ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers, 2 of them syntheses that pooled it.
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Who cites it
111 citing papers in PubMed, 2 syntheses or guidelines pooled it, 190 citations in OpenAlex.
- Intellectual Disability and Potassium Channelopathies: A Systematic Review.Frontiers in genetics · 2020Pooled it
- Genetic etiologies of the electrical status epilepticus during slow wave sleep: systematic review.BMC genetics · 2018Pooled it
- Molecular Basis for Activation to Inhibition Switching in Kv7.2 Channel Modulators.Angewandte Chemie (International ed. in English) · 2026Article
- Inward rectifier potassium channels interact with calcium channels to promote robust and physiological bistability.PLoS computational biology · 2026Article
- Assessment of gabapentin efficacy in patients with KCNQ2-developmental epileptic encephalopathy.Scientific reports · 2026Article
- Article
- Novel proteolytic post-translational modification in voltage-gated potassium channel KCNQ2.Scientific reports · 2026Article
- Neurodevelopmental features in KCNQ2 developmental and epileptic encephalopathy may have limited associations with KEpilepsia open · 2026Article
- Quantum Mechanical Mechanisms in the Therapeutic Effects of Spinal Cord Stimulation to Treat Chronic Neuropathic Pain: A Quantum Computational Model.Journal of pain research · 2026Article
- Endosomal 2Cl-/H+ exchangers regulate neuronal excitability by tuning Kv7/KCNQ channel density.Brain : a journal of neurology · 2025Article
- Mapping the knowledge of epilepsy and Potassium Channels: A scientometric analysis in CiteSpace and VOSviewer.IBRO neuroscience reports · 2025Article
- Human iPSC-derived glutamatergic neurons with pathogenic KCNQ2 variants display hyperactive bursting phenotypes.Neurobiology of disease · 2025Article
- Electrophysiological Abnormalities and Pharmacological Corrections of Pathogenic Missense Variants in KCNQ3.Neuroscience bulletin · 2025Article
- Small molecule inhibits KCNQ channels with a non-blocking mechanism.Nature chemical biology · 2025Article
- Transcriptomic Profiling of Zebrafish Mutant forInternational journal of molecular sciences · 2025Article
- Beyond the hype: a comprehensive exploration of CBD's biological impacts and mechanisms of action.Journal of cannabis research · 2025Review
- The conductance of KCNQ2 and its pathogenic variants is determined by individual subunit gating.Science advances · 2025Article
- Constitutive opening of the Kv7.2 pore activation gate causesProceedings of the National Academy of Sciences of the United States of America · 2024Article
- The Fundamentals of Antiseizure Medications: A Through Z.Epilepsy currents · 2024Article
- Lipophilic compounds restore function to neurodevelopmental-associated KCNQ3 mutations.Communications biology · 2024Article
51 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Mutations in Kv7.2 (KCNQ2) and Kv7.3 (KCNQ3) genes, encoding for voltage-gated K(+) channel subunits underlying the neuronal M-current, have been associated with a wide spectrum of early-onset epileptic disorders ranging from benign familial neonatal seizures to severe epileptic encephalopathies. The aim of the present work has been to investigate the molecular mechanisms of channel dysfunction caused by voltage-sensing domain mutations in Kv7.2 (R144Q, R201C, and R201H) or Kv7.3 (R230C) recently found in patients with epileptic encephalopathies and/or intellectual disability. Electrophysiological studies in mammalian cells transfected with human Kv7.2 and/or Kv7.3 cDNAs revealed that each of these four mutations stabilized the activated state of the channel, thereby producing gain-of-function effects, which are opposite to the loss-of-function effects produced by previously found mutations. Multistate structural modeling revealed that the R201 residue in Kv7.2, corresponding to R230 in Kv7.3, stabilized the resting and nearby voltage-sensing domain states by forming an intricate network of electrostatic interactions with neighboring negatively charged residues, a result also confirmed by disulfide trapping experiments. Using a realistic model of a feedforward inhibitory microcircuit in the hippocampal CA1 region, an increased excitability of pyramidal neurons was found upon incorporation of the experimentally defined parameters for mutant M-current, suggesting that changes in network interactions rather than in intrinsic cell properties may be responsible for the neuronal hyperexcitability by these gain-of-function mutations. Together, the present results suggest that gain-of-function mutations in Kv7.2/3 currents may cause human epilepsy with a severe clinical course, thus revealing a previously unexplored level of complexity in disease pathogenetic mechanisms.
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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.