Chongyang Han1,2,3, Yang Yang1,2,3, Rene H Te Morsche4, Joost P H Drenth4, Juan M Politei5, Stephen G Waxman1,2,3, Sulayman D Dib-Hajj1,2,3. 1. Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA. 2. Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA. 3. Center for Restoration of Nervous System Function, Veterans Affairs Medical Center, West Haven, Connecticut, USA. 4. Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. 5. Department of Neurology, Fundación para el Estudio de las Enfermedades Neurometabólicas, Buenos Aires, Argentina.
Abstract
OBJECTIVE: Gain-of-function mutations in Nav1.9 have been identified in three families with rare heritable pain disorders, and in patients with painful small-fibre neuropathy. Identification and functional assessment of new Nav1.9 mutations will help to elucidate the phenotypic spectrum of Nav1.9 channelopathies. METHODS: Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations in SCN9A and SCN11A. Electrophysiological recordings and multistate modelling analysis were implemented for functional analyses. RESULTS: A novel Nav1.9 mutation, p.Arg222His, was identified in patients with early-onset pain in distal extremities including joints and gastrointestinal disturbances, but was absent from an asymptomatic blood relative. This mutation alters channel structure by substituting the highly conserved first arginine residue in transmembrane segment 4 (domain 1), the voltage sensor, with histidine. Voltage-clamp recordings demonstrate a hyperpolarising shift and acceleration of activation of the p.Arg222His mutant channel, which make it easier to open the channel. When expressed in dorsal root ganglion neurons, mutant p.Arg222His channels increase excitability via a depolarisation of resting potential and increased evoked firing. CONCLUSIONS: This study expands the spectrum of heritable pain disorders linked to gain-of-function mutations in Nav1.9, strengthening human validation of this channel as a potential therapeutic target for pain. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
OBJECTIVE: Gain-of-function mutations in Nav1.9 have been identified in three families with rare heritable pain disorders, and in patients with painful small-fibre neuropathy. Identification and functional assessment of new Nav1.9 mutations will help to elucidate the phenotypic spectrum of Nav1.9channelopathies. METHODS:Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations in SCN9A and SCN11A. Electrophysiological recordings and multistate modelling analysis were implemented for functional analyses. RESULTS: A novel Nav1.9 mutation, p.Arg222His, was identified in patients with early-onset pain in distal extremities including joints and gastrointestinal disturbances, but was absent from an asymptomatic blood relative. This mutation alters channel structure by substituting the highly conserved first arginine residue in transmembrane segment 4 (domain 1), the voltage sensor, with histidine. Voltage-clamp recordings demonstrate a hyperpolarising shift and acceleration of activation of the p.Arg222His mutant channel, which make it easier to open the channel. When expressed in dorsal root ganglion neurons, mutant p.Arg222His channels increase excitability via a depolarisation of resting potential and increased evoked firing. CONCLUSIONS: This study expands the spectrum of heritable pain disorders linked to gain-of-function mutations in Nav1.9, strengthening human validation of this channel as a potential therapeutic target for pain. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Jianying Huang; Carlos G Vanoye; Alison Cutts; Y Paul Goldberg; Sulayman D Dib-Hajj; Charles J Cohen; Stephen G Waxman; Alfred L George Journal: J Clin Invest Date: 2017-05-22 Impact factor: 14.808
Authors: Daria V Sizova; Jianying Huang; Elizabeth J Akin; Mark Estacion; Carolina Gomis-Perez; Stephen G Waxman; Sulayman D Dib-Hajj Journal: J Biol Chem Date: 2019-12-10 Impact factor: 5.157
Authors: Ryan Castoro; Megan Simmons; Vignesh Ravi; Derek Huang; Christopher Lee; John Sergent; Lan Zhou; Jun Li Journal: Neurol Genet Date: 2018-07-20