ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2008
NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 161 citations in OpenAlex.
- Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation.The Journal of biological chemistry · 2014Trial
- Peripheral NabioRxiv : the preprint server for biology · 2026Article
- Article
- Shaping the Action Potential in Dorsal Root and Trigeminal Ganglia Neurons: Relevance to Pain Mechanisms.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Review
- Correction of sodium channel mutations in sensory neurons reverses aberrant properties.Brain : a journal of neurology · 2025Article
- Voltage-Gated Ion Channels in Neuropathic Pain Signaling.Life (Basel, Switzerland) · 2025Review
- A Novel Antigen Design Strategy to Isolate Single-Domain Antibodies that Target Human Nav1.7 and Reduce Pain in Animal Models.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- A Reinterpretation of the Relationship between Persistent and Resurgent Sodium Currents.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- A Narrative Review of the Dorsal Root Ganglia and Spinal Cord Mechanisms of Action of Neuromodulation Therapies in Neuropathic Pain.Brain sciences · 2024Review
- A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents.bioRxiv : the preprint server for biology · 2024Article
- Anxiety and dysautonomia symptoms in patients with a NaClinical autonomic research : official journal of the Clinical Autonomic Research Society · 2024Article
- Identification and In-Silico study of non-synonymous functional SNPs in the human SCN9A gene.PloS one · 2024Article
- A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for Pain Relief in Current Human Clinical Trials.Journal of pain research · 2023Review
- Electrophysiological Alterations Driving Pain-Associated Spontaneous Activity in Human Sensory Neuron Somata Parallel Alterations Described in Spontaneously Active Rodent Nociceptors.The journal of pain · 2022Article
- Hydropathicity-based prediction of pain-causing NaV1.7 variants.BMC bioinformatics · 2021Article
- Synthetic Analogues of Huwentoxin-IV Spider Peptide With Altered Human NaFrontiers in cell and developmental biology · 2021Article
- A mini-review: Bridging the gap between autism spectrum disorder and pain comorbidities.Canadian journal of pain = Revue canadienne de la douleur · 2020Review
- Computational pipeline to probe NaV1.7 gain-of-function variants in neuropathic painful syndromes.Scientific reports · 2020Article
- Uncoupling sodium channel dimers restores the phenotype of a pain-linked NaBritish journal of pharmacology · 2020Article
- Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels.Pflugers Archiv : European journal of physiology · 2020Review
16 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gain-of-function mutations of Na(V)1.7 have been shown to produce two distinct disorders: Na(V)1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities; Na(V)1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain. Here we report a novel Na(V)1.7 mutation associated with a mixed clinical phenotype with characteristics of IEM and PEPD, with an alanine 1632 substitution by glutamate (A1632E) in domain IV S4-S5 linker. Patch-clamp analysis shows that A1632E produces changes in channel function seen in both IEM and PEPD mutations: A1632E hyperpolarizes (-7 mV) the voltage dependence of activation, slows deactivation, and enhances ramp responses, as observed in Na(V)1.7 mutations that produce IEM. A1632E depolarizes (+17mV) the voltage dependence of fast inactivation, slows fast inactivation, and prevents full inactivation, resulting in persistent inward currents similar to PEPD mutations. Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable. These results demonstrate a Na(V)1.7 mutant with biophysical characteristics common to PEPD (impaired fast inactivation) and IEM (hyperpolarized activation, slow deactivation, and enhanced ramp currents) associated with a clinical phenotype with characteristics of both IEM and PEPD and show that this mutation renders DRG and trigeminal ganglion neurons hyperexcitable. These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.