title: Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.
abstract: Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.7 produce several pain syndromes, including inherited erythromelalgia (IEM), a disorder in which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning pain triggered by warmth, the effects of increased temperature on DRG neurons expressing mutant Nav1.7 channels have not been well documented. Here, using structural modeling, voltage-clamp, current-clamp, and multielectrode array recordings, we have studied a newly identified Nav1.7 mutation, Ala1632Gly, from a multigeneration family with IEM. Structural modeling suggests that Ala1632 is a molecular hinge and that the Ala1632Gly mutation may affect channel gating. Voltage-clamp recordings revealed that the Nav1.7-A1632G mutation hyperpolarizes activation and depolarizes fast-inactivation, both gain-of-function attributes at the channel level. Whole-cell current-clamp recordings demonstrated increased spontaneous firing, lower current threshold, and enhanced evoked firing in rat DRG neurons expressing Nav1.7-A1632G mutant channels. Multielectrode array recordings further revealed that intact rat DRG neurons expressing Nav1.7-A1632G mutant channels are more active than those expressing Nav1.7 WT channels. We also showed that physiologically relevant thermal stimuli markedly increase the mean firing frequencies and the number of active rat DRG neurons expressing Nav1.7-A1632G mutant channels, whereas the same thermal stimuli only increase these parameters slightly in rat DRG neurons expressing Nav1.7 WT channels. The response of DRG neurons expressing Nav1.7-A1632G mutant channels upon increase in temperature suggests a cellular basis for warmth-triggered pain in IEM.
  
  
  
  Inherited erythromelalgia (IEM), a severe pain syndrome characterized by episodes of intense burning pain triggered by warmth, is caused by mutations in sodium channel Nav1.7, which are preferentially expressed in sensory and sympathetic neurons. More than 20 gain-of-function Nav1.7 mutations have been identified from IEM patients, but the question of how warmth triggers episodes of pain in IEM has not been well addressed. Combining multielectrode array, voltage-clamp, and current-clamp recordings, we assessed a newly identified IEM mutation (Nav1.7-A1632G) from a multigeneration family. Our data demonstrate gain-of-function attributes at the channel level and differential effects of physiologically relevant thermal stimuli on the excitability of DRG neurons expressing mutant and WT Nav1.7 channels, suggesting a cellular mechanism for warmth-triggered pain episodes in IEM patients.
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, and.
authors.forename: Jianying
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, and.
authors.forename: Malgorzata A
authors.initials: MA
authors.lastname: Mis
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, and.
authors.forename: Mark
authors.identifier: 0000-0002-7271-1165
authors.initials: M
authors.lastname: Estacion
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, and.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Macala
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, and.
authors.forename: Palak
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, and.
authors.forename: Betsy R
authors.initials: BR
authors.lastname: Schulman
authors.affiliation: Rutgers Robert Wood Johnson Medical School, Department of Pediatrics, Child Health Institute of New Jersey, New Brunswick, New Jersey 08901.
authors.forename: Daniel B
authors.identifier: 0000-0002-1831-1339
authors.initials: DB
authors.lastname: Horton
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, and.
authors.forename: Sulayman D
authors.identifier: 0000-0002-4137-1655
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, and stephen.waxman@yale.edu.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D004916:Erythromelalgia / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000473:pathology*; D005973:Glutamine / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013696:Temperature; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D005973:Glutamine; D013779:Tetrodotoxin; D000409:Alanine
keywords: chronic pain; man on fire syndrome; sensory neurons; temperature responses; thermosensation; voltage-gated sodium channel