A novel gain-of-function Na(v)1.7 mutation in a carbamazepine-responsive patient with adult-onset painful peripheral neuropathy

Voltage-gated sodium channel Na(v)1.7 is a threshold channel in peripheral dorsal root ganglion (DRG), trigeminal ganglion, and sympathetic ganglion neurons. Gain-of-function mutations in Na(v)1.7 have been shown to increase excitability in DRG neurons and have been linked to rare Mendelian and more common pain disorders. Discovery of Na(v)1.7 variants in patients with pain disorders may expand the spectrum of painful peripheral neuropathies associated with a well-defined molecular target, thereby providing a basis for more targeted approaches for treatment. We screened the genome of a patient with adult-onset painful peripheral neuropathy characterized by severe burning pain and report here the new Na(v)1.7-V810M variant. Voltage-clamp recordings were used to assess the effects of the mutation on biophysical properties of Na(v)1.7 and the response of the mutant channel to treatment with carbamazepine (CBZ), and multi-electrode array (MEA) recordings were used to assess the effects of the mutation on the excitability of neonatal rat pup DRG neurons. The V810M variant increases current density, shifts activation in a hyperpolarizing direction, and slows kinetics of deactivation, all gain-of-function attributes. We also show that DRG neurons that express the V810M variant become hyperexcitable. The patient responded to treatment with CBZ. Although CBZ did not depolarize activation of the mutant channel, it enhanced use-dependent inhibition. Our results demonstrate the presence of a novel gain-of-function variant of Na(v)1.7 in a patient with adult-onset painful peripheral neuropathy and the responsiveness of that patient to treatment with CBZ, which is likely due to the classical mechanism of use-dependent inhibition.