Abstract
BackgroundPrimary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na+ channel NaV1.7 have been linked with primary erythromelalgia. Recently, a new substitution NaV1.7/I136V has been reported in a Taiwanese family, in which pain appeared at later ages (9–22 years, with onset at 17 years of age or later in 5 of 7 family members), with relatively slow progression (8–10 years) to involvement of the hands. The proband reported onset of symptoms first in his feet at the age of 11, which then progressed to his hands at the age of 19. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all NaV1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III.ResultsIn this study, we characterized the gating and kinetic properties of I136V mutant channels in HEK293 cells using whole-cell patch clamp. I136V shifts the voltage-dependence of activation by -5.7 mV, a smaller shift in activation than the other erythromelalgia mutations that have been characterized. I136V also decreases the deactivation rate, and generates larger ramp currents.ConclusionThe I136V substitution in NaV1.7 alters channel gating and kinetic properties. Each of these changes may contribute to increased excitability of nociceptive dorsal root ganglion neurons, which underlies pain in erythromelalgia. The smaller shift in voltage-dependence of activation of NaV1.7, compared to the other reported cases of inherited erythromelalgia, may contribute to the later age of onset and slower progression of the symptoms reported in association with this mutation.
Highlights
Primary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date
Currents generated by isoleucine 136 with valine (I136V) mutant channels activated and reached the maximal amplitudes at more hyperpolarized potentials compared with wild type channels
Boltzmann fits of conductance show that the I136V mutation significantly shifted the midpoint of the activation curve in a hyperpolarizing direction (I136V: V1/2,act = -28.8 ± 0.5 mV, n = 43; NaV1.7R: -23.1 ± 0.7 mV, n = 40, p < 0.05, Figure 1C, Table 1)
Summary
Primary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na+ channel NaV1.7 have been linked with primary erythromelalgia. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all NaV1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III. Primary erythromelalgia is a rare, inherited, autosomal dominant disorder, characterized by intermittent burning pain in the extremities and skin redness of the affected areas. Primary erythromelalgia has been linked to mutations in SCN9A, the gene that encodes voltage-gated sodium channel NaV1.7 [10]. Gain-of-function mutations of the NaV1.7 channel might be expected to contribute to the hyperexcitability of nociceptive neurons which underlies chronic pain in patients with erythromelagia
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