A novel gain-of-function sodium channel b2 subunit mutation in idiopathic small fiber neuropathy

Matthew Alsaloum, Julie I.R. Labau, Daniel Sosniak, Peng Zhao, Rowida Almomani, Monique Gerrits, Janneke G.J. Hoeijmakers, Giuseppe Lauria, Catharina G. Faber, Stephen G. Waxman, Sulayman Dib-Hajj

Research output: Contribution to journalArticlepeer-review


Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Ad 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 pore-forming voltage-gated sodium channel a subunits (NaV) in a subset of patients with SFN, but the auxiliary sodium channel b subunits have been less implicated in the development of the disease. b subunits modulate NaV 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 b2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel b 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 b2 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 b2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of b2 subunits in SFN and strengthens the link between sodium channel b subunits and the development of neuropathic pain in humans.

Original languageEnglish
Pages (from-to)827-839
Number of pages13
JournalJournal of Neurophysiology
Issue number3
Publication statusPublished - Sept 9 2021


  • B 2 subunit
  • Small fiber neuropathy (SFN)
  • Sodium channel b subunits
  • Tetrodotoxin-sensitive voltage-gated sodium channels
  • Voltage-gated sodium (Nav) channels

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology


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