Affinage

SCN2A

Sodium channel protein type 2 subunit alpha · UniProt Q99250

Length
2005 aa
Mass
228.0 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SCN2A encodes the voltage-gated sodium channel Nav1.2, which initiates and propagates action potentials and is required for dendritic excitability, backpropagation, and synaptic plasticity in neocortical and hippocampal pyramidal neurons (PMID:31230762, PMID:31249508). Channel function is shaped by accessory and regulatory partners: the beta1 subunit enhances surface expression in an ankyrinG-dependent manner (PMID:14761957), FGF12 and FGF14 form complexes at the axon initial segment and modulate current density and gating (PMID:19465131, PMID:25724910), and ankyrin-B scaffolds Nav1.2 to the dendritic membrane such that ANK2 haploinsufficiency phenocopies Scn2a loss (PMID:38290518). Nav1.2 activity is further tuned by phosphorylation, with CaMKII enhancing persistent current and depolarizing inactivation (PMID:28137877) and GSK3beta phosphorylating C-terminal T1966 to suppress surface expression and current (PMID:25615535). Fast inactivation depends on a hydrogen bond between N1662 and Q1494 (PMID:38939966), and a developmentally regulated neonatal splice isoform is intrinsically less excitable than the adult isoform, conferring early-life seizure protection (PMID:25378553). Disease variants segregate mechanistically: gain-of-function variants that slow inactivation and increase persistent, resurgent, or aberrant ion permeability cause early-onset epileptic encephalopathy (PMID:11166117, PMID:31558572, PMID:35417922), whereas loss-of-function variants that reduce current, protein level, or excitability cause autism and intellectual disability phenotypes (PMID:28256214, PMID:31558572, PMID:37010102), with haploinsufficiency in excitatory neurons driving absence-like seizures and synaptic deficits (PMID:30175250, PMID:34156984). Nav1.2 function extends across cell types beyond cortical excitatory neurons, including cerebellar granule cells where it supports LTP and VOR plasticity (PMID:38412857), olfactory bulb granule cells (PMID:30125271), and spiking oligodendrocyte precursors required for their maturation (PMID:34496232). Genetic upregulation of the functional allele by CRISPRa or reduction of gain-of-function transcript by antisense oligonucleotides rescues disease-relevant deficits in mice and human iPSC-derived neurons (PMID:34850743, PMID:40963013).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2001 High

    Established that a Nav1.2 mutation slowing inactivation and increasing persistent current is sufficient to cause seizures, defining gain-of-function as an epileptogenic mechanism.

    Evidence S4-S5 linker mutant in Xenopus oocytes plus transgenic mice with EEG and CA1 recording

    PMID:11166117

    Open questions at the time
    • Did not address developmental timing of vulnerability
    • Single engineered mutation rather than patient variants
  2. 2003 Low

    Identified calmodulin as a binding partner of Nav1.2 via an autism-associated variant reducing calcium-calmodulin affinity.

    Evidence Calmodulin binding assay of the R1902C variant

    PMID:12610651

    Open questions at the time
    • No functional electrophysiology follow-up
    • Single binding assay, single report
    • Physiological consequence of altered CaM binding unestablished
  3. 2004 High

    Defined how accessory subunits and truncation variants control Nav1.2 surface expression and gating, linking the beta1 subunit to ankyrinG-dependent modulation and implicating cytoskeletal interactions.

    Evidence Co-IP, biotinylation, patch-clamp and chimera/mutant analysis in transfected cells; R102X dominant-negative analysis in HEK293

    PMID:14761957 PMID:15028761

    Open questions at the time
    • beta1-ankyrinG mechanism not tested in neurons
    • Native scaffold composition at AIS not resolved
  4. 2005 High

    Distinguished Nav1.2 biophysics from Nav1.6, showing more depolarized activation, greater inactivation accumulation, and smaller persistent current, rationalizing channel-specific roles.

    Evidence Head-to-head whole-cell patch-clamp in mouse spinal sensory neurons

    PMID:15760941

    Open questions at the time
    • Functional division of labor in intact axon not addressed
    • Single neuronal expression system
  5. 2006 High

    Demonstrated that Nav1.2 persistent current interacts epistatically with the Kv7.2 M current to set seizure threshold, establishing channel-network determinants of epilepsy severity.

    Evidence Genetic crosses of Scn2aQ54 with two independent Kcnq2 mutant lines, seizure and survival analysis

    PMID:16464983

    Open questions at the time
    • Molecular mechanism of channel interaction not defined
    • Limited to engineered alleles
  6. 2009 High

    Showed FGF14 isoforms target to the axon initial segment and regulate Nav1.2 current, with the FGF14 N-terminus required for localization and modulation.

    Evidence Heterologous co-expression patch-clamp, confocal imaging, N-terminal deletion constructs

    PMID:19465131

    Open questions at the time
    • Direct binding interface with Nav1.2 not mapped
    • Isoform-specific physiological role in vivo not tested
  7. 2014 High

    Established that the neonatal Nav1.2 splice isoform is intrinsically less excitable, providing seizure protection during early brain development.

