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Sporadic onset of erythermalgia: A gain‐of‐function mutation in Na v 1.7
Author(s) -
Han Chongyang,
Rush Anthony M.,
DibHajj Sulayman D.,
Li Song,
Xu Zhe,
Wang Yun,
Tyrrell Lynda,
Wang Xiaoliang,
Yang Yong,
Waxman Stephen G.
Publication year - 2006
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20776
Subject(s) - asymptomatic , mutation , erythromelalgia , gain of function , mutant , genetics , sodium channel , asymptomatic carrier , medicine , chemistry , biology , gene , neuroscience , sodium , organic chemistry
ObjectiveInherited 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.Interpretation Founder mutations in Na v 1.7, which can confer hyperexcitability on peripheral sensory neurons, can underlie sporadic erythermalgia. Ann Neurol 2006