ArticleAnnals of clinical and translational neurology2016
Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy.
Article in Annals of clinical and translational neurology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 110 citations in OpenAlex.
- Editing Out Seizures? Base Editing Shows Promise for SCN8A DEE.Epilepsy currents · 2026Article
- Distinct neuronal mechanisms for motor impairment and seizures in a novel mouse model of SCN8A epileptic encephalopathy.Neurobiology of disease · 2026Article
- Base editing rescues seizures and sudden death in a SCN8A mutation-associated developmental epileptic encephalopathy model.The Journal of clinical investigation · 2026Article
- Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability.Cell reports · 2025Article
- Transcriptomic Profiling of Zebrafish Mutant forInternational journal of molecular sciences · 2025Article
- Early mortality in STXBP1-related disorders.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- 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
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- Experimental and computational evidence that Calpain-10 binds to the carboxy terminus of NaScientific reports · 2024Article
- A novelThe Journal of international medical research · 2023Article
- Cryo-EM structure of human voltage-gated sodium channel NaProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Phenotypic expansion of KCNH1-associated disorders to include isolated epilepsy and its associations with genotypes and molecular sub-regional locations.CNS neuroscience & therapeutics · 2023Article
- SCN8A epileptic encephalopathy mutations display a gain-of-function phenotype and divergent sensitivity to antiepileptic drugs.Acta pharmacologica Sinica · 2022Article
- The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.Brain : a journal of neurology · 2022Article
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- Correction of the hypomorphicHGG advances · 2022Article
- Sudden unexpected death in epilepsy: Respiratory mechanisms.Handbook of clinical neurology · 2022Review
- 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
7 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
objectiveThe early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage-gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872. Our goal was to determine the functional effects of these mutations on channel properties.
methodsClinical exome sequencing was carried out on patients with early-onset seizures, developmental delay, and cognitive impairment. Two mutations identified here, p.Arg1872Leu and p.Arg1872Gln, and two previously identified mutations, p.Arg1872Trp and p.Arg1617Gln, were introduced into Nav1.6 cDNA, and effects on electrophysiological properties were characterized in transfected ND7/23 cells. Interactions with FGF14, G-protein subunit Gβγ, and sodium channel subunit β1 were assessed by coimmunoprecipitation.
resultsWe identified two patients with the novel mutation p.Arg1872Leu and one patient with the recurrent mutation p.Arg1872Gln. The three mutations of Arg1872 and the mutation of Arg1617 all impaired the sodium channel transition from open state to inactivated state, resulting in channel hyperactivity. Other observed abnormalities contributing to elevated channel activity were increased persistent current, increased peak current density, hyperpolarizing shift in voltage dependence of activation, and depolarizing shift in steady-state inactivation. Protein interactions were not affected.
interpretationRecurrent mutations at Arg1617 and Arg1872 lead to elevated Nav1.6 channel activity by impairing channel inactivation. Channel hyperactivity is the major pathogenic mechanism for gain-of-function mutations of SCN8A. EIEE13 differs mechanistically from Dravet syndrome, which is caused by loss-of-function mutations of SCN1A. This distinction has important consequences for selection of antiepileptic drugs and the development of gene- and mutation-specific treatments.
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