    Evidence Knock-in mice expressing only adult isoform with cortical patch-clamp and seizure threshold testing

    PMID:25378553

    Open questions at the time
    • Molecular basis of isoform excitability difference not defined
    • Regulation of the developmental splice switch unknown
  8. 2015 High

    Identified phosphorylation-based regulation of Nav1.2, with GSK3beta phosphorylating C-terminal T1966 to suppress surface expression and FGF12 acting synergistically with CaMKII to tune gating.

    Evidence In vitro kinase assay/MS, surface labeling, siRNA, and patch-clamp; affinity purification/MS, Co-IP, imaging and electrophysiology

    PMID:25615535 PMID:25724910

    Open questions at the time
    • Upstream signals controlling these kinases in vivo not defined
    • Interplay between GSK3, CaMKII and FGF regulation not integrated
  9. 2017 High

    Resolved that CaMKII modulates Nav1.2 persistent current and inactivation and that disease variants bifurcate into gain-of-function (seizures) versus loss-of-function (ASD), with cell-type expression beyond excitatory neurons.

    Evidence Neuronal and heterologous patch-clamp with CaMKII assays; 11-variant electrophysiology with computational modeling; interneuron immunofluorescence

    PMID:28137877 PMID:28256214 PMID:28784306

    Open questions at the time
    • Variant classification rests on heterologous systems and modeling
    • In vivo CaMKII contribution to human disease not established
  10. 2018 High

    Showed via cell-type-specific deletion that Nav1.2 haplodeficiency in excitatory neurons drives absence-like seizures, with developmental redistribution from proximal to distal axons.

    Evidence Conditional and constitutive Scn2a knockouts, EEG, ethosuximide pharmacology, immunohistochemistry

    PMID:30175250

    Open questions at the time
    • Circuit basis of spike-and-wave discharges not fully mapped
    • Trigger for axonal redistribution unknown
  11. 2019 High

    Demonstrated that Nav1.2 supports dendritic backpropagation and synaptic plasticity even when lost late in mature neurons, and that haploinsufficiency impairs hippocampal LTP and memory.

    Evidence Cell-autonomous conditional Scn2a KO with dendritic recordings; Scn2a+/- mice with LTP and behavioral assays

    PMID:31230762 PMID:31249508

    Open questions at the time
    • Link between dendritic excitability loss and behavioral deficits not fully causal
    • Reversibility in adults addressed only later
  12. 2019 High

    Defined biophysical signatures separating gain- from loss-of-function variants, including resurgent and gating pore currents.

    Evidence Voltage-clamp in HEK and oocytes with Nav-beta4 resurgent and surface expression assays for R1882Q and R853Q

    PMID:31558572

    Open questions at the time
    • Neuronal consequences of gating pore current not measured
    • Heterologous-system limitations
  13. 2020 High

    Showed that EOEE variant dysfunction is amplified in the neonatal isoform, explaining the early-onset phenotype.

    Evidence Variant electrophysiology in neonatal and adult isoforms with compartmental modeling

    PMID:31995133

    Open questions at the time
    • In vivo validation in isoform-specific models lacking
    • Limited variant set
  14. 2021 High

    Extended Nav1.2 function across cell types — olfactory and cerebellar granule cells and spiking oligodendrocyte precursors — and showed therapeutic correction of gain-of-function epilepsy by transcript-lowering ASO.

    Evidence Conditional KOs with electrophysiology/behavior in olfactory bulb; single-cell transcriptomics plus patch-clamp in OLs; C-terminal truncation knock-in mice; ICV ASO in Q/+ mice

    PMID:30125271 PMID:34156984 PMID:34287911 PMID:34496232 PMID:34850743

    Open questions at the time
    • Mechanism of Nav1.2 in OL maturation not defined
    • ASO durability and translatability not established
  15. 2022 Medium

    Linked Nav1.2 to circadian/sleep regulation through SCN neuron firing and clock gene expression, and identified aberrant Ca2+ permeability as a distinct gain-of-function disease mechanism.

    Evidence Region-specific Scn2a deletion with sleep EEG, SCN patch-clamp and RNA-seq; K1422E knock-in mice with patch-clamp, calcium imaging and modeling

    PMID:35301122 PMID:35417922

    Open questions at the time
    • SCN role rests on region-specific deletion, not pure SCN
    • Ion-permeability mechanism studied in one variant
  16. 2023 High

    Showed in patient iPSC neurons that ID/autism variants reduce Nav1.2 protein levels and current while an epilepsy variant impairs inactivation without changing protein, mechanistically separating the two disease classes.

    Evidence Patient iPSC-derived cortical neurons with patch-clamp, Western blot, RT-PCR and single-cell transcriptomics

    PMID:37010102

    Open questions at the time
    • Early-stage neurons may not capture mature phenotypes
    • Genotype-phenotype generalization across variants limited
  17. 2024 High

    Established the structural basis of fast inactivation (N1662-Q1494 hydrogen bond), the ankyrin-B dendritic scaffold convergent with ASD genetics, cerebellar control of VOR plasticity, and microglial complement-mediated synaptic over-pruning as a Nav1.2 loss consequence.

