title: Gain-of-function Nav1.8 mutations in painful neuropathy.
abstract: Painful peripheral neuropathy often occurs without apparent underlying cause. Gain-of-function variants of sodium channel Na(v)1.7 have recently been found in ∼30% of cases of idiopathic painful small-fiber neuropathy. Here, we describe mutations in Na(v)1.8, another sodium channel that is specifically expressed in dorsal root ganglion (DRG) neurons and peripheral nerve axons, in patients with painful neuropathy. Seven Na(v)1.8 mutations were identified in 9 subjects within a series of 104 patients with painful predominantly small-fiber neuropathy. Three mutations met criteria for potential pathogenicity based on predictive algorithms and were assessed by voltage and current clamp. Functional profiling showed that two of these three Na(v)1.8 mutations enhance the channel's response to depolarization and produce hyperexcitability in DRG neurons. These observations suggest that mutations of Na(v)1.8 contribute to painful peripheral neuropathy.
authors.affiliation: Department of Neurology, University Medical Centre Maastricht, 6202 AZ Maastricht, The Netherlands.
authors.forename: Catharina G
authors.initials: CG
authors.lastname: Faber
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria
authors.forename: Ingemar S J
authors.initials: IS
authors.lastname: Merkies
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Cheng
authors.forename: Chongyang
authors.initials: C
authors.lastname: Han
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Ahn
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Persson
authors.forename: Janneke G J
authors.initials: JG
authors.lastname: Hoeijmakers
authors.forename: Monique M
authors.initials: MM
authors.lastname: Gerrits
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pierro
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lombardi
authors.forename: Dimos
authors.initials: D
authors.lastname: Kapetis
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D004252:DNA Mutational Analysis; D055724:Electrophysiological Phenomena; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics*; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D009437:Neuralgia / Q000235:genetics* / Q000503:physiopathology
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse