Gain-of-function Na _v 1.8 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.dorsal root ganglia | patch clamp P ainful peripheral neuropathy involving small-diameter nociceptive nerve fibers represents a significant public health challenge (1); in about one-half of cases, no cause can be identified (1). Faber et al. (2) recently described gain-of-function variants (single amino acid substitutions) in sodium channel Na v 1.7, which is abundantly expressed in spinal sensory [dorsal root ganglion (DRG)] neurons and their axons (3) in nearly 30% of patients with biopsy-confirmed, painful small-fiber neuropathy (SFN) and no other apparent cause. These variants increase the excitability of DRG neurons, providing an explanation for pain in these patients. Molecular substrates for pain in the remaining SFN patients remain unknown. Here, we describe gain-of-function mutations in Na v 1.8, another sodium channel that is specifically expressed in DRG neurons and peripheral nerve axons, in human subjects with painful neuropathy, including a father-son pair. These mutations alter gating properties of the channel in a proexcitatory manner and increase the excitability of DRG neurons. These genetic and functional observations suggest that Na v 1.8 mutations contribute to pain in some peripheral neuropathies.

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

“…Despite their well-established roles in nociception, the mechanisms by which Na v 1.7 and Na v 1.8 isoforms specifically contribute to neuropathic pain are still under debate. On the one hand, knocking down Na v 1.8 prevents neuropathic pain in mice (40), Na v 1.7 accumulates in human painful dental pulp (15), and gain-of-function mutations of Na v 1.7 and Na v 1.8 are linked to exaggerated pain in humans (12,13). A recent simulation study suggested that Na v 1.7 and Na v 1.8 may act synergistically to increase the amplitude of subthreshold oscillations and increase the frequency of repetitive firing in the periphery (41).…”

“…Naturally occurring mutations in SCN9A, the gene encoding Na v 1.7, lead to either congenital insensitivity or severe episodic hypersensitivity to pain (9)(10)(11). In addition, Na v 1.7 and Na v 1.8 gain-offunction mutations in painful peripheral neuropathy syndromes were recently described (12,13). Not only are Na v 1.7 and Na v 1.8 important in inherited pain disorders, but also in acquired pain disorders, where their increased expression has already been linked to diverse chronic pain symptoms (14)(15)(16).…”

New technologies for the assessment of neuropathies

“…SFN is also associated with a widening spectrum of systemic diseases; the most recent disease to be associated, in 2016, is Elhers-Danlos syndrome 105 . In many patients, SFN is idiopathic, but pathogenic mutations in genes that encode for various sodium channels have been identified in some patients [106][107][108] . A correlation between specific mutations and painful and autonomic symptoms has been reported 109 , and novel mutations in COL6A5 have been found in patients with neurogenic itch and SFN 110 .…”

Venom: the sharp end of pain therapeutics

“…Two gain-of-function mutations in SCN10A, which encode Na V 1.8 (found in patients with painful neuropathy) enhance the channel's response to depolarisation and produce hyperexcitability in DRG neurons. 8 Na V 1.9 is also a desirable drug target (as shown using mouse models) and is also expressed in DRG neurons but has proved difficult to functionally express in heterologous systems and is therefore challenging to study. 9 TRPV1 (a member of the TRP superfamily of excitatory ion channels that bind vanilloids) is predominantly expressed by nociceptors and is therefore also a popular pain relief target, 10 but in clinical trials, drugs inhibiting the TRPV1 channel cause hyperthermia and decreased sensitivity to painful levels of heat.…”