SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes

Neuron. 2006 Dec 7;52(5):767-74. doi: 10.1016/j.neuron.2006.10.006.


Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE). Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant. PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Analgesics, Non-Narcotic / pharmacology
  • Carbamazepine / pharmacology
  • Cell Line
  • Chromosome Mapping
  • Cloning, Molecular
  • DNA Mutational Analysis
  • Electrophysiology
  • Genetic Linkage / physiology
  • Genetic Variation
  • Genotype
  • Humans
  • Molecular Sequence Data
  • Mutation / physiology*
  • NAV1.7 Voltage-Gated Sodium Channel
  • Neuralgia / genetics*
  • Neuralgia / physiopathology
  • Patch-Clamp Techniques
  • Pedigree
  • Phenotype
  • Sodium Channel Blockers
  • Sodium Channels / drug effects
  • Sodium Channels / genetics*
  • Sodium Channels / physiology*
  • Transfection


  • Analgesics, Non-Narcotic
  • NAV1.7 Voltage-Gated Sodium Channel
  • SCN9A protein, human
  • Sodium Channel Blockers
  • Sodium Channels
  • Carbamazepine