ArticleThe Journal of general physiology2020
Alternative splicing potentiates dysfunction of early-onset epileptic encephalopathy SCN2A variants.
Article in The Journal of general physiology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 54 citations in OpenAlex.
- Functional and pharmacological characterization of theEpilepsy & behavior reports · 2026Article
- Epilepsy-Associated Variants of a Single SCN1A Codon Exhibit Divergent Functional Properties.Annals of clinical and translational neurology · 2026Article
- Excitatory Dysfunction and Phenotypic Rescue in a Human Neuronal Model ofbioRxiv : the preprint server for biology · 2026Article
- Neurologist's Black Swan: Molecular Basis of Prenatal Seizures.International journal of molecular sciences · 2025Review
- Review
- Human Cortical Organoids with a Novel SCN2A Variant Exhibit Hyperexcitability and Differential Responses to Anti-Seizure Compounds.Neuroscience bulletin · 2025Article
- A splice-switching antisense oligonucleotide approach for pediatric genetic epilepsies.bioRxiv : the preprint server for biology · 2025Article
- Voltage-Gated Sodium Channel Dysfunction in Epilepsy: Zebrafish Models for Therapeutics.Biomedicines · 2025Review
- Development and Adaptive Function in Individuals WithNeurology · 2025Article
- Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes.Nature neuroscience · 2025Article
- Axon initial segment structure and function in health and disease.Physiological reviews · 2025Review
- Nociceptor sodium channels shape subthreshold phase, upstroke, and shoulder of action potentials.The Journal of general physiology · 2025Article
- Rare dysfunctional SCN2A variants are associated with malformation of cortical development.Epilepsia · 2025Article
- DecipheringArXiv · 2024Article
- Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.Brain : a journal of neurology · 2024Article
- Crosstalk among WEE1 Kinase, AKT, and GSK3 in Nav1.2 Channelosome Regulation.International journal of molecular sciences · 2024Article
- Molecular and cellular context influences SCN8A variant function.JCI insight · 2024Article
- Distinctive In Vitro Phenotypes in iPSC-Derived Neurons From Patients With Gain- and Loss-of-FunctionThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Integrative analysis of epilepsy-associated genes reveals expression-phenotype correlations.Scientific reports · 2024Article
- Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties.The Journal of general physiology · 2023Article
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4 authors at 2 institutions in 1 country.
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Abstract
Epileptic encephalopathies are severe forms of infantile-onset epilepsy often complicated by severe neurodevelopmental impairments. Some forms of early-onset epileptic encephalopathy (EOEE) have been associated with variants in SCN2A, which encodes the brain voltage-gated sodium channel NaV1.2. Many voltage-gated sodium channel genes, including SCN2A, undergo developmentally regulated mRNA splicing. The early onset of these disorders suggests that developmentally regulated alternative splicing of NaV1.2 may be an important consideration when elucidating the pathophysiological consequences of epilepsy-associated variants. We hypothesized that EOEE-associated NaV1.2 variants would exhibit greater dysfunction in a splice isoform that is prominently expressed during early development. We engineered five EOEE-associated NaV1.2 variants (T236S, E999K, S1336Y, T1623N, and R1882Q) into the adult and neonatal splice isoforms of NaV1.2 and performed whole-cell voltage clamp to elucidate their functional properties. All variants exhibited functional defects that could enhance neuronal excitability. Three of the five variants (T236S, E999K, and S1336Y) exhibited greater dysfunction in the neonatal isoform compared with those observed in the adult isoform. Computational modeling of a developing cortical pyramidal neuron indicated that T236S, E999K, S1336Y, and R1882Q showed hyperexcitability preferentially in immature neurons. These results suggest that both splice isoform and neuronal developmental stage influence how EOEE-associated NaV1.2 variants affect neuronal excitability.
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