ArticleJCI insight2024
Molecular and cellular context influences SCN8A variant function.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Epilepsy-Associated Variants of a Single SCN1A Codon Exhibit Divergent Functional Properties.Annals of clinical and translational neurology · 2026Article
- Distinct neuronal mechanisms for motor impairment and seizures in a novel mouse model of SCN8A epileptic encephalopathy.Neurobiology of disease · 2026Article
- Neurologist's Black Swan: Molecular Basis of Prenatal Seizures.International journal of molecular sciences · 2025Review
- A splice-switching antisense oligonucleotide approach for pediatric genetic epilepsies.bioRxiv : the preprint server for biology · 2025Article
- FGF14 Peptide Derivative Differentially Regulates Nav1.2 and NaLife (Basel, Switzerland) · 2025Article
- A research roadmap for SCN8A-related disorders: addressing knowledge gaps and aligning research priorities across stakeholders.Orphanet journal of rare diseases · 2025Article
- Differential roles of NaeLife · 2025Article
- Automated patch clamp analysis of heterologously expressed Kir6.2/SUR1 and Kir6.1/SUR2B KAmerican journal of physiology. Cell physiology · 2025Article
- Deciphering the Natural History ofNeurology · 2025Article
- Nociceptor sodium channels shape subthreshold phase, upstroke, and shoulder of action potentials.The Journal of general physiology · 2025Article
- Allele-Specific Editing of a Dominant SCN8A Epilepsy Variant Protects against Seizures and Lethality in a Murine Model.Annals of neurology · 2024Article
- Protein isoform-centric therapeutics: expanding targets and increasing specificity.Nature reviews. Drug discovery · 2024Review
- Dentate gyrus granule cells are a locus of pathology in Scn8a developmental encephalopathy.Neurobiology of disease · 2024Article
- The Need for Speed; Investigating Channelopathy-Associated Epilepsy Using High Throughput Electrophysiological Approaches.Epilepsy currentsArticle
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Authors and funding
9 authors.
Funding
Abstract
Pathogenic variants in SCN8A, which encodes the voltage-gated sodium (NaV) channel NaV1.6, associate with neurodevelopmental disorders, including developmental and epileptic encephalopathy. Previous approaches to determine SCN8A variant function may be confounded by use of a neonatally expressed, alternatively spliced isoform of NaV1.6 (NaV1.6N) and engineered mutations rendering the channel tetrodotoxin (TTX) resistant. We investigated the impact of SCN8A alternative splicing on variant function by comparing the functional attributes of 15 variants expressed in 2 developmentally regulated splice isoforms (NaV1.6N, NaV1.6A). We employed automated patch clamp recording to enhance throughput, and developed a neuronal cell line (ND7/LoNav) with low levels of endogenous NaV current to obviate the need for TTX-resistance mutations. Expression of NaV1.6N or NaV1.6A in ND7/LoNav cells generated NaV currents with small, but significant, differences in voltage dependence of activation and inactivation. TTX-resistant versions of both isoforms exhibited significant functional differences compared with the corresponding WT channels. We demonstrated that many of the 15 disease-associated variants studied exhibited isoform-dependent functional effects, and that many of the studied SCN8A variants exhibited functional properties that were not easily classified as either gain- or loss-of-function. Our work illustrates the value of considering molecular and cellular context when investigating SCN8A variants.
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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.