Familial gain-of-function Na v 1.9 mutation in a painful channelopathy.

OBJECTIVE: Gain-of-function mutations in Nav 1.9 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 Nav 1.9 mutations will help to elucidate the phenotypic spectrum of Nav 1.9 channelopathies.

METHODS: Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations in SCN9A and SCN11A . Electrophysiological recordings and multistate modelling analysis were implemented for functional analyses.

RESULTS: A novel Nav 1.9 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 Nav 1.9, strengthening human validation of this channel as a potential therapeutic target for pain.