    Evidence Molecular dynamics and mutagenesis with electrophysiology; conditional Ank2 KO with dendritic recordings; granule-cell conditional KO with VOR and CRISPRa rescue; Scn2a-deficient mice and human organoids with microglial ablation

    PMID:38290518 PMID:38412857 PMID:38499656 PMID:38939966

    Open questions at the time
    • Trigger linking Nav1.2 loss to complement activation not defined
    • Generality of microglial pruning across brain regions unclear
  18. 2025 High

    Demonstrated allele-upregulating CRISPRa rescues electrophysiological and seizure phenotypes in adolescent haploinsufficient mice and in human iPSC neurons, providing a gene-dosage therapeutic strategy.

    Evidence AAV-delivered CRISPRa in Scn2a+/- mice with cortical patch-clamp and chemoconvulsant assays plus iPSC-neuron electrophysiology

    PMID:40963013

    Open questions at the time
    • Long-term safety and durability not established
    • Applicability to gain-of-function disease not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (CaMKII, GSK3beta, FGF12/14, ankyrin scaffolds, splice isoform switching) are integrated to set Nav1.2 function across development and cell types remains unresolved.
  • No unified model of combinatorial Nav1.2 regulation in vivo
  • Cryo-EM/structural model of full channel-partner complexes absent from corpus
  • Mechanism coupling channel loss to non-cell-autonomous microglial pruning undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4
Localization
GO:0005886 plasma membrane 7
Pathway
R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 4
Partners
ANK2ANK3CALM1FGF12FGF14SCN1B

