Gain-of-function mutations in sodium channel NaV1.9 in painful neuropathy

The aetiology of painful peripheral neuropathy is often unknown. Huang et al. sequence the gene encoding sodium channel Na(v)1.9 in 393 patients with small fibre neuropathy and identify eight variants in 12 individuals. Functional analysis of two variants reveals that they confer gain-of-function attributes to Na(v)1.9, and induce nociceptor hyperexcitability.Sodium channel Na(v)1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in sodium channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral sodium channels Na(v)1.7 and Na(v)1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A, and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Na(v)1.9 mutations confer gain-of-function attributes to the channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Na(v)1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Na(v)1.9 as a cause of painful peripheral neuropathy.