Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant

摘要: Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+) channel NaV1.9 cause severe pain disorders ranging from neuropathic to congenital insensitivity. However, entire spectrum of diseases has yet be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) NaV1.9, which leads cold-aggravated peripheral humans. Electrophysiological analysis reveals that p.V1184A shifts voltage dependence opening hyperpolarized potentials thereby conferring gain-of-function characteristics NaV1.9. Mutated channels diminish resting membrane potential mouse primary sensory neurons and cold-resistant hyperexcitability nociceptors, suggesting mechanistic basis for temperature phenotype. On direct comparison linked either or insensitivity, propose model physiological consequence mutation, is, augmented versus absent pain, is critically dependent on type hyperactivity.