Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy.
Sodium channel Nav1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in sodium channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral sodium channels Nav1.7 and Nav1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A, and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Nav1.9 mutations confer gain-of-function attributes to the channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Nav1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Nav1.9 as a cause of painful peripheral neuropathy.
1 Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, and Centre for Neuroscience and Regeneration Research, Veterans Affairs Medical Centre, West Haven, CT 06516, USA.
Jianying
J
Huang
1 Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, and Centre for Neuroscience and Regeneration Research, Veterans Affairs Medical Centre, West Haven, CT 06516, USA.
Chongyang
C
Han
1 Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, and Centre for Neuroscience and Regeneration Research, Veterans Affairs Medical Centre, West Haven, CT 06516, USA.
Mark
M
Estacion
1 Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, and Centre for Neuroscience and Regeneration Research, Veterans Affairs Medical Centre, West Haven, CT 06516, USA.
Dymtro
D
Vasylyev
2 Department of Neurology, University Medical Centre Maastricht, Maastricht, The Netherlands.
Janneke G J
JG
Hoeijmakers
3 Department of Clinical Genetics, University Medical Centre Maastricht, Maastricht, The Netherlands.
Monique M
MM
Gerrits
1 Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, and Centre for Neuroscience and Regeneration Research, Veterans Affairs Medical Centre, West Haven, CT 06516, USA.
Lynda
L
Tyrrell
4 Neuromuscular Diseases Unit and Bioinformatics Unit, IRCCS Foundation, 'Carlo Besta', Neurological Institute Milan, Italy.
Giuseppe
G
Lauria
2 Department of Neurology, University Medical Centre Maastricht, Maastricht, The Netherlands.
Catharina G
CG
Faber
1 Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, and Centre for Neuroscience and Regeneration Research, Veterans Affairs Medical Centre, West Haven, CT 06516, USA.
Sulayman D
SD
Dib-Hajj
2 Department of Neurology, University Medical Centre Maastricht, Maastricht, The Netherlands5 Department of Neurology, Spaarne Hospital, Hoofddorp, The Netherlands.
Ingemar S J
IS
Merkies
1 Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, and Centre for Neuroscience and Regeneration Research, Veterans Affairs Medical Centre, West Haven, CT 06516, USA stephen.waxman@yale.edu.
Stephen G
SG
Waxman
D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics*; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000235:genetics; D009474:Neurons / Q000502:physiology; D010146:Pain / Q000235:genetics* / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
D062556:NAV1.7 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; C491886:SCN11A protein, human
DRG; channelopathy; current-clamp; sensory neurons; voltage-clamp