{"gene":"SCN2A","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2001,"finding":"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.","method":"Xenopus oocyte expression + whole-cell patch-clamp; transgenic mouse model with in vivo EEG and neuronal recording","journal":"Neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with functional assay in oocytes replicated in transgenic mouse model with direct neuronal recording","pmids":["11166117"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Triple-labeled fluorescent immunocytochemistry in human MS tissue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization in human tissue, replicated across multiple MS cases, but single method (immunocytochemistry)","pmids":["15148385"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Patch-clamp electrophysiology in HEK293 cells; subcellular localization analysis","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — heterologous expression with patch-clamp and localization, single lab, two orthogonal methods","pmids":["15028761"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Co-immunoprecipitation, membrane biotinylation, whole-cell patch-clamp, beta1/beta2 chimeric subunit analysis in transfected cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (Co-IP, biochemical surface expression, electrophysiology, mutagenesis) in a single rigorous study","pmids":["14761957"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Whole-cell patch-clamp electrophysiology in mammalian neuronal expression system, direct comparison of Nav1.2 vs Nav1.6","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro electrophysiology with direct head-to-head comparison of the two channels in neuronal cells, single lab but multiple voltage-clamp protocols","pmids":["15760941"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Calmodulin binding assay (variant found in autism family screening)","journal":"Molecular psychiatry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single binding assay, single report, no functional electrophysiology follow-up","pmids":["12610651"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-expression in heterologous cells with patch-clamp electrophysiology; confocal microscopy of neuronal localization; FGF14 N-terminus deletion constructs","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — electrophysiology and direct imaging with mutagenesis, two orthogonal methods, single lab","pmids":["19465131"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Affinity purification from brain + mass spectrometry; co-immunoprecipitation in heterologous cells; confocal microscopy; patch-clamp electrophysiology","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (affinity purification/MS, Co-IP, imaging, electrophysiology), single lab","pmids":["25724910"],"is_preprint":false},{"year":2015,"finding":"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.","method":"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","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mass spectrometry identification of phosphosite, complemented by electrophysiology and surface expression assays, single lab multiple methods","pmids":["25615535"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Whole-cell patch-clamp of hippocampal neurons and heterologous Nav1.2; CaMKII activity assay in brain lysates; pharmacological CaMKII inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — electrophysiology in both neurons and heterologous cells plus biochemical CaMKII activity assay, single lab, multiple orthogonal methods","pmids":["28137877"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Whole-cell voltage-clamp electrophysiology in heterologous expression system; immunohistochemistry; compartmental computational neuron modeling","journal":"Biological psychiatry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro electrophysiology of 11 variants with computational modeling, single lab, multiple orthogonal methods","pmids":["28256214"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Immunofluorescence co-localization in mouse brain sections at postnatal day 15; multiple interneuron marker antibodies","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct immunofluorescence localization with multiple cell-type markers, single lab, single method","pmids":["28784306"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Conditional and constitutive Scn2a knockout mouse models; in vivo EEG recording; ethosuximide pharmacology; cell-type-specific Cre-mediated deletion; immunohistochemistry","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via conditional cell-type-specific knockouts with in vivo EEG, multiple mouse lines, pharmacological validation","pmids":["30175250"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Conditional Scn2a knockout in mice; whole-cell patch-clamp of pyramidal neurons; dendritic recordings; cell-autonomous sparse deletion; synaptic plasticity assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-autonomous conditional KO with direct dendritic electrophysiology and plasticity measurements, multiple approaches","pmids":["31230762"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Voltage-clamp electrophysiology in HEK cells; Xenopus oocyte expression; Nav-beta4 peptide resurgent current assay; surface expression measurement","journal":"eNeuro","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with multiple assay types (conventional, resurgent, gating pore) in two expression systems, single lab","pmids":["31558572"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Site-directed mutagenesis in neonatal and adult Nav1.2 splice isoforms; whole-cell voltage-clamp in transfected cells; compartmental neuron modeling","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological comparison of variants in two isoforms with computational modeling, single lab, multiple