Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7.
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.
Han
Chongyang
C
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Rush
Anthony M
AM
Dib-Hajj
Sulayman D
SD
Li
Song
S
Xu
Zhe
Z
Wang
Yun
Y
Tyrrell
Lynda
L
Wang
Xiaoliang
X
Yang
Yong
Y
Waxman
Stephen G
SG
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
D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels; D010649:Phenylalanine; D007930:Leucine