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A Nonsense Mutation of the Sodium Channel Gene SCN2A in a Patient with Intractable Epilepsy and Mental Decline
Open accessAbstract
Mutations, exclusively missense, of voltage-gated sodium channel α subunit type 1 (SCN1A) and type 2 (SCN2A) genes were reported in patients with idiopathic epilepsy: generalized epilepsy with febrile seizures plus. Nonsense and frameshift mutations of SCN1A, by contrast, were identified in intractable epilepsy: severe myoclonic epilepsy in infancy (SMEI). Here we describe a first nonsense mutation of SCN2A in a patient with intractable epilepsy and severe mental decline. The phenotype is similar to SMEI but distinct because of partial epilepsy, delayed onset (1 year 7 months), and absence of temperature sensitivity. A mutational analysis revealed that the patient had a heterozygous de novo nonsense mutation R102X of SCN2A. Patch-clamp analysis of Na v 1.2 wild-type channels and the R102X mutant protein coexpressed in human embryonic kidney 293 cells showed that the truncated mutant protein shifted the voltage dependence of inactivation of wild-type channels in the hyperpolarizing direction. Analysis of the subcellular localization of R102X truncated protein suggested that its dominant negative effect could arise from direct or indirect cytoskeletal interactions of the mutant protein. Haploinsufficiency of Na v 1.2 protein is one plausible explanation for the pathology of this patient; however, our biophysical findings suggest that the R102X truncated protein exerts a dominant negative effect leading to the patient's intractable epilepsy.
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“The second strongest overall association, with two truncating mutations in ASD cases and three such mutations in ID cases, is SCN2A, a gene previously associated with epilepsy and seizure disorders [52,53].”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [52]
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De novo mutations revealed by whole-exome sequencing are strongly associated with autism
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De novo mutations in epileptic encephalopathies
Epi4K Consortium, & Epilepsy Phenome/Genome Project (2013) · Nature · doi:10.1038/nature12439 · Cited by 1,514
Molecular Physiology of Cardiac Repolarization
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Metadata
- Authors
- Kamiya, K., Kaneda, M., Sugawara, T., Mazaki, E., Okamura, N., Montal, M., Makita, N., Tanaka, M., Fukushima, K., Fujiwara, T., Inoue, Y., & Yamakawa, K.
- Affiliations
- RIKEN (JP)
- Keio University (JP)
- University of California San Diego (US)
- Hokkaido University (JP)
- RIKEN Center for Brain Science (JP)
- National Epilepsy Center (JP)
- Corresponding author
- Yamakawa, Kazuhiro
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-03-17
- Volume
- 24
- Issue
- 11
- Pages
- 2690-2698
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729532
- OpenAlex
- W2096680774
- Cited by
- 199
- References
- 49
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 7 · 2022: 5 · 2021: 10 · 2020: 7 · 2019: 13 · 2018: 10 · 2017: 9 · 2016: 9 · 2015: 11 · 2014: 20 · 2013: 11 · 2012: 10
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Keio University
- National Institutes of Health
- RIKEN
- National Institute of General Medical Sciences (GM-49711, R01GM049711)
- RIKEN Brain Science Institute
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- SCN2A, nonsense mutation, drug-resistant epilepsy, intellectual disability, Dravet syndrome, de novo mutations, dominant negative effect, haploinsufficiency, voltage-gated sodium channels, voltage-dependent inactivation, subcellular localization, cytoskeletal interactions, focal epilepsy
- MeSH terms
- Adult, Autistic Disorder, Cell Line, DNA Mutational Analysis, Electroencephalography, Epilepsy, Female, Genes, Dominant, Humans, Hyperkinesis, Kidney, Intellectual Disability, Nerve Tissue Proteins, Pedigree, Transfection, Sodium Channels, Gene Expression, Codon, Nonsense, Patch-Clamp Techniques, Protein Subunits, NAV1.2 Voltage-Gated Sodium Channel
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