Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability

J Clin Invest. 2017 Jun 30;127(7):2805-2814. doi: 10.1172/JCI92373. Epub 2017 May 22.


Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1.9 mutation (L1302F) that is associated with insensitivity to pain. We investigated the effects of L1302F and a previously reported mutation (L811P) on neuronal excitability. In transfected heterologous cells, the L1302F mutation caused a large hyperpolarizing shift in the voltage-dependence of activation, leading to substantially enhanced overlap between activation and steady-state inactivation relationships. In transfected small rat dorsal root ganglion neurons, expression of L1302F and L811P evoked large depolarizations of the resting membrane potential and impaired action potential generation. Therefore, our findings implicate a cellular loss of function as the basis for impaired pain sensation. We further demonstrated that a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why NaV1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain.

Publication types

  • Case Reports

MeSH terms

  • Action Potentials / genetics*
  • Adult
  • Amino Acid Substitution
  • Female
  • Humans
  • Ion Channel Gating / genetics*
  • Mutation, Missense*
  • NAV1.9 Voltage-Gated Sodium Channel / genetics
  • NAV1.9 Voltage-Gated Sodium Channel / metabolism
  • Neurons / metabolism*
  • Pain Insensitivity, Congenital* / genetics
  • Pain Insensitivity, Congenital* / metabolism
  • Pain Insensitivity, Congenital* / physiopathology


  • NAV1.9 Voltage-Gated Sodium Channel
  • SCN11A protein, human