Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli

J Neurosci. 2016 Jul 13;36(28):7511-22. doi: 10.1523/JNEUROSCI.0462-16.2016.


Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.7 produce several pain syndromes, including inherited erythromelalgia (IEM), a disorder in which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning pain triggered by warmth, the effects of increased temperature on DRG neurons expressing mutant Nav1.7 channels have not been well documented. Here, using structural modeling, voltage-clamp, current-clamp, and multielectrode array recordings, we have studied a newly identified Nav1.7 mutation, Ala1632Gly, from a multigeneration family with IEM. Structural modeling suggests that Ala1632 is a molecular hinge and that the Ala1632Gly mutation may affect channel gating. Voltage-clamp recordings revealed that the Nav1.7-A1632G mutation hyperpolarizes activation and depolarizes fast-inactivation, both gain-of-function attributes at the channel level. Whole-cell current-clamp recordings demonstrated increased spontaneous firing, lower current threshold, and enhanced evoked firing in rat DRG neurons expressing Nav1.7-A1632G mutant channels. Multielectrode array recordings further revealed that intact rat DRG neurons expressing Nav1.7-A1632G mutant channels are more active than those expressing Nav1.7 WT channels. We also showed that physiologically relevant thermal stimuli markedly increase the mean firing frequencies and the number of active rat DRG neurons expressing Nav1.7-A1632G mutant channels, whereas the same thermal stimuli only increase these parameters slightly in rat DRG neurons expressing Nav1.7 WT channels. The response of DRG neurons expressing Nav1.7-A1632G mutant channels upon increase in temperature suggests a cellular basis for warmth-triggered pain in IEM.

Significance statement: Inherited erythromelalgia (IEM), a severe pain syndrome characterized by episodes of intense burning pain triggered by warmth, is caused by mutations in sodium channel Nav1.7, which are preferentially expressed in sensory and sympathetic neurons. More than 20 gain-of-function Nav1.7 mutations have been identified from IEM patients, but the question of how warmth triggers episodes of pain in IEM has not been well addressed. Combining multielectrode array, voltage-clamp, and current-clamp recordings, we assessed a newly identified IEM mutation (Nav1.7-A1632G) from a multigeneration family. Our data demonstrate gain-of-function attributes at the channel level and differential effects of physiologically relevant thermal stimuli on the excitability of DRG neurons expressing mutant and WT Nav1.7 channels, suggesting a cellular mechanism for warmth-triggered pain episodes in IEM patients.

Keywords: chronic pain; man on fire syndrome; sensory neurons; temperature responses; thermosensation; voltage-gated sodium channel.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alanine / genetics
  • Animals
  • Cells, Cultured
  • Erythromelalgia / genetics*
  • Erythromelalgia / pathology*
  • Female
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / pathology*
  • Glutamine / genetics
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics*
  • Models, Molecular
  • Mutation / genetics*
  • NAV1.7 Voltage-Gated Sodium Channel / genetics*
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channel Blockers / pharmacology
  • Temperature
  • Tetrodotoxin / pharmacology


  • NAV1.7 Voltage-Gated Sodium Channel
  • SCN9A protein, human
  • Sodium Channel Blockers
  • Glutamine
  • Tetrodotoxin
  • Alanine

Associated data

  • PDB/3RVY