ArticleProceedings of the National Academy of Sciences of the United States of America2022
Gain of function due to increased opening probability by two
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- Bibliometric and visualized analysis of current advances and future directions in epilepsy: from molecular basis to therapy.Frontiers in neurology · 2025Pooled it
- Pharmacological Actions of Potassium Channel Openers on Voltage-Gated Potassium Channels.Pharmaceuticals (Basel, Switzerland) · 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
- KCNQ4 c.546C>G variant is associated with early-onset high-frequency hearing loss, tinnitus, and cardiovascular comorbidities in Taiwanese adults.Scientific reports · 2025Article
- Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Prenatal Diagnosis of Okur-Chung Syndrome: Ultrasound Findings and Implications of CSNK2A1 and KCNQ5 Variants.Maternal-fetal medicine (Wolters Kluwer Health, Inc.) · 2025Article
- Targeting Kv7 Potassium Channels for Epilepsy.CNS drugs · 2025Review
- Navigating Uncertainty: Assessing Variants of Uncertain Significance in the CDKL5 Gene for Developmental and Epileptic Encephalopathy Using In Silico Prediction Tools and Computational Analysis.Journal of molecular neuroscience : MN · 2025Article
- Constitutive opening of the Kv7.2 pore activation gate causesProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Novel KCNQ2 missense variant expands the genotype spectrum of DEE7.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- Discovery of a potent, Kv7.3-selective potassium channel opener from a Polynesian traditional botanical anticonvulsant.Communications chemistry · 2024Article
- Review
- In vitro human cell culture models in a bench-to-bedside approach to epilepsy.Epilepsia open · 2024Review
- Kv7 channel activation reduces brain endothelial cell permeability and prevents kainic acid-induced blood-brain barrier damage.American journal of physiology. Cell physiology · 2024Article
- Voltage-gated potassium channels and genetic epilepsy.Frontiers in neurology · 2024Review
- Phox2b-expressing neurons contribute to breathing problems in Kcnq2 loss- and gain-of-function encephalopathy models.Nature communications · 2023Article
- Ion channels in neurodevelopment: lessons from the Integrin-KCNB1 channel complex.Neural regeneration research · 2023Article
- Clinically RelevantInternational journal of molecular sciences · 2022Article
Corrections and comments
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Authors and funding
16 authors at 10 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Developmental and epileptic encephalopathies (DEEs) are neurodevelopmental diseases characterized by refractory epilepsy, distinct electroencephalographic and neuroradiological features, and various degrees of developmental delay. Mutations in KCNQ2, KCNQ3, and, more rarely, KCNQ5 genes encoding voltage-gated potassium channel subunits variably contributing to excitability control of specific neuronal populations at distinct developmental stages have been associated to DEEs. In the present work, the clinical features of two DEE patients carrying de novo KCNQ5 variants affecting the same residue in the pore region of the Kv7.5 subunit (G347S/A) are described. The in vitro functional properties of channels incorporating these variants were investigated with electrophysiological and biochemical techniques to highlight pathophysiological disease mechanisms. Currents carried by Kv7.5 G347 S/A channels displayed: 1) large (>10 times) increases in maximal current density, 2) the occurrence of a voltage-independent component, 3) slower deactivation kinetics, and 4) hyperpolarization shift in activation. All these functional features are consistent with a gain-of-function (GoF) pathogenetic mechanism. Similar functional changes were also observed when the same variants were introduced at the corresponding position in Kv7.2 subunits. Nonstationary noise analysis revealed that GoF effects observed for both Kv7.2 and Kv7.5 variants were mainly attributable to an increase in single-channel open probability, without changes in membrane abundance or single-channel conductance. The mutation-induced increase in channel opening probability was insensitive to manipulation of membrane levels of the critical Kv7 channel regulator PIP2. These results reveal a pathophysiological mechanism for KCNQ5-related DEEs, which might be exploited to implement personalized treatments.
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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.