title: The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy.
abstract: Painful small fiber neuropathy is a challenging medical condition with no effective treatment. Non-genetic causes can be identified in one half of the subjects. Gain-of-function variants of sodium channels Nav1.7 and Nav1.8 have recently been associated with painful small fiber neuropathy. More recently, mutations of sodium channel Nav1.9 have been linked to human pain disorders, with two gain-of-function mutations found in patients with painful small fiber neuropathy. Here we report a novel Nav1.9 mutation, a glycine 699 substitution by arginine (G699R) in the domain II S4-S5 linker, identified in a patient with painful small fiber neuropathy. In this study, we assayed the mutant channels by voltage-clamp in superior cervical ganglion neurons, which do not produce endogenous Nav1.8 or Nav1.9 currents, and provide a novel platform where Nav1.9 is expressed at relatively high levels. Voltage-clamp analysis showed that the mutation hyperpolarizes (-10.1 mV) channel activation, depolarizes (+6.3 mV) steady-state fast inactivation, slows deactivation, and enhances ramp responses compared with wild-type Nav1.9 channels. Current-clamp analysis showed that the G699R mutant channels render dorsal root ganglion neurons hyperexcitable, via depolarized resting membrane potential, reduced current threshold and increased evoked firing. These observations show that the domain II S4-S5 linker plays an important role in the gating of Nav1.9 and demonstrates that a mutation in this linker is linked to a common pain disorder.
authors: Department of Neurology, Yale University School of Medicine, New Haven, CT, 06510, USA.
authors: Chongyang
authors: C
authors: Han
authors: Yang
authors: Y
authors: Yang
authors: Bianca T A
authors: BT
authors: de Greef
authors: Janneke G J
authors: JG
authors: Hoeijmakers
authors: Monique M
authors: MM
authors: Gerrits
authors: Camiel
authors: C
authors: Verhamme
authors: Jian
authors: J
authors: Qu
authors: Giuseppe
authors: G
authors: Lauria
authors: Ingemar S J
authors: IS
authors: Merkies
authors: Catharina G
authors: CG
authors: Faber
authors: Sulayman D
authors: SD
authors: Dib-Hajj
authors: Stephen G
authors: SG
authors: Waxman
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D004916:Erythromelalgia / Q000235:genetics*; D005727:Ganglia, Spinal / Q000503:physiopathology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D017783:Superior Cervical Ganglion / Q000166:cytology; D014162:Transfection
chemical_list: D062558:NAV1.9 Voltage-Gated Sodium Channel; D011993:Recombinant Fusion Proteins; C491886:SCN11A protein, human