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

CG Faber, G Lauria, ISJ Merkies… - Proceedings of the …, 2012 - National Acad Sciences
CG Faber, G Lauria, ISJ Merkies, X Cheng, C Han, HS Ahn, AK Persson, JGJ Hoeijmakers…
Proceedings of the National Academy of Sciences, 2012National Acad Sciences
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 …
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 Nav1.8 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.
National Acad Sciences