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

Abstract

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ 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 the pore-forming voltage-gated sodium channel α subunits (NaVs) in a subset of patients with SFN, but the auxiliary sodium channel β subunits have been less implicated in the development of the disease. β 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 β2-subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel β 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 β2 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 β2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of β2 subunits in SFN and strengthens the link between sodium channel β subunits and the development of neuropathic pain in humans.

Depolarizing NaV and Hyperpolarizing KV Channels Are Co-Trafficked in Sensory Neurons

“…Na V channels are composed of a pore-forming a subunit (Na V 1.1-1.9) and associated b subunits (Na V b 1-4), which modulate various aspects of Na V function and neuronal excitability (O'Malley and Isom, 2015; Alsaloum et al, 2019Alsaloum et al, , 2021. Thus, we Figure 6.…”

Advances in diagnosis and management of distal sensory polyneuropathies

“…A recent Brazilian study using WGS identified two new mutations 50. Very rarely, patients have pathogenic variants in the auxiliary beta, rather than the alpha, sodium channel subunits or loss-of-function variants associated with reduced pain sensitivity that can be lethal 59 60. Two cases harbouring new SCN9A variants with neuropathic pain and biopsy-proven small fibre neuropathy appeared to respond to intravenous immunoglobulin administered pretesting,61 though it is uncertain if this was coincidental.…”

Genetic Analysis of SCN11A, SCN10A, and SCN9A in Familial Episodic Pain Syndrome (FEPS) in Japan and Proposal of Clinical Diagnostic Criteria

“…VGSCs comprise a pore-forming α subunit, which is associated with auxiliary β subunits. Among the nine different VGSCs (Nav1.1-Nav1.9) expressed in humans, Nav1.9, Nav1.8, and Nav1.7, encoded by SCN11A, SCN10A, and SCN9A, respectively, have been genetically and functionally validated as drivers of chronic pain in humans [2,3]. The biophysical properties of the three VGSCs determine nociceptor excitability; therefore, a gain-of-function or changed expression can lead to neuropathic pain.…”