title: Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7.
abstract: OBJECTIVE
  Inherited erythermalgia (erythromelalgia) is an autosomal dominant disorder in which patients experience severe burning pain in the extremities, in response to mild thermal stimuli and exercise. Although mutations in sodium channel Na(v)1.7 have been shown to underlie erythermalgia in several multigeneration families with the disease that have been investigated to date, the molecular basis of erythermalgia in sporadic cases is enigmatic. We investigated the role of Na(v)1.7 in a sporadic case of erythermalgia in a Chinese family.
  
  
  METHODS
  Genomic DNA from patients and their asymptomatic family members were sequenced to identify mutations in Na(v)1.7. Whole-cell patch clamp analysis was used to characterize biophysical properties of wild-type and mutant Na(v)1.7 channels in mammalian cells.
  
  
  RESULTS
  A single amino acid substitution in the DIIS4-S5 linker of Na(v)1.7 was present in two children whose parents were asymptomatic. The asymptomatic father was genetically mosaic for the mutation. This mutation produces a hyperpolarizing shift in channel activation and an increase in amplitude of the response to slow, small depolarizations.
  
  
  CONCLUSIONS
  Founder mutations in Na(v)1.7, which can confer hyperexcitability on peripheral sensory neurons, can underlie sporadic erythermalgia.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Chongyang
authors.initials: C
authors.lastname: Han
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Rush
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xu
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Lynda
authors.initials: L
authors.lastname: Tyrrell
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002460:Cell Line; D002681:China; D004252:DNA Mutational Analysis / Q000379:methods; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D004916:Erythromelalgia / Q000235:genetics*; D005091:Exons; D005192:Family Health; D006801:Humans; D007930:Leucine / Q000235:genetics; D008297:Male; D008564:Membrane Potentials / Q000235:genetics / Q000528:radiation effects; D008958:Models, Molecular; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques / Q000379:methods; D010649:Phenylalanine / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*; D014162:Transfection / Q000379:methods
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels; D010649:Phenylalanine; D007930:Leucine