orthogonal methods","pmids":["31995133"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Knock-in mouse model expressing only adult Nav1.2 isoform; whole-cell patch-clamp of cortical pyramidal neurons; in vivo seizure threshold testing","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse with direct neuronal electrophysiology and in vivo seizure assay, multiple phenotypic readouts","pmids":["25378553"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Genetic crosses between Scn2aQ54 transgenic and two independent Kcnq2 mutant mouse lines; in vivo seizure monitoring and survival analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis confirmed with two independent Kcnq2 alleles, clear double-mutant phenotype","pmids":["16464983"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Transgenic alteration of Cacna1g expression in Scn2aQ54 mice; in vivo seizure frequency monitoring","journal":"Epilepsia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with transgenic lines in both directions, single lab","pmids":["27112236"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Conditional Scn2a knockout in granule cells; patch-clamp recording; GABA release measurement; olfactory behavioral assay","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with direct electrophysiology, neurotransmitter release measurement, and behavioral readout","pmids":["30125271"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Scn2a+/- mice; whole-cell patch-clamp; LTP recording in hippocampal slices; behavioral tests (Morris water maze, fear conditioning)","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — heterozygous KO with direct neuronal electrophysiology, LTP, and behavioral assays, single lab multiple methods","pmids":["31249508"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Single-cell transcriptomics paired with whole-cell patch-clamp recordings; conditional SCN2A deletion in OLs; lineage marker analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-cell transcriptomics combined with direct electrophysiology and conditional gene deletion, multiple orthogonal approaches","pmids":["34496232"],"is_preprint":false},{"year":2021,"finding":"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.","method":"ASO intracerebroventricular delivery in transgenic mouse model; seizure monitoring; behavioral testing; lifespan analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function rescue with ASO with multiple behavioral and electrophysiological endpoints, clear mechanistic link","pmids":["34850743"],"is_preprint":false},{"year":2021,"finding":"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.","method":"CRISPR-generated mouse model; patch-clamp in heterologous cells, neuronal cultures, and brain slices; cell-type specific analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR knock-in mouse with electrophysiology in multiple systems (heterologous, neuronal culture, brain slice), single lab with orthogonal approaches","pmids":["34156984"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Site-directed mutagenesis; whole-cell patch-clamp in HEK293T cells co-expressing beta1 and beta2 subunits; comparison of neonatal and adult splice isoforms","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with isoform comparison and multiple voltage-clamp protocols, single lab, mechanistically rigorous","pmids":["34287911"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Conditional Ank2 knockout in neocortical neurons; whole-cell patch-clamp dendritic recordings; immunofluorescence co-localization; comparison with Scn2a+/- phenotypes","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with direct dendritic electrophysiology and imaging, phenotypic comparison across two gene models, single lab multiple methods","pmids":["38290518"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Conditional Scn2a haploinsufficiency in granule cells; VOR measurement in humans and mice; cerebellar electrophysiology; CRISPR-activator rescue","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with direct synaptic electrophysiology, behavioral VOR measurement, and CRISPR rescue, multiple orthogonal approaches","pmids":["38412857"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Scn2a-deficient mouse model; microglial ablation with PLX3397; confocal imaging of synaptic markers; electrophysiology; human cerebral organoids with SCN2A mutation; complement pathway analysis","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with pharmacological rescue, extended to human organoid model, multiple orthogonal methods including electrophysiology and imaging","pmids":["38499656"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Molecular dynamics simulation; patch-clamp electrophysiology; dynamic action potential clamp; site-directed mutagenesis of N1662 and Q1494 residues","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-function study combining molecular dynamics with mutagenesis at two residues and functional validation by electrophysiology, multiple orthogonal approaches","pmids":["38939966"],"is_preprint":false},{"year":2025,"finding":"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.","method":"AAV-delivered CRISPRa in Scn2a+/- mice; whole-cell patch-clamp of neocortical pyramidal cells; chemoconvulsant seizure threshold assay; human iPSC-derived neuron electrophysiology","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo AAV-CRISPRa rescue with direct electrophysiology in mice and human iPSC neurons, multiple endpoints, cross-species validation","pmids":["40963013"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Patch-clamp electrophysiology in HEK293T and COS-7 cells; pharmacological receptor antagonist controls; site-directed mutagenesis of IV-S6 domain residues","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with mutagenesis of drug binding site, receptor-independence