Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation

Journal article

Publication Details

Author(s): Eberhardt M, Nakajima J, Klinger A, Neacsu C, Hühne K, o' Reilly A, Kist A, Lampe AK, Fischer K, Gibson J, Nau C, Winterpacht A, Lampert A
Journal: Journal of Biological Chemistry
Publisher: American Society for Biochemistry and Molecular Biology
Publication year: 2014
Volume: 289
Journal issue: 4
Pages range: 1971-80
ISSN: 0021-9258


Inherited erythromelalgia (IEM) causes debilitating episodic neuropathic pain characterized by burning in the extremities. Inherited "paroxysmal extreme pain disorder" (PEPD) differs in its clinical picture and affects proximal body areas like the rectal, ocular, or jaw regions. Both pain syndromes have been linked to mutations in the voltage-gated sodium channel Nav1.7. Electrophysiological characterization shows that IEM-causing mutations generally enhance activation, whereas mutations leading to PEPD alter fast inactivation. Previously, an A1632E mutation of a patient with overlapping symptoms of IEM and PEPD was reported (Estacion, M., Dib-Hajj, S. D., Benke, P. J., Te Morsche, R. H., Eastman, E. M., Macala, L. J., Drenth, J. P., and Waxman, S. G. (2008) NaV1.7 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. J. Neurosci. 28, 11079-11088), displaying a shift of both activation and fast inactivation. Here, we characterize a new mutation of Nav1.7, A1632T, found in a patient suffering from IEM. Although transfection of A1632T in sensory neurons resulted in hyperexcitability and spontaneous firing of dorsal root ganglia (DRG) neurons, whole-cell patch clamp of transfected HEK cells revealed that Nav1.7 activation was unaltered by the A1632T mutation but that steady-state fast inactivation was shifted to more depolarized potentials. This is a characteristic normally attributed to PEPD-causing mutations. In contrast to the IEM/PEPD crossover mutation A1632E, A1632T failed to slow current decay (i.e. open-state inactivation) and did not increase resurgent currents, which have been suggested to contribute to high-frequency firing in physiological and pathological conditions. Reduced fast inactivation without increased resurgent currents induces symptoms of IEM, not PEPD, in the new Nav1.7 mutation, A1632T. Therefore, persistent and resurgent currents are likely to determine whether a mutation in Nav1.7 leads to IEM or PEPD.

FAU Authors / FAU Editors

Eberhardt, Mirjam
Professur für Physiologie
Kist, Andreas
Lehrstuhl für Physiologie
Klinger, Alexandra
o' Reilly, Andrias
Institut für Physiologie und Pathophysiologie
Lampert, Angelika PD Dr.
Lehrstuhl für Physiologie
Sertel-Nakajima, Julika
Lehrstuhl für Physiologie
Neacsu, Cristian
Institut für Physiologie und Pathophysiologie
Lehrstuhl für Physiologie
Winterpacht, Andreas Prof. Dr.
Professur für Humangenetik

External institutions with authors

Western General Hospital
Whytemans Brae Hospital

How to cite

Eberhardt, M., Nakajima, J., Klinger, A., Neacsu, C., Hühne, K., o' Reilly, A.,... Lampert, A. (2014). Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation. Journal of Biological Chemistry, 289(4), 1971-80.

Eberhardt, Mirjam, et al. "Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation." Journal of Biological Chemistry 289.4 (2014): 1971-80.


Last updated on 2018-08-10 at 02:39