ArticleJCI insight2022
High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity.
Article in JCI insight, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 62 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
- From Pathogenicity to Mechanism: A Variant Interpretation Framework for Monogenic Epilepsy.Clinical genetics · 2026Article
- An upstream open reading frame represses translation of the neuronal potassium channel KCNQ2.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Epilepsy-Associated Variants of a Single SCN1A Codon Exhibit Divergent Functional Properties.Annals of clinical and translational neurology · 2026Article
- Assessment of gabapentin efficacy in patients with KCNQ2-developmental epileptic encephalopathy.Scientific reports · 2026Article
- Discovery of Kv3.1 channel inhibitors reveals VU0521426 as a state-dependent inactivator preferentially active against pathogenic gain-of-function mutants.American journal of physiology. Cell physiology · 2026Article
- 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
- Mislocalization of KCNQ2 Channels as a Pathogenic Mechanism in KCNQ2 Developmental and Epileptic Encephalopathy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.Frontiers in genetics · 2026Review
- Molecular dynamics of the pathogenic KCNQ2 variant G256W reveal mechanisms of channel dysfunction in epileptic encephalopathy.bioRxiv : the preprint server for biology · 2025Article
- TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD.Nature neuroscience · 2025Article
- Variants in BSN, encoding the presynaptic protein Bassoon, result in a distinct neurodevelopmental disorder with a broad phenotypic range.American journal of human genetics · 2025Article
- Article
- The evolution of patch-clamp electrophysiology: Robotic, multiplex, and dynamic.Molecular pharmacology · 2025Review
- Electrophysiological classification ofFrontiers in pharmacology · 2025Article
- A small-molecule activation mechanism that directly opens the KCNQ2 channel.Nature chemical biology · 2024Article
- Plural molecular and cellular mechanisms of pore domainbioRxiv : the preprint server for biology · 2024Article
- Independent compartmentalization of functional, metabolic, and transcriptional maturation of hiPSC-derived cardiomyocytes.Cell reports · 2024Article
- Molecular and cellular context influences SCN8A variant function.JCI insight · 2024Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation for KCNQ2 variants hinders identification of individuals who may benefit from emerging precision therapies. We employed automated patch clamp recordings to assess at, to our knowledge, an unprecedented scale the functional and pharmacological properties of 79 missense and 2 inframe deletion KCNQ2 variants. Among the variants we studied were 18 known pathogenic variants, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. We analyzed electrophysiological data recorded from 9,480 cells. The functional properties of 18 known pathogenic variants largely matched previously published results and validated automated patch clamp for this purpose. Unlike rare population variants, most disease-associated KCNQ2 variants exhibited prominent loss-of-function with dominant-negative effects, providing strong evidence in support of pathogenicity. All variants responded to retigabine, although there were substantial differences in maximal responses. Our study demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine, a proposed precision therapy for KCNQ2 developmental and epileptic encephalopathy.
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Registered trials
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.