confirmed in sigma-1 negative cells, single lab","pmids":["23139844"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Two-electrode voltage-clamp in Xenopus oocytes expressing Nav1.2 with beta1 subunit","journal":"Anesthesia and analgesia","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro electrophysiology but single lab, single expression system","pmids":["24557103"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Gene-trap Scn2a-deficient mice; brain region-specific Cre-mediated deletion; EEG/EMG sleep analysis; patch-clamp of SCN neurons; RNA sequencing","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with direct neuronal electrophysiology and transcriptomics, single lab, links Nav1.2 to SCN firing and sleep","pmids":["35301122"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Scn2aK1422E knock-in mice; whole-cell patch-clamp of cortical neurons and slices; calcium imaging; compartmental neuron modeling; in vivo EEG","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model with direct neuronal patch-clamp, calcium imaging, and computational modeling, multiple orthogonal methods","pmids":["35417922"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Patient iPSC-derived early-stage cortical neurons; patch-clamp electrophysiology; Western blot; RT-PCR; single-cell transcriptomics","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived neurons with electrophysiology, protein quantification, and transcriptomics, distinguishes ID vs epilepsy variants mechanistically","pmids":["37010102"],"is_preprint":false}],"current_model":"SCN2A encodes the voltage-gated sodium channel Nav1.2, which initiates and propagates action potentials in excitatory neurons and select interneurons; Nav1.2 is scaffolded to the axon initial segment and dendritic membrane via ankyrin-B, regulated by CaMKII (which enhances persistent current and depolarizes inactivation) and GSK3β (which phosphorylates T1966 in the C-terminal tail to suppress surface expression and channel activity), and modulated by FGF12 and FGF14 at the axon initial segment; fast inactivation depends critically on a hydrogen bond between N1662 and Q1494; gain-of-function variants that increase persistent or resurgent current, slow inactivation, or expand ion permeability cause neonatal/infantile-onset epileptic encephalopathy, while loss-of-function variants cause reduced neuronal excitability, impaired dendritic backpropagation, synaptic depression, and LTP deficits associated with autism spectrum disorder and intellectual disability; haploinsufficiency specifically in excitatory neurons drives absence-like seizures, while Nav1.2 in cerebellar granule cells is required for LTP and VOR gain modulation, and Nav1.2 in oligodendrocyte precursors is required for their spiking and maturation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2001,"claim":"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","pmids":["11166117"],"confidence":"High","gaps":["Did not address developmental timing of vulnerability","Single engineered mutation rather than patient variants"]},{"year":2003,"claim":"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","pmids":["12610651"],"confidence":"Low","gaps":["No functional electrophysiology follow-up","Single binding assay, single report","Physiological consequence of altered CaM binding unestablished"]},{"year":2004,"claim":"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","pmids":["14761957","15028761"],"confidence":"High","gaps":["beta1-ankyrinG mechanism not tested in neurons","Native scaffold composition at AIS not resolved"]},{"year":2005,"claim":"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","pmids":["15760941"],"confidence":"High","gaps":["Functional division of labor in intact axon not addressed","Single neuronal expression system"]},{"year":2006,"claim":"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","pmids":["16464983"],"confidence":"High","gaps":["Molecular mechanism of channel interaction not defined","Limited to engineered alleles"]},{"year":2009,"claim":"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","pmids":["19465131"],"confidence":"High","gaps":["Direct binding interface with Nav1.2 not mapped","Isoform-specific physiological role in vivo not tested"]},{"year":2014,"claim":"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","pmids":["25378553"],"confidence":"High","gaps":["Molecular basis of isoform excitability difference not defined","Regulation of the developmental splice switch unknown"]},{"year":2015,"claim":"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","pmids":["25615535","25724910"],"confidence":"High","gaps":["Upstream signals controlling these kinases in vivo not defined","Interplay between GSK3, CaMKII and FGF regulation not integrated"]},{"year":2017,"claim":"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","pmids":["28137877","28256214","28784306"],"confidence":"High","gaps":["Variant classification rests on heterologous systems and modeling","In vivo CaMKII contribution to human disease not established"]},{"year":2018,"claim":"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","pmids":["30175250"],"confidence":"High","gaps":["Circuit basis of spike-and-wave discharges not fully mapped","Trigger for axonal redistribution unknown"]},{"year":2019,"claim":"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","pmids":["31230762","31249508"],"confidence":"High","gaps":["Link between dendritic excitability loss and behavioral deficits not fully causal","Reversibility in adults addressed only later"]},{"year":2019,"claim":"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","pmids":["31558572"],"confidence":"High","gaps":["Neuronal consequences of gating pore current not measured","Heterologous-system limitations"]},{"year":2020,"claim":"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","pmids":["31995133"],"confidence":"High","gaps":["In