Brain Advance Access originally published online on June 15, 2005
Brain 2005 128(8):1847-1854; doi:10.1093/brain/awh514
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Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons
1 Department of Neurology and 2 Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, 3 Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT and 4 Department of Pharmacology and Toxicology, Stark Neurosciences Institute, Indiana University School of Medicine, Indianapolis, IN, USA
Correspondence to: Stephen G. Waxman, MD, PhD, Department of Neurology, LCI 707, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA E-mail: stephen.waxman{at}yale.edu
Erythromelalgia is an autosomal dominant disorder characterized by burning pain in response to warm stimuli or moderate exercise. We describe a novel mutation in a family with erythromelalgia in SCN9A, the gene that encodes the Nav1.7 sodium channel. Nav1.7 produces threshold currents and is selectively expressed within sensory neurons including nociceptors. We demonstrate that this mutation, which produces a hyperpolarizing shift in activation and a depolarizing shift in steady-state inactivation, lowers thresholds for single action potentials and high frequency firing in dorsal root ganglion neurons. Erythromelalgia is the first inherited pain disorder in which it is possible to link a mutation with an abnormality in ion channel function and with altered firing of pain signalling neurons.
Key Words: channel; channelopathy; erythromelalgia; mutation; pain; sodium
Abbreviations: DRG = dorsal root ganglion
Received January 25, 2005. Revised February 24, 2005. Accepted March 23, 2005.
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