CMT 2C: TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Toot

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Neurology. 2011 Feb 2

TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth

neuropathies.

Klein CJ, Shi Y, Fecto F, Donaghy M, Nicholson G, McEntagart ME, Crosby AH, Wu

Y, Lou H, McEvoy KM, Siddique T, Deng HX, Dyck PJ.

From the Department of Neurology and Division of Peripheral Nerve Diseases

(C.J.K., K.M.M., P.J.D.) and Department of Laboratory Medicine and Pathology

(Y.W.), Mayo Clinic Foundation, Rochester, MN; Davee Department of Neurology and

Clinical Neurosciences (Y.S., F.F., H.L., T.S., H.-X.D.), Northwestern

University Feinberg School of Medicine, Chicago, IL; Department of Clinical

Neurology (M.D.), Radcliffe Hospital, Oxford, England; Molecular Medicine

Laboratory & ANZAC Research Institute (G.N.), Concord Hospital, Australia; and

Department of Medical Genetics (M.E.M., A.H.C.), St 's University of

London, London, England.

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 Ca(2+) 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 Ca(2+)

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.