A novel gain-of-function sodium channel β2 subunit mutation in idiopathic small fiber neuropathy

M. Alsaloum, J.I.R. Labau, D. Sosniak, P. Zhao, R. Almomani, M. Gerrits, J.G.J. Hoeijmakers, G. Lauria, C.G. Faber, S.G. Waxman, S. Dib-Hajj*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

Abstract

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated A delta and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several poreforming voltage-gated sodium channel alpha subunits (Na-v) in a subset of patients with SFN, but the auxiliary sodium channel beta-subunits have been less implicated in the development of the disease. beta subunits modulate Na-v trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the beta 2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel beta subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the beta(2) subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the beta(2)-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of beta(2) subunits in SFN and strengthens the link between sodium channel beta subunits and the development of neuropathic pain in humans.NEW & NOTEWORTHY Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel alpha subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary beta 2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel beta 2 subunit mutations and human pain disorders.
Original languageEnglish
Pages (from-to)827-839
Number of pages13
JournalJournal of Neurophysiology
Volume126
Issue number3
DOIs
Publication statusPublished - 1 Sep 2021

Keywords

  • beta 2 subunit
  • small fiber neuropathy (SFN)
  • sodium channel beta subunits
  • tetrodotoxin-sensitive voltage-gated sodium channels
  • voltage-gated sodium (Nav) channels
  • VOLTAGE-GATED SODIUM
  • FEBRILE SEIZURES
  • PERIPHERAL NEUROPATHY
  • GENERALIZED EPILEPSY
  • DIAGNOSTIC-CRITERIA
  • NA(V)1.8 MUTATION
  • GENE
  • INACTIVATION
  • EXPRESSION
  • PAIN

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