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

• Published in: Nature communications 2015-12, Vol.6 (1), p.10049-10049, Article 10049
• Main Authors: Leipold, Enrico, Hanson-Kahn, Andrea, Frick, Miya, Gong, Ping, Bernstein, Jonathan A., Voigt, Martin, Katona, Istvan, Oliver Goral, R., Altmüller, Janine, Nürnberg, Peter, Weis, Joachim, Hübner, Christian A., Heinemann, Stefan H., Kurth, Ingo
• Format: Article
• Language: English
• Subjects: 631/208/737; 631/378/1697/1635; 631/378/2620/410; 631/45/269/1152; 9/74; Animals; Channel opening; Coding; Cold; Cold Temperature; Electric potential; Humanities and Social Sciences; Humans; Hyperactivity; Low temperature resistance; Membrane potential; Mice; Mice, Inbred C57BL; multidisciplinary; Mutation; Mutation, Missense; NAV1.9 Voltage-Gated Sodium Channel - genetics; NAV1.9 Voltage-Gated Sodium Channel - metabolism; Nociceptors; Pain; Pain - genetics; Pain - metabolism; Pain perception; Peripheral neuropathy; Phenotypes; Science; Science (multidisciplinary); Sensory neurons; Sodium channels (voltage-gated); Temperature dependence
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10049

Gain-of-function mutations in the human SCN11A -encoded voltage-gated Na + channel Na V 1.9 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 V 1.9, 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 V 1.9. 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 V 1.9 hyperactivity. A mutation in the sodium channel Nav1.9 has been identified in a family and shown to associate with cold-aggravated pain. Here, the authors characterize the electrophysiological consequences of this mutation and propose a mechanism for the pain that the individuals experience.