title: Familial gain-of-function Nav1.9 mutation in a painful channelopathy.
abstract: Gain-of-function mutations in Nav1.9 have been identified in three families with rare heritable pain disorders, and in patients with painful small-fibre neuropathy. Identification and functional assessment of new Nav1.9 mutations will help to elucidate the phenotypic spectrum of Nav1.9 channelopathies.
  
  
  
  Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations inSCN9AandSCN11A. Electrophysiological recordings and multistate modelling analysis were implemented for functional analyses.
  
  
  
  A novel Nav1.9 mutation, p.Arg222His, was identified in patients with early-onset pain in distal extremities including joints and gastrointestinal disturbances, but was absent from an asymptomatic blood relative. This mutation alters channel structure by substituting the highly conserved first arginine residue in transmembrane segment 4 (domain 1), the voltage sensor, with histidine. Voltage-clamp recordings demonstrate a hyperpolarising shift and acceleration of activation of the p.Arg222His mutant channel, which make it easier to open the channel. When expressed in dorsal root ganglion neurons, mutant p.Arg222His channels increase excitability via a depolarisation of resting potential and increased evoked firing.
  
  
  
  This study expands the spectrum of heritable pain disorders linked to gain-of-function mutations in Nav1.9, strengthening human validation of this channel as a potential therapeutic target for pain.
authors: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.|Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA.|Center for Restoration of Nervous System Function, Veterans Affairs Medical Center, West Haven, Connecticut, USA.
authors: Chongyang
authors: C
authors: Han
authors: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.|Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA.|Center for Restoration of Nervous System Function, Veterans Affairs Medical Center, West Haven, Connecticut, USA.
authors: Yang
authors: Y
authors: Yang
authors: Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Rene H
authors: RH
authors: Te Morsche
authors: Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Joost P H
authors: JP
authors: Drenth
authors: Department of Neurology, Fundación para el Estudio de las Enfermedades Neurometabólicas, Buenos Aires, Argentina.
authors: Juan M
authors: JM
authors: Politei
authors: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.|Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA.|Center for Restoration of Nervous System Function, Veterans Affairs Medical Center, West Haven, Connecticut, USA.
authors: Stephen G
authors: SG
authors: Waxman
authors: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.|Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA.|Center for Restoration of Nervous System Function, Veterans Affairs Medical Center, West Haven, Connecticut, USA.
authors: Sulayman D
authors: SD
authors: Dib-Hajj
mesh_terms: D053447:Channelopathies / Q000175:diagnosis* / Q000235:genetics*; D005727:Ganglia, Spinal / Q000503:physiopathology; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics*; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000235:genetics; D009474:Neurons / Q000502:physiology; D010146:Pain / Q000235:genetics*; D018408:Patch-Clamp Techniques / Q000379:methods
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; C491886:SCN11A protein, human; C486866:SCN9A protein, human