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 A gain-of-function mutation (GAL879-881QQQ) in the cytoplasmic S4-S5 linker of domain 2 of Nav1.2 results in slowed inactivation and increased persistent sodium current when expressed in Xenopus oocytes, and transgenic mice expressing this mutation develop spontaneous focal hippocampal seizures with increased persistent sodium current in hippocampal CA1 neurons. Xenopus oocyte expression + whole-cell patch-clamp; transgenic mouse model with in vivo EEG and neuronal recording Neuroscience High 11166117
2004 Nav1.2 is redistributed from nodes of Ranvier to diffuse expression along demyelinated axons in acute multiple sclerosis plaques, as demonstrated by triple-labeled fluorescent immunocytochemistry; this redistribution is distinct from Nav1.6, which co-localizes with the Na+/Ca2+ exchanger and a marker of axonal injury. Triple-labeled fluorescent immunocytochemistry in human MS tissue Proceedings of the National Academy of Sciences of the United States of America Medium 15148385
2004 The truncated R102X SCN2A mutant protein, when co-expressed with wild-type Nav1.2 in HEK293 cells, shifts the voltage dependence of inactivation in the hyperpolarizing direction, suggesting a dominant negative effect; subcellular localization analysis implicated cytoskeletal interactions in this dominant negative mechanism. Patch-clamp electrophysiology in HEK293 cells; subcellular localization analysis The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 15028761
2004 The Nav1.2 beta1 subunit enhances channel cell surface expression and modulates channel function via interactions with both contactin and ankyrinG; beta1Y181E, a mutant that cannot interact with ankyrinG, fails to modulate Nav1.2 function despite efficient association with Nav1.2 and contactin, demonstrating that beta1-ankyrinG interaction is required for functional modulation. Co-immunoprecipitation, membrane biotinylation, whole-cell patch-clamp, beta1/beta2 chimeric subunit analysis in transfected cells The Journal of biological chemistry High 14761957
2005 Nav1.2 channels display more depolarized activation and availability properties compared to Nav1.6, greater accumulation of inactivation at higher stimulation frequencies (20–100 Hz), and produce a smaller persistent current than Nav1.6; these properties were directly compared in mouse spinal sensory neurons. Whole-cell patch-clamp electrophysiology in mammalian neuronal expression system, direct comparison of Nav1.2 vs Nav1.6 The Journal of physiology High 15760941
2003 The SCN2A variant R1902C, located in the calmodulin binding site, reduces binding affinity for calcium-bound calmodulin, identifying calmodulin as a binding partner of Nav1.2 at this site. Calmodulin binding assay (variant found in autism family screening) Molecular psychiatry Low 12610651
2009 FGF14-1b, but not FGF14-1a, attenuates Nav1.2 current densities; both FGF14 splice variants localize to the axon initial segment in neurons, and deletion of the FGF14 N-terminus abolishes this localization. The FGF14 N-terminus is required for targeting and functional regulation of Nav1.2 channels. Co-expression in heterologous cells with patch-clamp electrophysiology; confocal microscopy of neuronal localization; FGF14 N-terminus deletion constructs Molecular and cellular neurosciences High 19465131
2015 FGF12 (fibroblast growth factor 12) co-immunoprecipitates with Nav1.2 in a heterologous expression system and forms a native complex with Nav1.2 at the axon initial segment in brain tissue. FGF12 acts synergistically with CaMKII to modulate Nav1.2-encoded currents: in the presence of CaMKII inhibitors, FGF12 shifts voltage-dependence of activation to more depolarized potentials and steady-state inactivation to more hyperpolarized potentials, increasing channel availability. Affinity purification from brain + mass spectrometry; co-immunoprecipitation in heterologous cells; confocal microscopy; patch-clamp electrophysiology Molecular & cellular proteomics : MCP High 25724910
2015 GSK3β phosphorylates T1966 at the C-terminal tail of Nav1.2, as identified by in vitro phosphorylation and high-resolution mass spectrometry. GSK3 inhibition potentiates Nav1.2 peak current density and increases Nav1.2 cell surface expression without changing total protein or mRNA levels; GSK3β overexpression suppresses Nav1.2 currents. In vitro phosphorylation assay + mass spectrometry; patch-clamp electrophysiology in HEK293 cells; siRNA knockdown; cell surface labeling with CD4-chimeric constructs; RT-PCR and Western blot Biochimica et biophysica acta High 25615535
2017 CaMKII modulates Nav1.2 persistent sodium current and channel inactivation in hippocampal neurons: activated CaMKII enhances persistent current and depolarizes channel inactivation in heterologously expressed Nav1.2, while CaMKII inhibition attenuates persistent current, hyperpolarizes inactivation, and suppresses neuronal excitability. CaMKII activity is elevated in the more severe epileptic strain of Scn2aQ54 mice. Whole-cell patch-clamp of hippocampal neurons and heterologous Nav1.2; CaMKII activity assay in brain lysates; pharmacological CaMKII inhibition Proceedings of the National Academy of Sciences of the United States of America High 28137877
2017 ASD-associated SCN2A variants (11 tested) dampen or eliminate Nav1.2 channel function (loss-of-function) in heterologous expression systems, in contrast to infantile seizure variants which are gain-of-function; computational models predict that ASD variants cause deficits in neuronal excitability in developing neurons but minimal change in mature neurons. Whole-cell voltage-clamp electrophysiology in heterologous expression system; immunohistochemistry; compartmental computational neuron modeling Biological psychiatry High 28256214
2017 Nav1.2 is expressed in CGE-derived disinhibitory interneurons (reelin+/SST- and VIP+ neurons) in addition to excitatory neurons; Nav1.1 and Nav1.2 show mutually exclusive distributions in many brain regions. Nav1.2 is absent from PV+ and SST+ inhibitory neurons. Immunofluorescence co-localization in mouse brain sections at postnatal day 15; multiple interneuron marker antibodies Biochemical and biophysical research communications Medium 28784306
