disclosures. Dr. Siddique serves on the scientific advisory board of NIH: Skeletal Muscle and Exercise Physiology (SMEP) Study Section; serves on the editorial boards of Neurogenetics and Amyotrophic Lateral Sclerosis; holds a patent re: Human α-tocopherol transport protein: compositions and methods; and receives research support from the NIH (NINDS and NIEHS), the Harold Post ALS Research Fund, the Les Turner ALS Foundation/Herbert C. Wenske Foundation, Vena Schaaf, Frank White ALS Research Fund, the Spastic Paraplegia Foundation, Inc., the Amyotrophic Lateral Sclerosis Association, the CVS/ALS Therapy Alliance, and the Blazeman Foundation for ALS. Dr. Deng reports no disclosures. Dr. Dyck receives research support from the NIH and the FDA.
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