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

Enrico Leipold (), Andrea Hanson-Kahn, Miya Frick, Ping Gong, Jonathan A. Bernstein, Martin Voigt, Istvan Katona, R. Oliver Goral, Janine Altmüller, Peter Nürnberg, Joachim Weis, Christian A. Hübner, Stefan H. Heinemann and Ingo Kurth ()
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Enrico Leipold: Center for Molecular Biomedicine, Friedrich Schiller University Jena & Jena University Hospital
Andrea Hanson-Kahn: Stanford University School of Medicine
Miya Frick: Stanford University School of Medicine
Ping Gong: Stanford University School of Medicine
Jonathan A. Bernstein: Stanford University School of Medicine
Martin Voigt: Institute of Human Genetics, Jena University Hospital
Istvan Katona: Institute of Neuropathology, RWTH Aachen University Hospital
R. Oliver Goral: Center for Molecular Biomedicine, Friedrich Schiller University Jena & Jena University Hospital
Janine Altmüller: Cologne Center for Genomics (CCG), University of Cologne
Peter Nürnberg: Cologne Center for Genomics (CCG), University of Cologne
Joachim Weis: Institute of Neuropathology, RWTH Aachen University Hospital
Christian A. Hübner: Institute of Human Genetics, Jena University Hospital
Stefan H. Heinemann: Center for Molecular Biomedicine, Friedrich Schiller University Jena & Jena University Hospital
Ingo Kurth: Institute of Human Genetics, Jena University Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na+ channel NaV1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the NaV1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, 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 NaV1.9. 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 NaV1.9 hyperactivity.

Date: 2015
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DOI: 10.1038/ncomms10049

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