2018 Heterozygous Scn2a knockout and knock-in (nonsense mutation) mice exhibit ethosuximide-sensitive absence-like seizures with spike-and-wave discharges. Conditional deletion of Scn2a specifically in dorsal-telencephalic excitatory neurons reproduces these seizures, whereas selective deletion in inhibitory neurons does not, establishing that Nav1.2 haplodeficiency in excitatory neurons drives this seizure phenotype. In adult cortex, Nav1.2 redistributes from proximal to distal axons during development. Conditional and constitutive Scn2a knockout mouse models; in vivo EEG recording; ethosuximide pharmacology; cell-type-specific Cre-mediated deletion; immunohistochemistry Communications biology High 30175250
2019 NaV1.2 is critical for dendritic excitability and synaptic function in mature prefrontal cortex pyramidal neurons: loss of Nav1.2 reduces action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when disrupted cell-autonomously late in development. Conditional Scn2a knockout in mice; whole-cell patch-clamp of pyramidal neurons; dendritic recordings; cell-autonomous sparse deletion; synaptic plasticity assays Neuron High 31230762
2019 The R1882Q SCN2A mutation produces gain-of-function effects including slowed fast inactivation, depolarized voltage dependence of inactivation, increased persistent current, and increased resurgent current. The R853Q mutation produces loss-of-function effects including reduced current amplitude, hyperpolarized inactivation, decreased persistent current, decreased resurgent current, reduced surface expression, and a gating pore current at negative membrane potentials absent in wild-type channels. Voltage-clamp electrophysiology in HEK cells; Xenopus oocyte expression; Nav-beta4 peptide resurgent current assay; surface expression measurement eNeuro High 31558572
2020 EOEE-associated Nav1.2 variants (T236S, E999K, S1336Y) exhibit greater gain-of-function dysfunction in the neonatal splice isoform compared to the adult isoform; computational modeling of developing cortical pyramidal neurons confirms isoform-dependent hyperexcitability preferentially in immature neurons. Site-directed mutagenesis in neonatal and adult Nav1.2 splice isoforms; whole-cell voltage-clamp in transfected cells; compartmental neuron modeling The Journal of general physiology High 31995133
2014 The 'neonatal' Nav1.2 splice isoform (expressing exon 6N) is less excitable than the 'adult' isoform; mice expressing only the adult isoform show significantly increased action potential firing in cortical pyramidal neurons and increased seizure susceptibility at P3, directly linking the neonatal isoform to seizure protection in early brain development. Knock-in mouse model expressing only adult Nav1.2 isoform; whole-cell patch-clamp of cortical pyramidal neurons; in vivo seizure threshold testing Human molecular genetics High 25378553
2006 Genetic interaction between Scn2a gain-of-function (Q54 transgene) and loss-of-function alleles of Kcnq2 (M current channel) dramatically exacerbates epilepsy severity, causing early-onset generalized tonic-clonic seizures and juvenile lethality in double mutants, demonstrating epistatic interaction between Nav1.2 persistent sodium current and Kv7.2 M current in seizure threshold determination. Genetic crosses between Scn2aQ54 transgenic and two independent Kcnq2 mutant mouse lines; in vivo seizure monitoring and survival analysis Human molecular genetics High 16464983
2016 Transgenic elevation of Cacna1g (Cav3.1 T-type calcium channel) expression increases spontaneous seizure frequency in Scn2aQ54 mice, while decreased Cacna1g expression decreases seizure frequency, establishing Cacna1g as a genetic modifier of Nav1.2-driven epilepsy. Transgenic alteration of Cacna1g expression in Scn2aQ54 mice; in vivo seizure frequency monitoring Epilepsia Medium 27112236
2018 NaV1.2 expressed in olfactory bulb granule cells is distributed in clusters throughout the cell surface including dendritic spines; deletion of Nav1.2 specifically in granule cells abolishes spiking and dendritic GABA release, as well as inhibition of connected mitral cells, impairing rapid discrimination of similar odorants. Conditional Scn2a knockout in granule cells; patch-clamp recording; GABA release measurement; olfactory behavioral assay PLoS biology High 30125271
2019 Scn2a haploinsufficiency in mice suppresses hippocampal neuronal excitability, excitatory synaptic drive, and long-term potentiation (LTP), and impairs spatial learning and memory, linking Nav1.2 to hippocampal synaptic plasticity and memory. Scn2a+/- mice; whole-cell patch-clamp; LTP recording in hippocampal slices; behavioral tests (Morris water maze, fear conditioning) Frontiers in molecular neuroscience High 31249508
2021 SCN2A is specifically expressed in spiking oligodendrocyte lineage cells (OLs) in the brainstem and cerebellum; deletion of SCN2A eliminates the Nav-driven spiking OL population and disrupts maturation of a subpopulation of OLs, indicating Nav1.2 is essential for spiking and contributes to OL lineage heterogeneity and development. Single-cell transcriptomics paired with whole-cell patch-clamp recordings; conditional SCN2A deletion in OLs; lineage marker analysis Cell reports High 34496232
2021 Antisense oligonucleotide (ASO) targeting Scn2a mRNA, administered centrally to gain-of-function Scn2a Q/+ mice, reduces spontaneous seizures and significantly extends lifespan, demonstrating that targeted reduction of SCN2A expression can correct gain-of-function Nav1.2-driven developmental epileptic encephalopathy. ASO intracerebroventricular delivery in transgenic mouse model; seizure monitoring; behavioral testing; lifespan analysis The Journal of clinical investigation High 34850743
2021 A protein truncation variant (Scn2aΔ1898) eliminating the distal Nav1.2 C-terminal domain causes decreased channel function in heterologous cells; cultured pyramidal neurons from Scn2aΔ1898/+ mice show reduced voltage-gated Na+ currents specifically in excitatory neurons (not inhibitory neurons), reduced excitability, and reduced excitatory synaptic input in brain slices. CRISPR-generated mouse model; patch-clamp in heterologous cells, neuronal cultures, and brain slices; cell-type specific analysis JCI insight High 34156984
