Gain-of-function Nav1.8 mutations in painful neuropathy

Catharina G. Faber, Giuseppe Lauria, Ingemar S J Merkies, Xiaoyang Cheng, Chongyang Han, Hye Sook Ahn, Anna Karin Persson, Janneke G J Hoeijmakers, Monique M. Gerrits, Tiziana Pierro, Raffaella Lombardi, Dimos Kapetis, Sulayman D. Dib-Hajj, Stephen G. Waxman

Research output: Contribution to journalArticle

196 Citations (Scopus)

Abstract

Painful peripheral neuropathy often occurs without apparent underlying cause. Gain-of-function variants of sodium channel Nav1.7 have recently been found in ~30% of cases of idiopathic painful small-fiber neuropathy. Here, we describe mutations in Nav1.8, another sodium channel that is specifically expressed in dorsal root ganglion (DRG) neurons and peripheral nerve axons, in patients with painful neuropathy. Seven Nav1.8 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 v1.8 mutations enhance the channel's response to depolarization and produce hyperexcitability in DRG neurons. These observations suggest that mutations of Nav1.8 contribute to painful peripheral neuropathy.

Original languageEnglish
Pages (from-to)19444-19449
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number47
DOIs
Publication statusPublished - Nov 20 2012

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Mutation
Sodium Channels
Spinal Ganglia
Peripheral Nervous System Diseases
Neurons
Peripheral Nerves
Axons
Virulence
Painful Neuropathy
Small Fiber Neuropathy

Keywords

  • Dorsal root ganglia
  • Patch clamp

ASJC Scopus subject areas

  • General

Cite this

Gain-of-function Nav1.8 mutations in painful neuropathy. / Faber, Catharina G.; Lauria, Giuseppe; Merkies, Ingemar S J; Cheng, Xiaoyang; Han, Chongyang; Ahn, Hye Sook; Persson, Anna Karin; Hoeijmakers, Janneke G J; Gerrits, Monique M.; Pierro, Tiziana; Lombardi, Raffaella; Kapetis, Dimos; Dib-Hajj, Sulayman D.; Waxman, Stephen G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 47, 20.11.2012, p. 19444-19449.

Research output: Contribution to journalArticle

Faber, CG, Lauria, G, Merkies, ISJ, Cheng, X, Han, C, Ahn, HS, Persson, AK, Hoeijmakers, JGJ, Gerrits, MM, Pierro, T, Lombardi, R, Kapetis, D, Dib-Hajj, SD & Waxman, SG 2012, 'Gain-of-function Nav1.8 mutations in painful neuropathy', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 47, pp. 19444-19449. https://doi.org/10.1073/pnas.1216080109
Faber, Catharina G. ; Lauria, Giuseppe ; Merkies, Ingemar S J ; Cheng, Xiaoyang ; Han, Chongyang ; Ahn, Hye Sook ; Persson, Anna Karin ; Hoeijmakers, Janneke G J ; Gerrits, Monique M. ; Pierro, Tiziana ; Lombardi, Raffaella ; Kapetis, Dimos ; Dib-Hajj, Sulayman D. ; Waxman, Stephen G. / Gain-of-function Nav1.8 mutations in painful neuropathy. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 47. pp. 19444-19449.
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