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The Journal of Neuroscience, October 22, 2008, 28(43):11079-11088; doi:10.1523/JNEUROSCI.3443-08.2008

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Cellular/Molecular
Na_V1.7 Gain-of-Function Mutations as a Continuum: A1632E Displays Physiological Changes Associated with Erythromelalgia and Paroxysmal Extreme Pain Disorder Mutations and Produces Symptoms of Both Disorders

M. Estacion,^1,2,3 S. D. Dib-Hajj,^1,2,3 P. J. Benke,⁴ Rene H. M. te Morsche,⁵ E. M. Eastman,^1,2,3 L. J. Macala,^1,2,3 J. P. H. Drenth,⁵ and S. G. Waxman^1,2,3

¹Department of Neurology and ²Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, ³Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516, ⁴Department of Genetics, Joe DiMaggio Children's Hospital, Hollywood, Florida 33021, and ⁵Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands

Correspondence should be addressed to Dr. S. G. Waxman, Department of Neurology, LCI 707, Yale Medical School, P.O. Box 208018, New Haven, CT 06520. Email: stephen.waxman{at}yale.edu

Gain-of-function mutations of Na_V1.7 have been shown to produce two distinct disorders: Na_V1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities; Na_V1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain. Here we report a novel Na_V1.7 mutation associated with a mixed clinical phenotype with characteristics of IEM and PEPD, with an alanine 1632 substitution by glutamate (A1632E) in domain IV S4–S5 linker. Patch-clamp analysis shows that A1632E produces changes in channel function seen in both IEM and PEPD mutations: A1632E hyperpolarizes (–7 mV) the voltage dependence of activation, slows deactivation, and enhances ramp responses, as observed in Na_V1.7 mutations that produce IEM. A1632E depolarizes (+17mV) the voltage dependence of fast inactivation, slows fast inactivation, and prevents full inactivation, resulting in persistent inward currents similar to PEPD mutations. Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable. These results demonstrate a Na_V1.7 mutant with biophysical characteristics common to PEPD (impaired fast inactivation) and IEM (hyperpolarized activation, slow deactivation, and enhanced ramp currents) associated with a clinical phenotype with characteristics of both IEM and PEPD and show that this mutation renders DRG and trigeminal ganglion neurons hyperexcitable. These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes.

Key words: sodium channel; neuropathic pain; sensory neuron; voltage-clamp; current-clamp; dorsal root ganglion

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Received July 22, 2008; revised Aug. 27, 2008; accepted Sept. 9, 2008.

Correspondence should be addressed to Dr. S. G. Waxman, Department of Neurology, LCI 707, Yale Medical School, P.O. Box 208018, New Haven, CT 06520. Email: stephen.waxman{at}yale.edu

This article has been cited by other articles:

				S. Schorge and D. M. Kullmann Sodium channelopathy of peripheral nerve: tightening the genotype-phenotype relationship Brain, July 1, 2009; 132(7): 1690 - 1692. [Full Text] [PDF]

				W. A. Catterall, S. Dib-Hajj, M. H. Meisler, and D. Pietrobon Inherited Neuronal Ion Channelopathies: New Windows on Complex Neurological Diseases J. Neurosci., November 12, 2008; 28(46): 11768 - 11777. [Abstract] [Full Text] [PDF]

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