title: A de novo gain-of-function mutation in SCN11A causes loss of pain perception.
abstract: The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Jena, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Leipold
authors.forename: Lutz
authors.initials: L
authors.lastname: Liebmann
authors.forename: G Christoph
authors.initials: GC
authors.lastname: Korenke
authors.forename: Theresa
authors.initials: T
authors.lastname: Heinrich
authors.forename: Sebastian
authors.initials: S
authors.lastname: Giesselmann
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.forename: Matthias
authors.initials: M
authors.lastname: Ebbinghaus
authors.forename: R Oliver
authors.initials: RO
authors.lastname: Goral
authors.forename: Tommy
authors.initials: T
authors.lastname: Stödberg
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Hennings
authors.forename: Markus
authors.initials: M
authors.lastname: Bergmann
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Andrea
authors.initials: A
authors.lastname: Wetzel
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Robert
authors.initials: R
authors.lastname: Blum
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Schaible
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D053447:Channelopathies / Q000235:genetics; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000235:genetics; D009619:Nociceptors / Q000502:physiology; D010146:Pain / Q000235:genetics*; D058748:Pain Perception / Q000502:physiology*
chemical_list: D062558:NAV1.9 Voltage-Gated Sodium Channel; C491886:SCN11A protein, human
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