vivo validation in isoform-specific models lacking","Limited variant set"]},{"year":2021,"claim":"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","pmids":["30125271","34496232","34156984","34850743","34287911"],"confidence":"High","gaps":["Mechanism of Nav1.2 in OL maturation not defined","ASO durability and translatability not established"]},{"year":2022,"claim":"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","pmids":["35301122","35417922"],"confidence":"Medium","gaps":["SCN role rests on region-specific deletion, not pure SCN","Ion-permeability mechanism studied in one variant"]},{"year":2023,"claim":"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","pmids":["37010102"],"confidence":"High","gaps":["Early-stage neurons may not capture mature phenotypes","Genotype-phenotype generalization across variants limited"]},{"year":2024,"claim":"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","pmids":["38939966","38290518","38412857","38499656"],"confidence":"High","gaps":["Trigger linking Nav1.2 loss to complement activation not defined","Generality of microglial pruning across brain regions unclear"]},{"year":2025,"claim":"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","pmids":["40963013"],"confidence":"High","gaps":["Long-term safety and durability not established","Applicability to gain-of-function disease not addressed"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,4,14,33]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,6,7,12,19,25]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[13,19,20,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,10,14,33,34]}],"complexes":[],"partners":["SCN1B","FGF12","FGF14","ANK2","ANK3","CALM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99250","full_name":"Sodium channel protein type 2 subunit alpha","aliases":["HBSC II","Sodium channel protein brain II subunit alpha","Sodium channel protein type II subunit alpha","Voltage-gated sodium channel subunit alpha Nav1.2"],"length_aa":2005,"mass_kda":228.0,"function":"Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:1325650, PubMed:17021166, PubMed:28256214, PubMed:29844171). Implicated in the regulation of hippocampal replay occurring within sharp wave ripples (SPW-R) important for memory (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q99250/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCN2A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SCN2A","total_profiled":1310},"omim":[{"mim_id":"618924","title":"EPISODIC ATAXIA, TYPE 9; EA9","url":"https://www.omim.org/entry/618924"},{"mim_id":"617935","title":"EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 4; FFEVF4","url":"https://www.omim.org/entry/617935"},{"mim_id":"617350","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 52; DEE52","url":"https://www.omim.org/entry/617350"},{"mim_id":"615828","title":"VULTO-VAN SILFHOUT-DE VRIES SYNDROME; VSVS","url":"https://www.omim.org/entry/615828"},{"mim_id":"613721","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 11; DEE11","url":"https://www.omim.org/entry/613721"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":67.0}],"url":"https://www.proteinatlas.org/search/SCN2A"},"hgnc":{"alias_symbol":["Nav1.2","HBSCII","HBSCI"],"prev_symbol":["SCN2A1","SCN2A2"]},"alphafold":{"accession":"Q99250","domains":[{"cath_id":"-","chopping":"20-35_53-216","consensus_level":"medium","plddt":80.1392,"start":20,"end":216},{"cath_id":"1.10.287.70","chopping":"248-273_367-454","consensus_level":"medium","plddt":84.2002,"start":248,"end":454},{"cath_id":"-","chopping":"276-284_314-339_351-366","consensus_level":"medium","plddt":85.0988,"start":276,"end":366},{"cath_id":"1.20.120.350","chopping":"737-864","consensus_level":"high","plddt":82.3405,"start":737,"end":864},{"cath_id":"1.20.120.350","chopping":"1208-1319","consensus_level":"high","plddt":85.0405,"start":1208,"end":1319},{"cath_id":"1.10.287.70","chopping":"1321-1364_1402-1489","consensus_level":"medium","plddt":85.4412,"start":1321,"end":1489},{"cath_id":"1.20.120.350","chopping":"1525-1606_1613-1632","consensus_level":"medium","plddt":82.7199,"start":1525,"end":1632},{"cath_id":"1.10.287,1.20.1440","chopping":"1646-1788","consensus_level":"medium","plddt":84.1187,"start":1646,"end":1788},{"cath_id":"1.10.238.10","chopping":"1789-1911","consensus_level":"medium","plddt":75.2594,"start":1789,"end":1911}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99250","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99250-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99250-F1-predicted_aligned_error_v6.png","plddt_mean":68.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCN2A","jax_strain_url":"https://www.jax.org/strain/search?query=SCN2A"},"sequence":{"accession":"Q99250","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99250.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99250/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99250"}},"corpus_meta":[{"pmid":"28379373","id":"PMC_28379373","title":"Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.","date":"2017","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28379373","citation_count":432,"is_preprint":false},{"pmid":"15148385","id":"PMC_15148385","title":"Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15148385","citation_count":365,"is_preprint":false},{"pmid":"29691040","id":"PMC_29691040","title":"Progress in Understanding and Treating SCN2A-Mediated Disorders.","date":"2018","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/29691040","citation_count":261,"is_preprint":false},{"pmid":"12610651","id":"PMC_12610651","title":"Sodium channels SCN1A, SCN2A and SCN3A in familial