2021 The recurrent SCN2A R853Q mutation enhances slow inactivation of Nav1.2 as a major driver of loss-of-function; slow inactivation is more pronounced in the adult/canonical splice isoform, potentially explaining the later onset of neurological features associated with this mutation. Multiple additional loss-of-function defects were also identified. Site-directed mutagenesis; whole-cell patch-clamp in HEK293T cells co-expressing beta1 and beta2 subunits; comparison of neonatal and adult splice isoforms The Journal of physiology High 34287911
2024 Ankyrin-B (encoded by ANK2) is essential for scaffolding Nav1.2 to the dendritic membrane of mouse neocortical pyramidal neurons; haploinsufficiency of Ank2 phenocopies the intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions, establishing a direct physical and functional link between two major ASD risk genes. Conditional Ank2 knockout in neocortical neurons; whole-cell patch-clamp dendritic recordings; immunofluorescence co-localization; comparison with Scn2a+/- phenotypes Neuron High 38290518
2024 Heterozygous loss of Nav1.2 in cerebellar granule cells impairs high-frequency synaptic transmission to Purkinje cells and prevents long-term potentiation (LTP), causing hypersensitization of the vestibulo-ocular reflex (VOR). CRISPRa-mediated upregulation of Scn2a expression in Scn2a+/- mice rescues VOR plasticity. Conditional Scn2a haploinsufficiency in granule cells; VOR measurement in humans and mice; cerebellar electrophysiology; CRISPR-activator rescue Neuron High 38412857
2024 Scn2a-deficient mice show excessive microglial phagocytic pruning of post-synapses, related to complement C3 cascades, during selective developmental stages; ablation of microglia with PLX3397 partially restores synaptic transmission and spine density. Human cerebral organoids carrying an SCN2A protein-truncating mutation also show increased microglial elimination of post-synapses. Scn2a-deficient mouse model; microglial ablation with PLX3397; confocal imaging of synaptic markers; electrophysiology; human cerebral organoids with SCN2A mutation; complement pathway analysis Molecular psychiatry High 38499656
2025 The N1662D Nav1.2 mutation almost completely prevents fast inactivation; molecular dynamics simulations demonstrate that the hydrogen bond between N1662 and Q1494 is essential for fast inactivation gate stability; engineered Q1494A/L variants also prevent inactivation, while Q1494E/K variants produce incomplete inactivation and persistent current, confirming the N1662-Q1494 interaction as the structural basis for fast inactivation. Molecular dynamics simulation; patch-clamp electrophysiology; dynamic action potential clamp; site-directed mutagenesis of N1662 and Q1494 residues Brain : a journal of neurology High 38939966
2025 CRISPRa-mediated upregulation of the functional Scn2a allele in adolescent heterozygous Scn2a conditional knock-in mice rescues electrophysiological deficits (intrinsic and synaptic) in neocortical pyramidal cells and protects against chemoconvulsant-induced seizures; AAV-delivered CRISPRa also rescues excitability in SCN2A haploinsufficient human iPSC-derived neurons. AAV-delivered CRISPRa in Scn2a+/- mice; whole-cell patch-clamp of neocortical pyramidal cells; chemoconvulsant seizure threshold assay; human iPSC-derived neuron electrophysiology Nature High 40963013
2012 Sigma-1 receptor agonists (+)-SKF 10047, dextromethorphan, and DTG directly inhibit Nav1.2 channel currents independently of sigma-1 receptor activation, with use- and frequency-dependent block; point mutations at Phe1764 and Tyr1771 in the IV-S6 domain of Nav1.2 reduce inhibition, identifying these residues as critical for drug binding. Patch-clamp electrophysiology in HEK293T and COS-7 cells; pharmacological receptor antagonist controls; site-directed mutagenesis of IV-S6 domain residues PloS one High 23139844
2014 Anandamide inhibits Nav1.2 currents in a concentration-dependent manner (IC50 ~17 µM) with use-dependent block; it shifts the activation curve in the depolarizing direction and the inactivation curve in the hyperpolarizing direction, indicating inhibition via decreased activation and increased inactivation. Two-electrode voltage-clamp in Xenopus oocytes expressing Nav1.2 with beta1 subunit Anesthesia and analgesia Medium 24557103
2022 Scn2a deficiency in the suprachiasmatic nucleus (SCN) region disrupts the firing pattern of spontaneously active SCN neurons and alters circadian clock gene expression (Per1, Per2); brain region-specific Scn2a deletion in the SCN-containing region partially recapitulates sleep disturbance phenotypes seen in global Scn2a-deficient mice. Gene-trap Scn2a-deficient mice; brain region-specific Cre-mediated deletion; EEG/EMG sleep analysis; patch-clamp of SCN neurons; RNA sequencing Neurobiology of disease Medium 35301122
2022 The SCN2A K1422E variant confers Ca2+ permeability to Nav1.2, lowers overall Na+ conductance, and confers TTX resistance; Scn2aK1422E/+ cortical neurons show lower current density with TTX-resistant component, reversal potential consistent with mixed ion permeation, impaired AP initiation, and larger Ca2+ transients at the axon initial segment during AP rising phase. Scn2aK1422E knock-in mice; whole-cell patch-clamp of cortical neurons and slices; calcium imaging; compartmental neuron modeling; in vivo EEG Human molecular genetics High 35417922
2023 ID/autism-associated SCN2A loss-of-function variants reduce Nav1.2 protein levels (via nonsense-mediated decay for frameshift or protein instability for missense variants) in patient iPSC-derived neurons, leading to decreased sodium current density and impaired AP firing. In contrast, an epileptic encephalopathy variant (E1803G) does not alter Nav1.2 protein levels or sodium current density but impairs sodium channel inactivation. Patient iPSC-derived early-stage cortical neurons; patch-clamp electrophysiology; Western blot; RT-PCR; single-cell transcriptomics Human molecular genetics High 37010102

