Opposing Effects on Na V 1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures
Open accessAbstract
Background Variants in the SCN2A gene that disrupt the encoded neuronal sodium channel Na V 1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect Na V 1.2 function and neuronal excitability are unclear. Methods We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry. Resultant data were incorporated into computational models of developing and mature cortical pyramidal cells that express Na V 1.2. Results In contrast to gain of function variants that contribute to seizure, we found that all ASD-associated variants dampened or eliminated channel function. Incorporating these electrophysiological results into a compartmental model of developing excitatory neurons demonstrated that all ASD variants, regardless of their mechanism of action, resulted in deficits in neuronal excitability. Corresponding analysis of mature neurons predicted minimal change in neuronal excitability. Conclusions This functional characterization thus identifies SCN2A mutation and Na V 1.2 dysfunction as the most frequently observed ASD risk factor detectable by exome sequencing and suggests that associated changes in neuronal excitability, particularly in developing neurons, may contribute to ASD etiology.
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Infantile epileptic encephalopathy is characterized by infantile-onset seizures before 12 months of age followed by neurodevelopmental delay.
“1) infantile epileptic encephalopathy (IEE), characterized by infantile-onset seizures, before 12 months of age, followed by neurodevelopmental delay;”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
The Results describe SCN2A-associated epileptic encephalopathy as involving infantile seizures and moderate to severe developmental delay. Our copy does not specify seizure onset before 12 months or establish that developmental delay follows the seizures; it also describes a group of SCN2A cases rather than all infantile epileptic encephalopathy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBenign familial infantile seizures are characterized by infantile-onset seizures before 12 months of age that resolve by 2 years of age without overt long-term neuropsychiatric sequelae.
“2) benign (familial) infantile seizures (BIS), characterized by infantile-onset seizures, before 12 months of age, that resolve by 2 years of age without overt long-term neuropsychiatric sequelae;”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
The Introduction says BIFS seizures resolve before age two, and the Discussion describes their resolution without further apparent neurological impairment. The paper calls them infantile seizures but does not specify onset before 12 months, so that age cutoff is not supported by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAutism spectrum disorder/intellectual disability is characterized by global developmental delay, particularly in social and language milestones.
“3) autism spectrum disorder/intellectual disability (ASD/ID), characterized by global developmental delay, particularly of social and language milestones.”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
The Results (page not provided) report that many individuals with ASD have co-existing intellectual disability and developmental delay. The paper does not characterize that delay as global or say it particularly affects social and language milestones. (LLM, conf=0.84)
Experimental — accuracy not yet measuredOnly about 20 of the hundreds of disorder-associated SCN2A variants have been electrophysiologically assessed to date.
“To date, only about 20 of the hundreds of disorder-associated variants have been electrophysiologically assessed (summarized in [24,25]).”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
The Results (page unavailable) report that seven BIFS and three epileptic-encephalopathy variants had been characterized electrophysiologically, and the Methods report electrophysiological examination of 11 ASD-associated variants—about 20 in total. But the paper’s literature review identified 148 disorder-associated SCN2A variants (117 unique), not the claimed hundreds. (LLM, conf=0.86)
Experimental — accuracy not yet measuredComputational modeling of loss-of-function variants suggests that neuronal excitability is restored in the mature brain as NaV1.6 replaces NaV1.2 as the critical channel for action potential generation at two years of age.
“In keeping with this concern, computational modeling of loss of function variants suggests that neuronal excitability is restored in the mature brain as NaV1.6 replaces NaV1.2 as the critical channel underlying action potential generation at two years of age [24].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
The Results and Discussion report that modeled loss-of-function variants reduce excitability during development but have minimal effects on excitability in the mature model as NaV1.6 replaces NaV1.2 in the distal axon initial segment. The Introduction links this transition to seizure resolution before two years of age; it does not establish that the channel replacement or restoration of excitability occurs at two years. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Analysis of data from publications and clinical cohorts has already provided insights into genotype-phenotype relationships and appropriate antiepileptic drugs.
“Analysis of data from publications and clinical cohorts has already provided insights into genotype-phenotype relationships and appropriate antiepileptic drugs [24,25].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
The Results (page unavailable) describe a literature review of SCN2A variants in 148 families and group the variants by phenotype; the Discussion (page unavailable) links variant function to infantile seizures versus ASD/developmental delay. These passages support the genotype–phenotype part, but the retrieved text does not establish an analysis of clinical-cohort data or provide guidance on appropriate antiepileptic drugs. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSCN2A variants are primarily associated with three distinct disorders: infantile epileptic encephalopathy, benign familial infantile seizures, and autism spectrum disorder/intellectual disability.
