Inherited Pain: Sodium Channel Nav1.7 A1632T Mutation Causes Erythromelalgia Due to a Shift of Fast Inactivation [Membrane Biology]

December 5th, 2013 by Eberhardt, M., Naka&jnodot;ima, J., Klinger, A. B., Neacsu, C., Huhne, K., O'Reilly, A. O., Kist, A. M., Lampe, A. K., Fischer, K., Gibson, J., Nau, C., Winterpacht, A., Lampert, A.

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 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 et al. 2008), 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. While transfection of A1632T in sensory neurons resulted in hyperexcitability and spontaneous firing of dorsal root ganglia neurons (DRGs), whole-cell patch clamp of transfected HEK cells revealed that Nav1.7 activation was unaltered by the A1632T mutation, but 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.