autism.","date":"2003","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/12610651","citation_count":229,"is_preprint":false},{"pmid":"28256214","id":"PMC_28256214","title":"Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures.","date":"2017","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/28256214","citation_count":219,"is_preprint":false},{"pmid":"15760941","id":"PMC_15760941","title":"Electrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed in mouse spinal sensory neurones.","date":"2005","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15760941","citation_count":218,"is_preprint":false},{"pmid":"26291284","id":"PMC_26291284","title":"SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures.","date":"2015","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26291284","citation_count":193,"is_preprint":false},{"pmid":"31230762","id":"PMC_31230762","title":"The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex.","date":"2019","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/31230762","citation_count":189,"is_preprint":false},{"pmid":"11166117","id":"PMC_11166117","title":"A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities.","date":"2001","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11166117","citation_count":187,"is_preprint":false},{"pmid":"15028761","id":"PMC_15028761","title":"A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline.","date":"2004","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15028761","citation_count":159,"is_preprint":false},{"pmid":"23935176","id":"PMC_23935176","title":"Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome.","date":"2013","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23935176","citation_count":158,"is_preprint":false},{"pmid":"20956790","id":"PMC_20956790","title":"SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain.","date":"2010","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20956790","citation_count":124,"is_preprint":false},{"pmid":"19465131","id":"PMC_19465131","title":"FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels.","date":"2009","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/19465131","citation_count":113,"is_preprint":false},{"pmid":"14761957","id":"PMC_14761957","title":"Sodium channel beta1 subunit-mediated modulation of Nav1.2 currents and cell surface density is dependent on interactions with contactin and ankyrin.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14761957","citation_count":100,"is_preprint":false},{"pmid":"31904126","id":"PMC_31904126","title":"Phenotypic spectrum and genetics of SCN2A-related disorders, treatment options, and outcomes in epilepsy and beyond.","date":"2019","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/31904126","citation_count":95,"is_preprint":false},{"pmid":"30175250","id":"PMC_30175250","title":"Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice.","date":"2018","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/30175250","citation_count":86,"is_preprint":false},{"pmid":"22029951","id":"PMC_22029951","title":"Clinical spectrum of SCN2A mutations.","date":"2011","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/22029951","citation_count":85,"is_preprint":false},{"pmid":"19783390","id":"PMC_19783390","title":"Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome.","date":"2009","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/19783390","citation_count":85,"is_preprint":false},{"pmid":"34850743","id":"PMC_34850743","title":"Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34850743","citation_count":85,"is_preprint":false},{"pmid":"17386050","id":"PMC_17386050","title":"SCN2A mutations and benign familial neonatal-infantile seizures: the phenotypic spectrum.","date":"2007","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/17386050","citation_count":84,"is_preprint":false},{"pmid":"18784617","id":"PMC_18784617","title":"Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression.","date":"2008","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18784617","citation_count":80,"is_preprint":false},{"pmid":"18479388","id":"PMC_18479388","title":"Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures.","date":"2008","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/18479388","citation_count":78,"is_preprint":false},{"pmid":"26645390","id":"PMC_26645390","title":"Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia.","date":"2015","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26645390","citation_count":74,"is_preprint":false},{"pmid":"19694741","id":"PMC_19694741","title":"Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population.","date":"2009","source":"British journal of clinical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19694741","citation_count":68,"is_preprint":false},{"pmid":"30962870","id":"PMC_30962870","title":"Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity.","date":"2019","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/30962870","citation_count":67,"is_preprint":false},{"pmid":"25378553","id":"PMC_25378553","title":"'Neonatal' Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25378553","citation_count":63,"is_preprint":false},{"pmid":"16417554","id":"PMC_16417554","title":"A novel SCN2A mutation in family with benign familial infantile seizures.","date":"2006","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/16417554","citation_count":61,"is_preprint":false},{"pmid":"16464983","id":"PMC_16464983","title":"Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2.","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16464983","citation_count":61,"is_preprint":false},{"pmid":"24579881","id":"PMC_24579881","title":"Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.","date":"2014","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/24579881","citation_count":58,"is_preprint":false},{"pmid":"30813884","id":"PMC_30813884","title":"Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes.","date":"2019","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/30813884","citation_count":55,"is_preprint":false},{"pmid":"23859570","id":"PMC_23859570","title":"SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis.","date":"2013","source":"Pharmacogenomics","url":"https://pubmed.ncbi.nlm.nih.gov/23859570","citation_count":52,"is_preprint":false},{"pmid":"33731876","id":"PMC_33731876","title":"Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A-related