Cold-aggravated pain in humans caused by a hyperactive Na_V1.9 channel mutant

Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na⁺ channel Na_V1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the Na_V 1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in Na_V1.9, which leads to cold-aggravated peripheral pain in humans. Electrophysiological analysis reveals that p.V1184A shifts the voltage dependence of channel opening to hyperpolarized potentials thereby conferring gain-of-function characteristics to Na_V1.9. Mutated channels diminish the resting membrane potential of mouse primary sensory neurons and cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype. On the basis of direct comparison of the mutations linked to either cold-aggravated pain or pain insensitivity, we propose a model in which the physiological consequence of a mutation, that is, augmented versus absent pain, is critically dependent on the type of Na_V1.9 hyperactivity.