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Published online before print September 20, 2006, doi:10.1212/01.wnl.0000231514.33603.1e)
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Received March 15, 2006
Accepted May 30, 2006

Inherited erythermalgia. Limb pain from an S4 charge-neutral Na channelopathy

Jin-Sung Choi PhD, Sulayman D. Dib-Hajj PhD, and Stephen G. Waxman MD, PhD*

From the Department of Neurology and Center for Neuroscience and Regeneration Research Yale University School of Medicine, New Haven, and Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT.


* To whom correspondence should be addressed. E-mail: Stephen.Waxman{at}yale.edu.

Abstract-- Background: Inherited erythermalgia (also termed "erythromelalgia"), characterized by episodic burning pain in the distal extremities evoked by warmth, has been causally linked with mutations of the Nav1.7 sodium channel, which is preferentially expressed in nociceptors. Thus far, Nav1.7 mutations within intracellular linker parts of the channel have been physiologically characterized. Objective: To investigate a Nav1.7 erythermalgia mutation that substitutes one uncharged amino acid for another within an S4 segment. Methods: Whole-cell patch-clamp analysis was used to study biophysical properties of wild-type and mutant (F216S) Nav1.7 channels in mammalian cells. Results: The F216S mutation hyperpolarizes the voltage dependence of activation by 11 mV, accelerates activation, slows deactivation, and enhances the response to slow, small depolarizations. Conclusion: These results provide a physiologic basis for the linkage to erythermalgia of an Nav1.7 mutation that substitutes one uncharged residue for another within an S4 segment of the channel. These changes should increase excitability of nociceptive dorsal root ganglion neurons in which the mutant channel is present, thus contributing to pain.




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