disorders.","date":"2021","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33731876","citation_count":51,"is_preprint":false},{"pmid":"31249508","id":"PMC_31249508","title":"Scn2a Haploinsufficiency in Mice Suppresses Hippocampal Neuronal Excitability, Excitatory Synaptic Drive, and Long-Term Potentiation, and Spatial Learning and Memory.","date":"2019","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31249508","citation_count":51,"is_preprint":false},{"pmid":"25724910","id":"PMC_25724910","title":"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.","date":"2015","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/25724910","citation_count":51,"is_preprint":false},{"pmid":"24650168","id":"PMC_24650168","title":"De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.","date":"2014","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24650168","citation_count":51,"is_preprint":false},{"pmid":"16293367","id":"PMC_16293367","title":"Comparison of the effects of four Na+ channel analgesics on TTX-resistant Na+ currents in rat sensory neurons and recombinant Nav1.2 channels.","date":"2005","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/16293367","citation_count":50,"is_preprint":false},{"pmid":"38499656","id":"PMC_38499656","title":"Microglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids.","date":"2024","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/38499656","citation_count":46,"is_preprint":false},{"pmid":"31995133","id":"PMC_31995133","title":"Alternative splicing potentiates dysfunction of early-onset epileptic encephalopathy SCN2A variants.","date":"2020","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31995133","citation_count":46,"is_preprint":false},{"pmid":"28784306","id":"PMC_28784306","title":"Nav1.2 is expressed in caudal ganglionic eminence-derived disinhibitory interneurons: Mutually exclusive distributions of Nav1.1 and Nav1.2.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28784306","citation_count":44,"is_preprint":false},{"pmid":"23550958","id":"PMC_23550958","title":"Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings.","date":"2013","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/23550958","citation_count":44,"is_preprint":false},{"pmid":"28334922","id":"PMC_28334922","title":"Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP).","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28334922","citation_count":43,"is_preprint":false},{"pmid":"25615535","id":"PMC_25615535","title":"The Nav1.2 channel is regulated by GSK3.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25615535","citation_count":42,"is_preprint":false},{"pmid":"26555645","id":"PMC_26555645","title":"Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation.","date":"2016","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26555645","citation_count":42,"is_preprint":false},{"pmid":"34716231","id":"PMC_34716231","title":"Hyperexcitability and Pharmacological Responsiveness of Cortical Neurons Derived from Human iPSCs Carrying Epilepsy-Associated Sodium Channel Nav1.2-L1342P Genetic Variant.","date":"2021","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34716231","citation_count":40,"is_preprint":false},{"pmid":"25155934","id":"PMC_25155934","title":"Association of SCN1A, SCN2A and ABCC2 gene polymorphisms with the response to antiepileptic drugs in Chinese Han patients with epilepsy.","date":"2014","source":"Pharmacogenomics","url":"https://pubmed.ncbi.nlm.nih.gov/25155934","citation_count":40,"is_preprint":false},{"pmid":"37578743","id":"PMC_37578743","title":"Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties.","date":"2023","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37578743","citation_count":39,"is_preprint":false},{"pmid":"31904120","id":"PMC_31904120","title":"SCN2A channelopathies: Mechanisms and models.","date":"2019","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/31904120","citation_count":39,"is_preprint":false},{"pmid":"38290518","id":"PMC_38290518","title":"Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites.","date":"2024","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/38290518","citation_count":38,"is_preprint":false},{"pmid":"31558572","id":"PMC_31558572","title":"Resurgent and Gating Pore Currents Induced by De Novo SCN2A Epilepsy Mutations.","date":"2019","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/31558572","citation_count":38,"is_preprint":false},{"pmid":"16753259","id":"PMC_16753259","title":"Expression of sodium channels Nav1.2 and Nav1.6 during postnatal development of the retina.","date":"2006","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/16753259","citation_count":38,"is_preprint":false},{"pmid":"27112236","id":"PMC_27112236","title":"Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a.","date":"2016","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/27112236","citation_count":38,"is_preprint":false},{"pmid":"28137877","id":"PMC_28137877","title":"CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28137877","citation_count":37,"is_preprint":false},{"pmid":"31501495","id":"PMC_31501495","title":"NaV1.2 haploinsufficiency in Scn2a knock-out mice causes an autistic-like phenotype attenuated with age.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31501495","citation_count":36,"is_preprint":false},{"pmid":"33369088","id":"PMC_33369088","title":"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.","date":"2021","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/33369088","citation_count":36,"is_preprint":false},{"pmid":"11245985","id":"PMC_11245985","title":"Genomic structures of SCN2A and SCN3A - candidate genes for deafness at the DFNA16 locus.