2023
Genetic, electrophysiological, and pathological studies on patients with SCN9A‐related pain disorders
Yuan J, Cheng X, Matsuura E, Higuchi Y, Ando M, Hashiguchi A, Yoshimura A, Nakachi R, Mine J, Taketani T, Maeda K, Kawakami S, Kira R, Tanaka S, Kanai K, Dib‐Hajj F, Dib‐Hajj S, Waxman S, Takashima H. Genetic, electrophysiological, and pathological studies on patients with SCN9A‐related pain disorders. Journal Of The Peripheral Nervous System 2023, 28: 597-607. PMID: 37555797, DOI: 10.1111/jns.12590.Peer-Reviewed Original ResearchConceptsParoxysmal extreme pain disorderPainful peripheral neuropathyPain disordersSCN9A mutationsPeripheral neuropathyNovel SCN9A mutationsVoltage-gated sodium channel Nav1.7Sodium channel Nav1.7Steady-state fast inactivationGene panel sequencingPatch-clamp analysisAutonomic neuropathyNeuropathic painSCN9A geneClinical featuresUnderlying pathogenesisPathological studiesPatientsChannel Nav1.7EM phenotypePhenotypic spectrumNeuropathyNav1.7 channelsPatch-clamp systemElectrophysiological analysisTRPA1 rare variants in chronic neuropathic and nociplastic pain patients
Marchi M, Salvi E, Andelic M, Mehmeti E, D'Amato I, Cazzato D, Chiappori F, Lombardi R, Cartelli D, Devigili G, Bella E, Gerrits M, Almomani R, Malik R, Ślęczkowska M, Mazzeo A, Gentile L, Dib-Hajj S, Waxman S, Faber C, Vecchio E, de Tommaso M, Lauria G. TRPA1 rare variants in chronic neuropathic and nociplastic pain patients. Pain 2023, 164: 2048-2059. PMID: 37079850, PMCID: PMC10443199, DOI: 10.1097/j.pain.0000000000002905.Peer-Reviewed Original ResearchConceptsNociplastic painPainful neuropathyPain patientsHealthy controlsRare variantsChronic neuropathic painChronic pain disordersChronic widespread painChronic pain patientsMolecular profilePainless neuropathyNeuropathic painPain disordersWidespread painChronic painPatient's molecular profileIndependent cohortPainPatientsClinical diagnosisDisease riskNeuropathyTRPA1 variantsNew risk genesPain genesNav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation
Wimalasena N, Taub D, Shim J, Hakim S, Kawaguchi R, Chen L, El-Rifai M, Geschwind D, Dib-Hajj S, Waxman S, Woolf C. Nav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation. Experimental Neurology 2023, 364: 114393. PMID: 37003485, PMCID: PMC10171359, DOI: 10.1016/j.expneurol.2023.114393.Peer-Reviewed Original ResearchConceptsParoxysmal extreme pain disorderSmall fiber neuropathyFunction mutationsDRG neuron hyperexcitabilityYoung adult miceVoltage-gated sodium channel NaSodium conductanceAge-related changesNeuron hyperexcitabilityPain disordersCongenital insensitivitySodium channel NaExcitability changesFemale miceMouse DRGYoung miceNeuronal excitabilityNoxious heatSkin lesionsVoltage-gated channelsAdult miceNeuron subtypesNervous systemProfound insensitivityMice
2020
Two independent mouse lines carrying the Nav1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype
Chen L, Wimalasena NK, Shim J, Han C, Lee SI, Gonzalez-Cano R, Estacion M, Faber CG, Lauria G, Dib-Hajj S, Woolf CJ, Waxman SG. Two independent mouse lines carrying the Nav1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype. Pain 2020, 162: 1758-1770. PMID: 33323889, PMCID: PMC8119301, DOI: 10.1097/j.pain.0000000000002171.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathyDorsal root ganglion neuron hyperexcitabilityNeuron hyperexcitabilityMouse linesIdiopathic small fiber neuropathyIntraepidermal nerve fiber lossPainful small fiber neuropathyFunction variantsDRG neuron hyperexcitabilityNerve fiber lossSodium channel Nav1.7Multielectrode array recordingsNeuropathic painThermal hyperalgesiaDRG neuronsFiber lossPain disordersSensory dysfunctionNeuropathy phenotypePain phenotypesM miceSensory neuronsHyperexcitabilityChannel Nav1.7Independent mouse lines
2018
Nav1.7 is phosphorylated by Fyn tyrosine kinase which modulates channel expression and gating in a cell type-dependent manner
