ArticleNeurobiology of disease2011
Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus.
Article in Neurobiology of disease, 2011. 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, 89 citations in OpenAlex.
- Integrative Drug-Target Causal Analysis, Single-Cell Sequencing and In-Vivo Validation for Dissecting Molecular Mechanisms Underlying Focal Epilepsy.CNS neuroscience & therapeutics · 2026Article
- Voltage-gated sodium channels in excitable cells as drug targets.Nature reviews. Drug discovery · 2025Review
- Spotlight on mechanism of sudden unexpected death in epilepsy in Dravet syndrome.Translational psychiatry · 2025Review
- Association between maternal usage of volatile organic compounds and West syndrome, the Japan Environment and Children's study.Scientific reports · 2024Article
- Investigating the effect of polygenic background on epilepsy phenotype in 'monogenic' families.EBioMedicine · 2024Article
- Voltage-Gated Ion Channel Compensatory Effect in DEE: Implications for Future Therapies.Cells · 2024Review
- Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults.JACC. Clinical electrophysiology · 2024Article
- Viral vector-mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome.The Journal of clinical investigation · 2023Article
- Strain-dependent effects on neurobehavioral and seizure phenotypes inbioRxiv : the preprint server for biology · 2023Article
- Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.Physiological reviews · 2023Review
- Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice.Human molecular genetics · 2022Article
- NBI-921352, a first-in-class, NaeLife · 2022Article
- Phenotypic and Genotypic Characteristics ofFrontiers in molecular neuroscience · 2022Article
- Autistic-like behavior, spontaneous seizures, and increased neuronal excitability in a Scn8a mouse model.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2021Article
- Gabra2 is a genetic modifier of Dravet syndrome in mice.Mammalian genome : official journal of the International Mammalian Genome Society · 2021Article
- The K328M substitution in the human GABANeurobiology of disease · 2021Article
- Sodium channelopathies in neurodevelopmental disorders.Nature reviews. Neuroscience · 2021Review
- Channelopathy of Dravet Syndrome and Potential Neuroprotective Effects of Cannabidiol.Journal of central nervous system disease · 2021Review
- Pathogenic in-Frame Variants inFrontiers in pharmacology · 2021Article
- Overlaps, gaps, and complexities of mouse models of Developmental and Epileptic Encephalopathy.Neurobiology of disease · 2021Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Mutations in the neuronal voltage-gated sodium channel genes SCN1A and SCN2A are associated with inherited epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (severe myoclonic epilepsy of infancy). The clinical presentation and severity of these epilepsies vary widely, even in people with the same mutation, suggesting the action of environmental or genetic modifiers. To gain support for the hypothesis that genetic modifiers can influence clinical presentation in patients with SCN1A-derived GEFS+, we used mouse models to study the effect of combining the human GEFS+ mutation SCN1A-R1648H with SCN2A, KCNQ2, and SCN8A mutations. Knock-in mice heterozygous for the R1648H mutation (Scn1a(RH/+)) have decreased thresholds to induced seizures and infrequent spontaneous seizures, whereas homozygotes display spontaneous seizures and premature lethality. Scn2a(Q54) transgenic mice have a mutation in Scn2a that results in spontaneous, adult-onset partial motor seizures, and mice carrying the Kcnq2-V182M mutation exhibit increased susceptibility to induced seizures, and rare spontaneous seizures as adults. Combining the Scn1a-R1648H allele with either Scn2a(Q54) or Kcnq2(V182M/+) results in early-onset, generalized tonic-clonic seizures and juvenile lethality in double heterozygous mice. In contrast, Scn8a mutants exhibit increased resistance to induced seizures. Combining the Scn1a-R1648H and Scn8a-med-jo alleles restores normal thresholds to flurothyl-induced seizures in Scn1a(RH/+) heterozygotes and improved survival of Scn1a(RH/RH) homozygotes. Our results demonstrate that variants in Scn2a, Kcnq2, and Scn8a can dramatically influence the phenotype of mice carrying the Scn1a-R1648H mutation and suggest that ion channel variants may contribute to the clinical variation seen in patients with monogenic epilepsy.
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