Alternative splicing may contribute to time-dependent manifestation of inherited erythromelalgia

Brain. 2010 Jun;133(Pt 6):1823-35. doi: 10.1093/brain/awq114. Epub 2010 May 16.


The Na(v)1.7 sodium channel is preferentially expressed in nocioceptive dorsal root ganglion and sympathetic ganglion neurons. Gain-of-function mutations in Na(v)1.7 produce the nocioceptor hyperexcitability underlying inherited erythromelalgia, characterized in most kindreds by early-age onset of severe pain. Here we describe a mutation (Na(v)1.7-G616R) in a pedigree with adult-onset of pain in some family members. The mutation shifts the voltage-dependence of channel fast-inactivation in a depolarizing direction in the adult-long, but not in the neonatal-short splicing isoform of Na(v)1.7 in dorsal root ganglion neurons. Altered inactivation does not depend on the age of the dorsal root ganglion neurons in which the mutant is expressed. Expression of the mutant adult-long, but not the mutant neonatal-short, isoform of Na(v)1.7 renders dorsal root ganglion neurons hyperexcitable, reducing the current threshold for generation of action potentials, increasing spontaneous activity and increasing the frequency of firing in response to graded suprathreshold stimuli. This study shows that a change in relative expression of splice isoforms can contribute to time-dependent manifestation of the functional phenotype of a sodium channelopathy.

Publication types

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

MeSH terms

  • Adolescent
  • Age of Onset
  • Aged, 80 and over
  • Alternative Splicing*
  • Animals
  • Animals, Newborn
  • Child
  • Erythromelalgia / genetics*
  • Erythromelalgia / physiopathology
  • Female
  • Ganglia, Spinal / physiopathology
  • Humans
  • In Vitro Techniques
  • Male
  • Middle Aged
  • NAV1.7 Voltage-Gated Sodium Channel
  • Pain / genetics
  • Pain / physiopathology
  • Phenotype
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channels / genetics*
  • Sodium Channels / metabolism
  • Young Adult


  • NAV1.7 Voltage-Gated Sodium Channel
  • Protein Isoforms
  • SCN9A protein, human
  • Sodium Channels