ArticleNeurobiology of disease2014
A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy.
Article in Neurobiology of disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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62 citing papers in PubMed, 102 citations in OpenAlex.
- Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions.Neural regeneration research · 2026Article
- Distinct neuronal mechanisms for motor impairment and seizures in a novel mouse model of SCN8A epileptic encephalopathy.Neurobiology of disease · 2026Article
- Parvalbumin interneuron impairment causes synaptic transmission deficits and seizures in SCN8A developmental and epileptic encephalopathy.JCI insight · 2024Article
- The Node of Ranvier as an Interface for Axo-Glial Interactions: Perturbation of Axo-Glial Interactions in Various Neurological Disorders.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2023Review
- SCN8A epileptic encephalopathy mutations display a gain-of-function phenotype and divergent sensitivity to antiepileptic drugs.Acta pharmacologica Sinica · 2022Article
- Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.Brain : a journal of neurology · 2022Article
- A nutraceutical product, extracted from Cannabis sativa, modulates voltage-gated sodium channel function.Journal of cannabis research · 2022Article
- Genotype-phenotype correlations in SCN8A-related epilepsy: a cohort study of Chinese children in southern China.Brain : a journal of neurology · 2022Article
- Somatostatin-Positive Interneurons Contribute to Seizures inThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia.Cell death & disease · 2021Article
- Rational Small Molecule Treatment for Genetic Epilepsies.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- Article
- Review
- SCN8A Encephalopathy: Case Report and Literature Review.Neurology international · 2021Article
- Persistent sodium currents inBrain communications · 2021Article
- Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions.Frontiers in neurology · 2021Review
- Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model ofFrontiers in neuroscience · 2021Article
- Pathogenic in-Frame Variants inFrontiers in pharmacology · 2021Article
- Maturation and phenotype of pathophysiological neuronal excitability of human cells in tau-related dementia.Journal of cell science · 2020Article
- Alternative splicing potentiates dysfunction of early-onset epileptic encephalopathy SCN2A variants.The Journal of general physiology · 2020Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 4 institutions in 1 country.
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Abstract
Rare de novo mutations of sodium channels are thought to be an important cause of sporadic epilepsy. The well established role of de novo mutations of sodium channel SCN1A in Dravet Syndrome supports this view, but the etiology of many cases of epileptic encephalopathy remains unknown. We sought to identify the genetic cause in a patient with early onset epileptic encephalopathy by whole exome sequencing of genomic DNA. The heterozygous mutation c. 2003C>T in SCN8A, the gene encoding sodium channel Nav1.6, was detected in the patient but was not present in either parent. The resulting missense substitution, p.Thr767Ile, alters an evolutionarily conserved residue in the first transmembrane segment of channel domain II. The electrophysiological effects of this mutation were assessed in neuronal cells transfected with mutant or wildtype cDNA. The mutation causes enhanced channel activation, with a 10mV depolarizing shift in voltage dependence of activation as well as increased ramp current. In addition, pyramidal hippocampal neurons expressing the mutant channel exhibit increased spontaneous firing with PDS-like complexes as well as increased frequency of evoked action potentials. The identification of this new gain-of-function mutation of Nav1.6 supports the inclusion of SCN8A as a causative gene in infantile epilepsy, demonstrates a novel mechanism for hyperactivity of Nav1.6, and further expands the role of de novo mutations in severe epilepsy.
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