A novel Na_v1.7 mutation producing carbamazepine‐responsive erythromelalgia

Abstract

Objective Human and animal studies have shown that Nav1.7 sodium channels, which are preferentially expressed within nociceptors and sympathetic neurons, play a major role in inflammatory and neuropathic pain. Inherited erythromelalgia (IEM) has been linked to gain-of-function mutations of Nav1.7. We now report a novel mutation (V400M) in a three-generation Canadian family in which pain is relieved by carbamazepine (CBZ). Methods We extracted genomic DNA from blood samples of eight members of the family, and the sequence of SCN9A coding exons was compared with the reference Nav1.7 complementary DNA. Wild-type Nav1.7 and V400M cell lines were then analyzed using whole-cell patch-clamp recording for changes in activation, deactivation, steady-state inactivation, and ramp currents. Results Whole-cell patch-clamp studies of V400M demonstrate changes in activation, deactivation, steady-state inactivation, and ramp currents that can produce dorsal root ganglia neuron hyperexcitability that underlies pain in these patients. We show that CBZ, at concentrations in the human therapeutic range, normalizes the voltage dependence of activation and inactivation of this inherited erythromelalgia mutation in Nav1.7 but does not affect these parameters in wild-type Nav1.7. Interpretation Our results demonstrate a normalizing effect of CBZ on mutant Nav1.7 channels in this kindred with CBZ-responsive inherited erythromelalgia. The selective effect of CBZ on the mutant Nav1.7 channel appears to explain the ameliorative response to treatment in this kindred. Our results suggest that functional expression and pharmacological studies may provide mechanistic insights into hereditary painful disorders.

Gain-of-function Na v 1.8 mutations in painful neuropathy

“…The A1304T mutation substitutes a highly conserved residue within the DIII S5 membrane-spanning segment with a larger polar residue. Although S5 segments have not been directly implicated in activation, mutations in DIII/S5 of Na v 1.5 (20), Na v 1.1 (21,22), and Na v 1.7 (23,24) have been linked to channelopathies, with the latter hyperpolarizing activation in a manner similar to A1304T.…”

Severe case and literature review of primary erythromelalgia: Novel SCN9A gene mutation

“…To date, around 20 mutations have been identified in patients with primary erythromelalgia (Table 2). [16][17][18][19][20][21][22][23][24][25][26][27] Most of the mutations identified so far cluster within D1 and D2 of the protein. Some mutations are located in the cytoplasmic linkers, and others, like the one reported here, are located at the transmembrane domains of the channel.…”

Inhibition of Navβ4 Peptide-Mediated Resurgent Sodium Currents in Nav1.7 Channels by Carbamazepine, Riluzole, and Anandamide

“…As such, we hypothesize that because resurgent currents arise after transition to a unique channel conformation (openchannel block), it may be possible to develop small molecules capable of selectively targeting resurgent currents. Furthermore, most patients with PEPD but only a few patients with IEM respond favorably to pain treatment with carbamazepine (Dib-Hajj et al, 2007;Fertleman et al, 2007;Fischer et al, 2009). Because enhanced resurgent currents are observed with PEPD mutations, but not IEM (Theile et al, 2011), we speculated that the clinical effectiveness of carbamazepine in PEPD might be due in part to the selective manifestation and resultant inhibition of resurgent currents in PEPD but not IEM mutant channels.…”