“Variants in SCN2A are primarily associated with three distinct disorders [24,25]: 1) infantile epileptic encephalopathy (IEE), characterized by infantile-onset seizures, before 12 months of age, followed by neurodevelopmental delay; 2) benign (familial) infantile seizures (BIS), characterized by infantile-onset seizures, before 12 months of age, that resolve by 2 years of age without overt long-t”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
An integrated analysis of genetic and electrophysiological data led to a model that accounts for the three disorders associated with SCN2A.
“An integrated analysis of genetic and electrophysiological data led to a model to account for the three disorders associated with SCN2A (Figure 2) [24].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
For infants with postnatal-onset seizures at 3 months or earlier, non-selective sodium channel blockers such as phenytoin and carbamazepine are more effective, as expected for a gain-of-function variant.
“However, for infants with postnatal-onset seizures (≤3 months), non-selective sodium channel blockers, such as phenytoin and carbamazepine, are more effective [25], as would be expected based on a gain of function variant [24].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
Compartmental modeling can provide insight into the net effect on neuronal excitability in such conditions.
“Compartmental modeling can provide insight into the net effect on neuronal excitability in such conditions [24].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
Although epileptic encephalopathy often presents with neonatal seizures, seizure onset after three months probably occurs in 20%-40% of cases.
“While epileptic encephalopathy frequently presents with seizures in the neonatal period, with some families retrospectively reporting rhythmic movements in utero, it is likely that seizure onset after three months occurs in 20%-40% of cases [24,25].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [24]
The Results (page not provided) describe SCN2A-associated epileptic encephalopathy as characterized by infantile seizures, but do not give a neonatal-onset frequency. Searches for seizure onset after three months and the 20%–40% estimate found no passage addressing either figure. (LLM, conf=0.74)
Experimental — accuracy not yet measured
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Wang, L., Pang, K., Zhou, L., Cebrián-Silla, A., González-Granero, S., Wang, S., Bi, Q., White, M. L., Ho, B., Li, J., et al. (2023) · Nature · doi:10.1038/s41586-023-06542-2 · Cited by 82 · see citing works
A cross-species proteomic map reveals neoteny of human synapse development
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Increased cortical reactivity to repeated tones at 8 months in infants with later ASD
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“21 SCN2A, mild gain-of-function variants lead to BFNE, while PTVs and loss-of-function missense 1 variants, expected to be hyperpolarizing, lead to ASD and NDD (5, 11, 17).”
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Primary cilia TRP channel regulates hippocampal excitability
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- Authors
- Ben-Shalom, R., Keeshen, C. M., Berrios, K. N., An, J. Y., Sanders, S. J., & Bender, K. J.
- Affiliations
- University of California, San Francisco (US)
- University of Puerto Rico at Río Piedras (PR)
- Corresponding author
- Bender, Kevin J.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 82
- Issue
- 3
- Pages
- 224-232
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5796785
- OpenAlex
- W2581269619
- Cited by
- 288
- References
- 51
- Citations by year
- 2026: 26 · 2025: 36 · 2024: 37 · 2023: 27 · 2022: 26 · 2021: 39 · 2020: 34 · 2019: 32 · 2018: 22 · 2017: 9
- FWCI
- 10.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of Mental Health (R01MH110928)
- National Institute on Deafness and Other Communication Disorders (R00DC011080)
- National Institute of Neurological Disorders and Stroke (F32NS095580)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- SCN2A, Nav1.2 sodium channel, autism spectrum disorder, infantile seizures, gain-of-function mutations, neuronal excitability, channel dysfunction, cortical pyramidal neurons, computational neuron model, developmental delay, ASD etiology
- MeSH terms
- Autism Spectrum Disorder, Cerebral Cortex, Computer Simulation, Humans, Immunohistochemistry, Infant, Membrane Potentials, Models, Neurological, Mutation, Seizures, Spasms, Infantile, Pyramidal Cells, Patch-Clamp Techniques, Genetic Predisposition to Disease, Epilepsy, Benign Neonatal, HEK293 Cells, NAV1.2 Voltage-Gated Sodium Channel
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