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11245985","citation_count":36,"is_preprint":false},{"pmid":"12941467","id":"PMC_12941467","title":"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.","date":"2003","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12941467","citation_count":35,"is_preprint":false},{"pmid":"38651838","id":"PMC_38651838","title":"Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.","date":"2024","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38651838","citation_count":34,"is_preprint":false},{"pmid":"2571571","id":"PMC_2571571","title":"Localization of a human brain sodium channel gene (SCN2A) to chromosome 2.","date":"1989","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/2571571","citation_count":34,"is_preprint":false},{"pmid":"30144217","id":"PMC_30144217","title":"Relationship of electrophysiological dysfunction and clinical severity in SCN2A-related epilepsies.","date":"2018","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/30144217","citation_count":33,"is_preprint":false},{"pmid":"23827426","id":"PMC_23827426","title":"SCN2A mutation is associated with infantile spasms and bitemporal glucose hypometabolism.","date":"2013","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23827426","citation_count":32,"is_preprint":false},{"pmid":"30361185","id":"PMC_30361185","title":"Lacosamide for SCN2A-related intractable neonatal and infantile seizures.","date":"2018","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/30361185","citation_count":32,"is_preprint":false},{"pmid":"35637276","id":"PMC_35637276","title":"Functional correlates of clinical phenotype and severity in recurrent SCN2A variants.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35637276","citation_count":31,"is_preprint":false},{"pmid":"24337656","id":"PMC_24337656","title":"Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy.","date":"2013","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24337656","citation_count":31,"is_preprint":false},{"pmid":"35301122","id":"PMC_35301122","title":"Deficiency of autism-related Scn2a gene in mice disrupts sleep patterns and circadian rhythms.","date":"2022","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/35301122","citation_count":30,"is_preprint":false},{"pmid":"32264956","id":"PMC_32264956","title":"SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells?","date":"2020","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/32264956","citation_count":30,"is_preprint":false},{"pmid":"26189305","id":"PMC_26189305","title":"ABCB1, ABCC2, SCN1A, SCN2A, GABRA1 gene polymorphisms and drug resistant epilepsy in the Chinese Han population.","date":"2015","source":"Die Pharmazie","url":"https://pubmed.ncbi.nlm.nih.gov/26189305","citation_count":30,"is_preprint":false},{"pmid":"24718902","id":"PMC_24718902","title":"Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals.","date":"2014","source":"JAMA psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/24718902","citation_count":30,"is_preprint":false},{"pmid":"11738931","id":"PMC_11738931","title":"The voltage-gated sodium channel gene SCN2A and idiopathic generalized epilepsy.","date":"2001","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/11738931","citation_count":29,"is_preprint":false},{"pmid":"26311622","id":"PMC_26311622","title":"Missense mutations in sodium channel SCN1A and SCN2A predispose children to encephalopathy with severe febrile seizures.","date":"2015","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/26311622","citation_count":29,"is_preprint":false},{"pmid":"35417922","id":"PMC_35417922","title":"Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35417922","citation_count":28,"is_preprint":false},{"pmid":"38412857","id":"PMC_38412857","title":"Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A-associated ASD.","date":"2024","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/38412857","citation_count":25,"is_preprint":false},{"pmid":"34156984","id":"PMC_34156984","title":"Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34156984","citation_count":25,"is_preprint":false},{"pmid":"30125271","id":"PMC_30125271","title":"Axonal sodium channel NaV1.2 drives granule cell dendritic GABA release and rapid odor discrimination.","date":"2018","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/30125271","citation_count":25,"is_preprint":false},{"pmid":"34496232","id":"PMC_34496232","title":"SCN2A contributes to oligodendroglia excitability and development in the mammalian brain.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34496232","citation_count":25,"is_preprint":false},{"pmid":"17544618","id":"PMC_17544618","title":"Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncoding sequences.","date":"2007","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17544618","citation_count":25,"is_preprint":false},{"pmid":"24557103","id":"PMC_24557103","title":"The endocannabinoid anandamide inhibits voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 in Xenopus oocytes.","date":"2014","source":"Anesthesia and analgesia","url":"https://pubmed.ncbi.nlm.nih.gov/24557103","citation_count":24,"is_preprint":false},{"pmid":"26259688","id":"PMC_26259688","title":"MicroRNA-9 induces defective trafficking of Nav1.1 and Nav1.2 by targeting Navβ2 protein coding region in rat with chronic brain hypoperfusion.","date":"2015","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/26259688","citation_count":24,"is_preprint":false},{"pmid":"30693367","id":"PMC_30693367","title":"SCN1A and SCN2A polymorphisms are associated with response to valproic acid in Chinese epilepsy patients.","date":"2019","source":"European journal of