Familial gain-of-function Na1.9 mutation in a painful channelopathy.

OBJECTIVE

Gain-of-function mutations in Na1.9 have been identified in three families with rare heritable pain disorders, and in patients with painful small-fibre neuropathy. Identification and functional assessment of new Na1.9 mutations will help to elucidate the phenotypic spectrum of Na1.9 channelopathies.

METHODS

Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations in and . Electrophysiological recordings and multistate modelling analysis were implemented for functional analyses.

RESULTS

A novel Na1.9 mutation, p.Arg222His, was identified in patients with early-onset pain in distal extremities including joints and gastrointestinal disturbances, but was absent from an asymptomatic blood relative. This mutation alters channel structure by substituting the highly conserved first arginine residue in transmembrane segment 4 (domain 1), the voltage sensor, with histidine. Voltage-clamp recordings demonstrate a hyperpolarising shift and acceleration of activation of the p.Arg222His mutant channel, which make it easier to open the channel. When expressed in dorsal root ganglion neurons, mutant p.Arg222His channels increase excitability via a depolarisation of resting potential and increased evoked firing.

CONCLUSIONS

This study expands the spectrum of heritable pain disorders linked to gain-of-function mutations in Na1.9, strengthening human validation of this channel as a potential therapeutic target for pain.