title: Small-fiber neuropathy Nav1.8 mutation shifts activation to hyperpolarized potentials and increases excitability of dorsal root ganglion neurons.
abstract: Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated sodium channel Nav1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium channel Nav1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Nav1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Nav1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Jianying
authors.initials: J
authors.lastname: Huang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Monique M
authors.initials: MM
authors.lastname: Gerrits
authors.forename: Janneke G J
authors.initials: JG
authors.lastname: Hoeijmakers
authors.forename: Kim
authors.initials: K
authors.lastname: Bekelaar
authors.forename: Ingemar S J
authors.initials: IS
authors.lastname: Merkies
authors.forename: Catharina G
authors.initials: CG
authors.lastname: Faber
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000200:Action Potentials; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000503:physiopathology*; D006801:Humans; D015640:Ion Channel Gating; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D010523:Peripheral Nervous System Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human