Background: Primary erythromelalgia (PE) is a dominant inherited disorder
characterized by recurrent pain, redness, and warmth of the extremities that is caused by
gain-of-function mutations in Nav1.7 encoding gene SCN9A. Most of the PE-causing
mutations of Nav1.7 have been shown to be able to render Nav1.7-expressing cells
hyperexcitable, however in most PE cases the symptoms are refractory to treatment with
sodium channel blockers and the mechanism underlying the intractability has not been
Objective: To identify the mutation of SCN9A in a Chinese Han family with typical
symptoms of PE and study the electrophysiological effect of the identified mutation.
Methods: A Chinese Han family with typical symptoms of PE was collected and the
proband's response to treatment was recorded. All the exons and flanking intronic
sequences of SCN9A were amplified with PCR and sequenced. Several online programs
were used to predict the damaging effect of variants. The functional effect of variants
was studied by voltage-clamp analysis in CHO-K1 cells.
Results: The PE symptoms of the proband are refractory to all kinds of reported
medications. Sequence analysis of SCN9A showed that a novel c.2477T>A (p. F826Y)
mutation co-segregated with the disease phenotype. Several online programs predicted
that the F826Y mutation has a deleterious effect on the gene product. Voltage-clamp
analysis showed that while compared with the wild-type channel, activation of the F826Y
mutant channel was shifted by 7.7 mV in a hyperpolarizing direction, whereas steadystate
inactivation was shifted by 4.3 mV in a depolarizing direction.
Conclusion: A novel disease-causing SCN9A Mutation (F826Y) was identified in a
Chinese family with typical PE symptoms refractory to treatment. F826Y of Nav1.7 could
render DRG neurons hyperexcitable, contributing to the pathogenesis of PE.