The G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying DRG neuron hyperexcitability

Han, Chongyang; Vasylyev, Dmytro V.; Macala, Lawrence J.; Gerrits, Monique M.; Hoeijmakers, Janneke G. J.; Bekelaar, Kim; Dib‐Hajj, Sulayman D.; Faber, Catharina G.; Merkies, Ingemar S. J.; Waxman, Stephen G.

doi:10.1136/jnnp-2013-306095

Cited by 88 publications

(105 citation statements)

References 35 publications

(57 reference statements)

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“…Sodium channels Nav1.7, Nav1.8, and Nav1.9 are preferentially expressed in peripheral neurons. Gain-of-function mutations of human Nav1.7 and Nav1.8 channels have been associated with SFN (Faber et al 2012a, b;Han et al 2012Han et al , 2014Hoeijmakers et al 2012b;Huang et al 2013). More recently, seven mutations in Nav1.9 channels were identified in patients with SFN (Huang et al 2014).…”

Section: Introductionmentioning

confidence: 98%

The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy

et al. 2015

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Painful small fiber neuropathy is a challenging medical condition with no effective treatment. Non-genetic causes can be identified in one half of the subjects. Gain-of-function variants of sodium channels Nav1.7 and Nav1.8 have recently been associated with painful small fiber neuropathy. More recently, mutations of sodium channel Nav1.9 have been linked to human pain disorders, with two gain-of-function mutations found in patients with painful small fiber neuropathy. Here we report a novel Nav1.9 mutation, a glycine 699 substitution by arginine (G699R) in the domain II S4-S5 linker, identified in a patient with painful small fiber neuropathy. In this study, we assayed the mutant channels by voltage-clamp in superior cervical ganglion neurons, which do not produce endogenous Nav1.8 or Nav1.9 currents, and provide a novel platform where Nav1.9 is expressed at relatively high levels. Voltage-clamp analysis showed that the mutation hyperpolarizes (-10.1 mV) channel activation, depolarizes (+6.3 mV) steady-state fast inactivation, slows deactivation, and enhances ramp responses compared with wild-type Nav1.9 channels. Current-clamp analysis showed that the G699R mutant channels render dorsal root ganglion neurons hyperexcitable, via depolarized resting membrane potential, reduced current threshold and increased evoked firing. These observations show that the domain II S4-S5 linker plays an important role in the gating of Nav1.9 and demonstrates that a mutation in this linker is linked to a common pain disorder.

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Section: Introductionmentioning

confidence: 98%

The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy

et al. 2015

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“…Na V 1.7 and Na V 1.8 channels have garnered intense interest because of evidence for their role in human pain disorders [2][3][4][5] , whereas there has previously been no such evidence for Na V 1.9. Our understanding of Na V 1.9 in general has also lagged behind as, unlike Na V 1.7 and Na V 1.8, it has proved difficult to study Na V 1.9 in heterologous expression systems, because it is only expressed at low levels and is difficult to study in isolation in native neurons.…”

mentioning

confidence: 98%

NaV1.9: a sodium channel linked to human pain

Dib‐Hajj¹,

Black²,

Waxman³

2015

Nat Rev Neurosci

169

128

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The voltage-gated sodium channel Na(V)1.9 is preferentially expressed in nociceptors and has been shown in rodent models to have a major role in inflammatory and neuropathic pain. These studies suggest that by selectively targeting Na(V)1.9, it might be possible to ameliorate pain without inducing adverse CNS side effects such as sedation, confusion and addictive potential. Three recent studies in humans--two genetic and functional studies in rare genetic disorders, and a third study showing a role for Na(V)1.9 in painful peripheral neuropathy--have demonstrated that Na(V)1.9 plays an important part both in regulating sensory neuron excitability and in pain signalling. With this human validation, attention is turning to this channel as a potential therapeutic target for pain.

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“…Excellent reviews can be found in [6,7 ]. Additional neuropathies have been identified that segregate with mutations on SCN10A and SCN11A, which encode the a-subunits of Na V 1.8 and Na V 1.9, respectively [8][9][10][11][12][13]. Na V 1.7, Na V 1.8 and Na V 1.9 are preferentially distributed in peripheral sensory neurons.…”

Section: Gain-of-function and Loss-of-function Mutationsmentioning

confidence: 98%