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A novel Na v 1.7 mutation producing carbamazepine‐responsive erythromelalgia
Author(s) -
Fischer Tanya Z.,
Gilmore Elaine S.,
Estacion Mark,
Eastman Emmanuella,
Taylor Sean,
Melanson Michel,
DibHajj Sulayman D.,
Waxman Stephen G.
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21678
Subject(s) - erythromelalgia , sodium channel , patch clamp , carbamazepine , nociceptor , mutant , dorsal root ganglion , mutation , neuropathic pain , chemistry , ankyrin repeat , pharmacology , microbiology and biotechnology , biophysics , neuroscience , electrophysiology , anesthesia , medicine , sodium , biology , epilepsy , nociception , biochemistry , gene , sensory system , receptor , organic chemistry
Objective Human and animal studies have shown that Na v 1.7 sodium channels, which are preferentially expressed within nociceptors and sympathetic neurons, play a major role in inflammatory and neuropathic pain. Inherited erythromelalgia (IEM) has been linked to gain‐of‐function mutations of Na v 1.7. We now report a novel mutation (V400M) in a three‐generation Canadian family in which pain is relieved by carbamazepine (CBZ). Methods We extracted genomic DNA from blood samples of eight members of the family, and the sequence of SCN9A coding exons was compared with the reference Na v 1.7 complementary DNA. Wild‐type Na v 1.7 and V400M cell lines were then analyzed using whole‐cell patch‐clamp recording for changes in activation, deactivation, steady‐state inactivation, and ramp currents. Results Whole‐cell patch‐clamp studies of V400M demonstrate changes in activation, deactivation, steady‐state inactivation, and ramp currents that can produce dorsal root ganglia neuron hyperexcitability that underlies pain in these patients. We show that CBZ, at concentrations in the human therapeutic range, normalizes the voltage dependence of activation and inactivation of this inherited erythromelalgia mutation in Na v 1.7 but does not affect these parameters in wild‐type Na v 1.7. Interpretation Our results demonstrate a normalizing effect of CBZ on mutant Na v 1.7 channels in this kindred with CBZ‐responsive inherited erythromelalgia. The selective effect of CBZ on the mutant Na v 1.7 channel appears to explain the ameliorative response to treatment in this kindred. Our results suggest that functional expression and pharmacological studies may provide mechanistic insights into hereditary painful disorders. Ann Neurol 2009;65:733–741