Gain-of-function mutations in SCN11A cause familial episodic pain

Am J Hum Genet. 2013 Nov 7;93(5):957-66. doi: 10.1016/j.ajhg.2013.09.016. Epub 2013 Oct 24.


Many ion channel genes have been associated with human genetic pain disorders. Here we report two large Chinese families with autosomal-dominant episodic pain. We performed a genome-wide linkage scan with microsatellite markers after excluding mutations in three known genes (SCN9A, SCN10A, and TRPA1) that cause similar pain syndrome to our findings, and we mapped the genetic locus to a 7.81 Mb region on chromosome 3p22.3-p21.32. By using whole-exome sequencing followed by conventional Sanger sequencing, we identified two missense mutations in the gene encoding voltage-gated sodium channel Nav1.9 (SCN11A): c.673C>T (p.Arg225Cys) and c.2423C>G (p.Ala808Gly) (one in each family). Each mutation showed a perfect cosegregation with the pain phenotype in the corresponding family, and neither of them was detected in 1,021 normal individuals. Both missense mutations were predicted to change a highly conserved amino acid residue of the human Nav1.9 channel. We expressed the two SCN11A mutants in mouse dorsal root ganglion (DRG) neurons and showed that both mutations enhanced the channel's electrical activities and induced hyperexcitablity of DRG neurons. Taken together, our results suggest that gain-of-function mutations in SCN11A can be causative of an autosomal-dominant episodic pain disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asians / genetics
  • Calcium Channels / genetics
  • Female
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Genetic Linkage
  • Genetic Markers
  • Humans
  • Male
  • Mice
  • Microsatellite Repeats
  • Mutation, Missense
  • NAV1.7 Voltage-Gated Sodium Channel / genetics
  • NAV1.9 Voltage-Gated Sodium Channel / genetics
  • Nerve Tissue Proteins / genetics
  • Neurons / metabolism
  • Neurons / pathology
  • Pain / genetics*
  • Pain / pathology
  • Pedigree
  • TRPA1 Cation Channel
  • Transient Receptor Potential Channels / genetics


  • Calcium Channels
  • Genetic Markers
  • NAV1.7 Voltage-Gated Sodium Channel
  • NAV1.9 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • SCN11A protein, human
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • Transient Receptor Potential Channels