TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies
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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.
Footnotes
Study funding: Supported by the NIH (K08 NS065007 to C.J.K., NS050641, and T32 AG20506), the Les Turner ALS Foundation, Vena E. Schaff ALS Research Fund, Harold Post Research Professorship, Herbert and Florence C. Wenske Foundation, the David C. Asselin MD Memorial Fund, Help America Foundation, and Les Turner ALS Foundation/Herbert C. Wenske Foundation Professorship (T.S). H.L. is supported by the Chinese Medical Association (08020530131).
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- CMT
- Charcot-Marie-Tooth
- dSMA
- distal spinal muscular atrophy
- HMSN2C
- hereditary motor and sensory neuropathy 2C
- PI
- propidium iodide
- SPSMA
- scapuloperoneal spinal muscular atrophy
- TRPV4
- transient receptor potential vanilloid 4.
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Editorial, page 856.
Supplemental data at www.neurology.org
- Received July 7, 2010.
- Accepted September 22, 2010.
- Copyright © 2011 by AAN Enterprises, Inc.
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