title: Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant.
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.
authors.affiliation: Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena &Jena University Hospital, 07745 Jena, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Leipold
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5208, USA.|Department of Genetics, Stanford University School of Medicine, Stanford California 94305-5208, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hanson-Kahn
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford California 94305-5208, USA.
authors.forename: Miya
authors.initials: M
authors.lastname: Frick
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford California 94305-5208, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5208, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: Institute of Human Genetics, Jena University Hospital, 07743 Jena, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Voigt
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, 52074 Aachen, Germany.
authors.forename: Istvan
authors.identifier: http://orcid.org/0000-0002-0955-8911
authors.initials: I
authors.lastname: Katona
authors.affiliation: Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena &Jena University Hospital, 07745 Jena, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Oliver Goral
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.|Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, 52074 Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: Institute of Human Genetics, Jena University Hospital, 07743 Jena, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.affiliation: Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena &Jena University Hospital, 07745 Jena, Germany.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.affiliation: Institute of Human Genetics, Jena University Hospital, 07743 Jena, Germany.
authors.forename: Ingo
authors.identifier: http://orcid.org/0000-0002-5642-8378
authors.initials: I
authors.lastname: Kurth
mesh_terms: D000818:Animals; D003080:Cold Temperature; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism*; D010146:Pain / Q000235:genetics* / Q000378:metabolism
chemical_list: D062558:NAV1.9 Voltage-Gated Sodium Channel; C491886:SCN11A protein, human; C491885:Scn11a protein, mouse