ArticleEpilepsia2022
Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants.
Article in Epilepsia, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 33 citations in OpenAlex.
- Targeted Sequencing and Haplotype Analysis of Voltage-Gated Potassium Channel Genes Reveal a Potential Association ofPharmaceuticals (Basel, Switzerland) · 2026Article
- Functional characterization of a human epilepsy-associated gene network reveals metabolic regulation as a critical factor underlying seizure susceptibilities.Disease models & mechanisms · 2026Article
- Transcriptomic Profiling of Zebrafish Mutant forInternational journal of molecular sciences · 2025Article
- Developmental and epileptic encephalopathies.Nature reviews. Disease primers · 2024Review
- Differential potassium channel inhibitory activities of a novel thermostable degradation peptide BmKcug1a-P1 from scorpion medicinal material and its N-terminal truncated/restored peptides.Scientific reports · 2024Article
- Unusual Voltage-Gated Sodium and Potassium Channelopathies Related to Epilepsy.Journal of clinical neurology (Seoul, Korea) · 2024Article
- Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights.Journal of neurology · 2024Review
- Voltage-gated potassium channels and genetic epilepsy.Frontiers in neurology · 2024Review
- Targeted suppression of mTORC2 reduces seizures across models of epilepsy.Nature communications · 2023Article
- Complexity in Genetic Epilepsies: A Comprehensive Review.International journal of molecular sciences · 2023Review
- Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia.Life (Basel, Switzerland) · 2023Review
- Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity ofInternational journal of molecular sciences · 2023Review
- Article
- KCNA1 gain-of-function epileptic encephalopathy treated with 4-aminopyridine.Annals of clinical and translational neurology · 2023Article
- Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia.International journal of molecular sciences · 2022Article
- Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning.EBioMedicine · 2022Article
- Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants.Epilepsia · 2022Article
- Modeling the kinetics of heteromeric potassium channels.Frontiers in cellular neuroscience · 2022Article
- Potassium Channels as a Target for Cancer Therapy: Current Perspectives.OncoTargets and therapy · 2022Review
- Diagnostic approach to episodic ataxia types 1 and 2: a proposed algorithm for limited resource-settings.Frontiers in neurologyArticle
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine-responsive, focal epilepsy. Patch-clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild-type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1-mediated currents, exerting loss-of-function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain-of-function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1-related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored.
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