Li Y, Zhu T, Yang H, Dib-Hajj S, Waxman S, Yu Y, Xu TL, Cheng X. Nav1.7 is phosphorylated by Fyn tyrosine kinase which modulates channel expression and gating in a cell type-dependent manner. Molecular Pain 2018, 14: 1744806918782229. PMID: 29790812, PMCID: PMC6024516, DOI: 10.1177/1744806918782229.Peer-Reviewed Original ResearchConceptsND7/23 cellsDRG neuron excitabilityModulation of Nav1.7New pain therapeuticsVoltage-gated sodium channel Nav1.7Fyn kinaseWhole-cell recordingsSodium channel Nav1.7Elevated protein expressionCell type-specific modulationHuman embryonic kidney 293 cellsTyrosine kinasePain disordersEmbryonic kidney 293 cellsPain therapeuticsNeuron excitabilityPain perceptionMutant channelsChannel Nav1.7Kidney 293 cellsNav1.7HEK-293 cellsNav1.7 channelsCell type-dependent mannerType-dependent mannerA novel gain-of-function Nav1.7 mutation in a carbamazepine-responsive patient with adult-onset painful peripheral neuropathy
Adi T, Estacion M, Schulman BR, Vernino S, Dib-Hajj S, Waxman S. A novel gain-of-function Nav1.7 mutation in a carbamazepine-responsive patient with adult-onset painful peripheral neuropathy. Molecular Pain 2018, 14: 1744806918815007. PMID: 30392441, PMCID: PMC6856981, DOI: 10.1177/1744806918815007.Peer-Reviewed Original ResearchConceptsPainful peripheral neuropathyDorsal root gangliaPeripheral neuropathyUse-dependent inhibitionDRG neuronsPain disordersM variantFunction Nav1.7 mutationsMulti-electrode array recordingsSympathetic ganglion neuronsCommon pain disordersVoltage-clamp recordingsVoltage-gated sodium channel NaRare MendelianNav1.7 mutationGanglion neuronsSodium channel NaTrigeminal ganglionRoot gangliaNeonatal ratsPatientsNeuropathyMutant channelsFunction variantsNeurons
2016
Familial gain-of-function Nav1.9 mutation in a painful channelopathy
Han C, Yang Y, Morsche R, Drenth JP, Politei JM, Waxman SG, Dib-Hajj SD. Familial gain-of-function Nav1.9 mutation in a painful channelopathy. Journal Of Neurology Neurosurgery & Psychiatry 2016, 88: 233. PMID: 27503742, DOI: 10.1136/jnnp-2016-313804.Peer-Reviewed Original ResearchConceptsPain disordersPainful small fiber neuropathyDorsal root ganglion neuronsSmall fiber neuropathyPotential therapeutic targetVoltage-clamp recordingsFunction mutationsPain symptomsGastrointestinal disturbancesGanglion neuronsClinical examinationHyperpolarising shiftFunctional assessmentTherapeutic targetDistal extremitiesPhenotypic spectrumElectrophysiological recordingsPatientsBlood relativesFirst arginine residuePainAcceleration of activationSegment 4ChannelopathiesDisorders
2009
Voltage-Gated Sodium Channels: Therapeutic Targets for Pain
Dib-Hajj S, Black JA, Waxman SG. Voltage-Gated Sodium Channels: Therapeutic Targets for Pain. Pain Medicine 2009, 10: 1260-1269. PMID: 19818036, DOI: 10.1111/j.1526-4637.2009.00719.x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsDifferent pain statesPain statesVoltage-gated sodium channelsPain syndromeTherapeutic targetParoxysmal extreme pain disorderFunction mutationsIsoform-specific blockersSodium channelsInflammatory pain conditionsDifferent pain syndromesTreatment of painDorsal root gangliaSodium channel expressionMajor medical needsSodium channel blockersSodium channel isoformsAmeliorate painPain conditionsPain disordersChronic painTreatment optionsRoot gangliaNociceptor neuronsChannel blockers
2005
Erythromelalgia: A hereditary pain syndrome enters the molecular era
Waxman SG, Dib‐Hajj S. Erythromelalgia: A hereditary pain syndrome enters the molecular era. Annals Of Neurology 2005, 57: 785-788. PMID: 15929046, DOI: 10.1002/ana.20511.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsPain syndromeGanglion neuronsCentral nervous system neuronsDorsal root ganglion neuronsChronic neuropathic painSodium channelsSympathetic ganglion neuronsIon channel mutationsChannel functionSodium channel functionAutosomal dominant disorderNeuropathic painPain disordersChronic painAltered excitabilityModerate exerciseSystem neuronsPrimary erythermalgiaRational therapyErythromelalgiaPainFirst human disorderModel diseaseWarm stimuliSyndrome