Sporadic onset of erythermalgia: A gain‐of‐function mutation in Nav1.7
C Han, AM Rush, SD Dib‐Hajj, S Li, Z Xu… - Annals of …, 2006 - Wiley Online Library
Annals of neurology, 2006•Wiley Online Library
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 Nav1. 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 Nav1. 7 in a sporadic case of erythermalgia in a …
which patients experience severe burning pain in the extremities, in response to mild
thermal stimuli and exercise. Although mutations in sodium channel Nav1. 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 Nav1. 7 in a sporadic case of erythermalgia in a …
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 Nav1.7 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 Nav1.7 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 Nav1.7. Whole‐cell patch clamp analysis was used to characterize biophysical properties of wild‐type and mutant Nav1.7 channels in mammalian cells.
Results
A single amino acid substitution in the DIIS4‐S5 linker of Nav1.7 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 Nav1.7, which can confer hyperexcitability on peripheral sensory neurons, can underlie sporadic erythermalgia. Ann Neurol 2006
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