title: A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia.
abstract: OBJECTIVE
  Human and animal studies have shown that Na(v)1.7 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 Na(v)1.7. 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 Na(v)1.7 complementary DNA. Wild-type Na(v)1.7 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 Na(v)1.7 but does not affect these parameters in wild-type Na(v)1.7.
  
  
  CONCLUSIONS
  Our results demonstrate a normalizing effect of CBZ on mutant Na(v)1.7 channels in this kindred with CBZ-responsive inherited erythromelalgia. The selective effect of CBZ on the mutant Na(v)1.7 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.
authors: Department of Neurology, Yale University School of Medicine, New Haven, CT 16510, USA.
authors: Tanya Z
authors: TZ
authors: Fischer
authors: Elaine S
authors: ES
authors: Gilmore
authors: Mark
authors: M
authors: Estacion
authors: Emmanuella
authors: E
authors: Eastman
authors: Sean
authors: S
authors: Taylor
authors: Michel
authors: M
authors: Melanson
authors: Sulayman D
authors: SD
authors: Dib-Hajj
authors: Stephen G
authors: SG
authors: Waxman
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D002220:Carbamazepine / Q000627:therapeutic use*; D002460:Cell Line; D004916:Erythromelalgia / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation / Q000187:drug effects; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010375:Pedigree; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D000927:Anticonvulsants; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels; D002220:Carbamazepine