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain : a journal of neurology 432 28379373
2004 Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proceedings of the National Academy of Sciences of the United States of America 365 15148385
2018 Progress in Understanding and Treating SCN2A-Mediated Disorders. Trends in neurosciences 261 29691040
2003 Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Molecular psychiatry 229 12610651
2017 Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures. Biological psychiatry 219 28256214
2005 Electrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed in mouse spinal sensory neurones. The Journal of physiology 218 15760941
2015 SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures. Neurology 193 26291284
2019 The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex. Neuron 189 31230762
2001 A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience 187 11166117
2004 A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. The Journal of neuroscience : the official journal of the Society for Neuroscience 159 15028761
2013 Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 158 23935176
2010 SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology 124 20956790
2009 FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels. Molecular and cellular neurosciences 113 19465131
2004 Sodium channel beta1 subunit-mediated modulation of Nav1.2 currents and cell surface density is dependent on interactions with contactin and ankyrin. The Journal of biological chemistry 100 14761957
2019 Phenotypic spectrum and genetics of SCN2A-related disorders, treatment options, and outcomes in epilepsy and beyond. Epilepsia 95 31904126
2018 Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice. Communications biology 86 30175250
2021 Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model. The Journal of clinical investigation 85 34850743
2011 Clinical spectrum of SCN2A mutations. Brain & development 85 22029951
2009 Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome. Brain & development 85 19783390
2007 SCN2A mutations and benign familial neonatal-infantile seizures: the phenotypic spectrum. Epilepsia 84 17386050
2008 Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression. Pharmacogenetics and genomics 80 18784617
2008 Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures. Epilepsia 78 18479388
2015 Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia. Journal of neurology 74 26645390
2009 Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population. British journal of clinical pharmacology 68 19694741
2019 Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity. Molecular autism 67 30962870
2014 'Neonatal' Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour. Human molecular genetics 63 25378553
2006 A novel SCN2A mutation in family with benign familial infantile seizures. Epilepsia 61 16417554
2006 Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. Human molecular genetics 61 16464983
2014 Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities. Epilepsia 58 24579881
2019 Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes. Molecular medicine (Cambridge, Mass.) 55 30813884
2013 SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis. Pharmacogenomics 52 23859570
2021 Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A-related disorders. Genetics in medicine : official journal of the American College of Medical Genetics 51 33731876
2019 Scn2a Haploinsufficiency in Mice Suppresses Hippocampal Neuronal Excitability, Excitatory Synaptic Drive, and Long-Term Potentiation, and Spatial Learning and Memory. Frontiers in molecular neuroscience 51 31249508
2015 Quantitative proteomics reveals protein-protein interactions with fibroblast growth factor 12 as a component of the voltage-gated sodium channel 1.2 (nav1.2) macromolecular complex in Mammalian brain. Molecular & cellular proteomics : MCP 51 25724910
2014 De novo SCN2A splice site mutation in a boy with Autism spectrum disorder. BMC medical genetics 51 24650168
2005 Comparison of the effects of four Na+ channel analgesics on TTX-resistant Na+ currents in rat sensory neurons and recombinant Nav1.2 channels. Neuroscience letters 50 16293367
2024 Microglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids. Molecular psychiatry 46 38499656
2020 Alternative splicing potentiates dysfunction of early-onset epileptic encephalopathy SCN2A variants. The Journal of general physiology 46 31995133
2017 Nav1.2 is expressed in caudal ganglionic eminence-derived disinhibitory interneurons: Mutually exclusive distributions of Nav1.1 and Nav1.2. Biochemical and biophysical research communications 44 28784306
2013 Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings. Epilepsia 44 23550958
2017 Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP). Human molecular genetics 43 28334922
2016 Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation. Psychiatric genetics 42 26555645
2015 The Nav1.2 channel is regulated by GSK3. Biochimica et biophysica acta 42 25615535
2021 Hyperexcitability and Pharmacological Responsiveness of Cortical Neurons Derived from Human iPSCs Carrying Epilepsy-Associated Sodium Channel Nav1.2-L1342P Genetic Variant. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 34716231
2014 Association of SCN1A, SCN2A and ABCC2 gene polymorphisms with the response to antiepileptic drugs in Chinese Han patients with epilepsy. Pharmacogenomics 40 25155934
2023 Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties. The Journal of general physiology 39 37578743
2019 SCN2A channelopathies: Mechanisms and models. Epilepsia 39 31904120
2024 Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites. Neuron 38 38290518
2019 Resurgent and Gating Pore Currents Induced by De Novo SCN2A Epilepsy Mutations. eNeuro 38 31558572
2016 Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a. Epilepsia 38 27112236
2006 Expression of sodium channels Nav1.2 and Nav1.6 during postnatal development of the retina. Neuroscience letters 38 16753259
2017 CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice. Proceedings of the National Academy of Sciences of the United States of America 37 28137877
2021 Generation and basic characterization of a gene-trap knockout mouse model of Scn2a with a substantial reduction of voltage-gated sodium channel Nav 1.2 expression. Genes, brain, and behavior 36 33369088
