ArticleEpilepsy research2014
Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy.
Article in Epilepsy research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 100 citations in OpenAlex.
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- Molecular mechanisms of sudden unexplained death and recent updates on molecular autopsy strategies for forensic investigation.International journal of legal medicine · 2026Review
- Parvalbumin interneuron impairment causes synaptic transmission deficits and seizures in SCN8A developmental and epileptic encephalopathy.JCI insight · 2024Article
- Molecular and cellular context influences SCN8A variant function.JCI insight · 2024Article
- Predicting functional effects of ion channel variants using new phenotypic machine learning methods.PLoS computational biology · 2023Article
- Structure of human NaNature communications · 2023Article
- Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.Brain : a journal of neurology · 2022Article
- Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning.EBioMedicine · 2022Article
- A nutraceutical product, extracted from Cannabis sativa, modulates voltage-gated sodium channel function.Journal of cannabis research · 2022Article
- Somatostatin-Positive Interneurons Contribute to Seizures inThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Sodium channelopathies of skeletal muscle and brain.Physiological reviews · 2021Review
- SCN8A Encephalopathy: Case Report and Literature Review.Neurology international · 2021Article
- Sodium channelopathies in neurodevelopmental disorders.Nature reviews. Neuroscience · 2021Review
- Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions.Frontiers in neurology · 2021Review
- Voltage-Gated Sodium Channel Modulation by a New Spider Toxin Ssp1a Isolated From an Australian Theraphosid.Frontiers in pharmacology · 2021Article
- Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model ofFrontiers in neuroscience · 2021Article
- Trafficking mechanisms underlying NaChannels (Austin, Tex.) · 2020Review
- Design, Synthesis, and Pharmacological Evaluation of Analogues Derived from the PLEV Tetrapeptide as Protein-Protein Interaction Modulators of Voltage-Gated Sodium Channel 1.6.Journal of medicinal chemistry · 2020Article
- Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review.Frontiers in pharmacology · 2020Review
- Immortalized Dorsal Root Ganglion Neuron Cell Lines.Frontiers in cellular neuroscience · 2020Review
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Authors and funding
13 authors at 5 institutions in 2 countries.
Funding
Abstract
objectiveRecently, de novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathies (EIEE13). Functional studies on the first described case demonstrated gain-of-function effects of the mutation. We describe a novel de novo mutation of SCN8A in a patient with epileptic encephalopathy, and functional characterization of the mutant protein.
designWhole exome sequencing was used to discover the variant. We generated a mutant cDNA, transfected HEK293 cells, and performed Western blotting to assess protein stability. To study channel functional properties, patch-clamp experiments were carried out in transfected neuronal ND7/23 cells.
resultsThe proband exhibited seizure onset at 6 months of age, diffuse brain atrophy, and more profound developmental impairment than the original case. The mutation p.Arg233Gly in the voltage sensing transmembrane segment D1S4 was present in the proband and absent in both parents. This mutation results in a temperature-sensitive reduction in protein expression as well as reduced sodium current amplitude and density and a relative increased response to a slow ramp stimulus, though this did not result in an absolute increased current at physiological temperatures.
conclusionThe new de novo SCN8A mutation is clearly deleterious, resulting in an unstable protein with reduced channel activity. This differs from the gain-of-function attributes of the first SCN8A mutation in epileptic encephalopathy, pointing to heterogeneity of mechanisms. Since Nav1.6 is expressed in both excitatory and inhibitory neurons, a differential effect of a loss-of-function of Nav1.6 Arg223Gly on inhibitory interneurons may underlie the epilepsy phenotype in this patient.
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