2019 NaV1.2 haploinsufficiency in Scn2a knock-out mice causes an autistic-like phenotype attenuated with age. Scientific reports 36 31501495
2001 Genomic structures of SCN2A and SCN3A - candidate genes for deafness at the DFNA16 locus. Gene 36 11245985
2003 L-type calcium channel activation up-regulates the mRNAs for two different sodium channel alpha subunits (Nav1.2 and Nav1.3) in rat pituitary GH3 cells. Brain research. Molecular brain research 35 12941467
2024 Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders. Brain : a journal of neurology 34 38651838
1989 Localization of a human brain sodium channel gene (SCN2A) to chromosome 2. Genomics 34 2571571
2018 Relationship of electrophysiological dysfunction and clinical severity in SCN2A-related epilepsies. Human mutation 33 30144217
2018 Lacosamide for SCN2A-related intractable neonatal and infantile seizures. Epileptic disorders : international epilepsy journal with videotape 32 30361185
2013 SCN2A mutation is associated with infantile spasms and bitemporal glucose hypometabolism. Pediatric neurology 32 23827426
2022 Functional correlates of clinical phenotype and severity in recurrent SCN2A variants. Communications biology 31 35637276
2013 Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy. Human genetics 31 24337656
2022 Deficiency of autism-related Scn2a gene in mice disrupts sleep patterns and circadian rhythms. Neurobiology of disease 30 35301122
2020 SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? Molecular autism 30 32264956
2015 ABCB1, ABCC2, SCN1A, SCN2A, GABRA1 gene polymorphisms and drug resistant epilepsy in the Chinese Han population. Die Pharmazie 30 26189305
2014 Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals. JAMA psychiatry 30 24718902
2015 Missense mutations in sodium channel SCN1A and SCN2A predispose children to encephalopathy with severe febrile seizures. Epilepsy research 29 26311622
2001 The voltage-gated sodium channel gene SCN2A and idiopathic generalized epilepsy. Epilepsy research 29 11738931
2022 Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice. Human molecular genetics 28 35417922
2024 Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A-associated ASD. Neuron 25 38412857
2021 Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors. JCI insight 25 34156984
2021 SCN2A contributes to oligodendroglia excitability and development in the mammalian brain. Cell reports 25 34496232
2018 Axonal sodium channel NaV1.2 drives granule cell dendritic GABA release and rapid odor discrimination. PLoS biology 25 30125271
2007 Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncoding sequences. Genomics 25 17544618
2015 MicroRNA-9 induces defective trafficking of Nav1.1 and Nav1.2 by targeting Navβ2 protein coding region in rat with chronic brain hypoperfusion. Molecular neurodegeneration 24 26259688
2014 The endocannabinoid anandamide inhibits voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 in Xenopus oocytes. Anesthesia and analgesia 24 24557103
2019 SCN1A and SCN2A polymorphisms are associated with response to valproic acid in Chinese epilepsy patients. European journal of clinical pharmacology 23 30693367
2018 SCN2A mutation in an infant presenting with migrating focal seizures and infantile spasm responsive to a ketogenic diet. Brain & development 21 29625812
2006 Immunolocalization of NaV1.2 channel subtypes in rat and cat brain and spinal cord with high affinity antibodies. Brain research 21 16815341
2012 Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. PloS one 20 23139844
2022 LncRNA PVT1 Promotes Neuronal Cell Apoptosis and Neuroinflammation by Regulating miR-488-3p/FOXD3/SCN2A Axis in Epilepsy. Neurochemical research 19 36378391
2007 Scn2a sodium channel mutation results in hyperexcitability in the hippocampus in vitro. Epilepsia 19 18031550
2014 SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet. Brain & development 18 25459969
2023 Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons. Human molecular genetics 17 37010102
2020 Variable patterns of mutation density among NaV1.1, NaV1.2 and NaV1.6 point to channel-specific functional differences associated with childhood epilepsy. PloS one 17 32845893
2019 Effects of GRM4, SCN2A and SCN3B polymorphisms on antiepileptic drugs responsiveness and epilepsy susceptibility. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 17 31297029
2014 A case of recurrent encephalopathy with SCN2A missense mutation. Brain & development 17 25457084
2025 CRISPR activation for SCN2A-related neurodevelopmental disorders. Nature 16 40963013
2020 Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy. Molecular genetics & genomic medicine 16 32400968
2020 Functional and pharmacological evaluation of a novel SCN2A variant linked to early-onset epilepsy. Annals of clinical and translational neurology 16 32750235
2020 The phenotype and treatment of SCN2A-related developmental and epileptic encephalopathy. Epileptic disorders : international epilepsy journal with videotape 16 33000761
2024 Distinctive In Vitro Phenotypes in iPSC-Derived Neurons From Patients With Gain- and Loss-of-Function SCN2A Developmental and Epileptic Encephalopathy. The Journal of neuroscience : the official journal of the Society for Neuroscience 15 38148154
2019 Understanding the schizophrenia phenotype in the first patient with the full SCN2A phenotypic spectrum. Psychiatric genetics 15 30741786
2018 Ketogenic diet as a successful early treatment modality for SCN2A mutation. Brain & development 15 30415926
2025 Nav1.2 channel mutations preventing fast inactivation lead to SCN2A encephalopathy. Brain : a journal of neurology 14 38939966
2025 Human IPSC-Derived Microglia Sense and Dampen Hyperexcitability of Cortical Neurons Carrying the Epilepsy-Associated SCN2A-L1342P Mutation. The Journal of neuroscience : the official journal of the Society for Neuroscience 14 39557580
2021 Enhanced slow inactivation contributes to dysfunction of a recurrent SCN2A mutation associated with developmental and epileptic encephalopathy. The Journal of physiology 14 34287911
2019 Biallelic SCN2A Gene Mutation Causing Early Infantile Epileptic Encephalopathy: Case Report and Review. Journal of central nervous system disease 13 31205438
2018 Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development. Neuropediatrics 13 30165711

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