clinical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30693367","citation_count":23,"is_preprint":false},{"pmid":"16815341","id":"PMC_16815341","title":"Immunolocalization of NaV1.2 channel subtypes in rat and cat brain and spinal cord with high affinity antibodies.","date":"2006","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/16815341","citation_count":21,"is_preprint":false},{"pmid":"29625812","id":"PMC_29625812","title":"SCN2A mutation in an infant presenting with migrating focal seizures and infantile spasm responsive to a ketogenic diet.","date":"2018","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/29625812","citation_count":21,"is_preprint":false},{"pmid":"23139844","id":"PMC_23139844","title":"Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23139844","citation_count":20,"is_preprint":false},{"pmid":"36378391","id":"PMC_36378391","title":"LncRNA PVT1 Promotes Neuronal Cell Apoptosis and Neuroinflammation by Regulating miR-488-3p/FOXD3/SCN2A Axis in Epilepsy.","date":"2022","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/36378391","citation_count":19,"is_preprint":false},{"pmid":"18031550","id":"PMC_18031550","title":"Scn2a sodium channel mutation results in hyperexcitability in the hippocampus in vitro.","date":"2007","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/18031550","citation_count":19,"is_preprint":false},{"pmid":"25459969","id":"PMC_25459969","title":"SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet.","date":"2014","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/25459969","citation_count":18,"is_preprint":false},{"pmid":"37010102","id":"PMC_37010102","title":"Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons.","date":"2023","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37010102","citation_count":17,"is_preprint":false},{"pmid":"31297029","id":"PMC_31297029","title":"Effects of GRM4, SCN2A and SCN3B polymorphisms on antiepileptic drugs responsiveness and epilepsy susceptibility.","date":"2019","source":"Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society","url":"https://pubmed.ncbi.nlm.nih.gov/31297029","citation_count":17,"is_preprint":false},{"pmid":"32845893","id":"PMC_32845893","title":"Variable patterns of mutation density among NaV1.1, NaV1.2 and NaV1.6 point to channel-specific functional differences associated with childhood epilepsy.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32845893","citation_count":17,"is_preprint":false},{"pmid":"25457084","id":"PMC_25457084","title":"A case of recurrent encephalopathy with SCN2A missense mutation.","date":"2014","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/25457084","citation_count":17,"is_preprint":false},{"pmid":"40963013","id":"PMC_40963013","title":"CRISPR activation for SCN2A-related neurodevelopmental disorders.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/40963013","citation_count":16,"is_preprint":false},{"pmid":"33000761","id":"PMC_33000761","title":"The phenotype and treatment of SCN2A-related developmental and epileptic encephalopathy.","date":"2020","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/33000761","citation_count":16,"is_preprint":false},{"pmid":"32400968","id":"PMC_32400968","title":"Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy.","date":"2020","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32400968","citation_count":16,"is_preprint":false},{"pmid":"32750235","id":"PMC_32750235","title":"Functional and pharmacological evaluation of a novel SCN2A variant linked to early-onset epilepsy.","date":"2020","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32750235","citation_count":16,"is_preprint":false},{"pmid":"38148154","id":"PMC_38148154","title":"Distinctive In Vitro Phenotypes in iPSC-Derived Neurons From Patients With Gain- and Loss-of-Function SCN2A Developmental and Epileptic Encephalopathy.","date":"2024","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38148154","citation_count":15,"is_preprint":false},{"pmid":"30741786","id":"PMC_30741786","title":"Understanding the schizophrenia phenotype in the first patient with the full SCN2A phenotypic spectrum.","date":"2019","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30741786","citation_count":15,"is_preprint":false},{"pmid":"30415926","id":"PMC_30415926","title":"Ketogenic diet as a successful early treatment modality for SCN2A mutation.","date":"2018","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/30415926","citation_count":15,"is_preprint":false},{"pmid":"38939966","id":"PMC_38939966","title":"Nav1.2 channel mutations preventing fast inactivation lead to SCN2A encephalopathy.","date":"2025","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38939966","citation_count":14,"is_preprint":false},{"pmid":"39557580","id":"PMC_39557580","title":"Human IPSC-Derived Microglia Sense and Dampen Hyperexcitability of Cortical Neurons Carrying the Epilepsy-Associated SCN2A-L1342P Mutation.","date":"2025","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39557580","citation_count":14,"is_preprint":false},{"pmid":"34287911","id":"PMC_34287911","title":"Enhanced slow inactivation contributes to dysfunction of a recurrent SCN2A mutation associated with developmental and epileptic encephalopathy.","date":"2021","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34287911","citation_count":14,"is_preprint":false},{"pmid":"31205438","id":"PMC_31205438","title":"Biallelic SCN2A Gene Mutation Causing Early Infantile Epileptic Encephalopathy: Case Report and Review.","date":"2019","source":"Journal of central nervous system disease","url":"https://pubmed.ncbi.nlm.nih.gov/31205438","citation_count":13,"is_preprint":false},{"pmid":"30165711","id":"PMC_30165711","title":"Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development.","date":"2018","source":"Neuropediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/30165711","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51265,"output_tokens":8860,"usd":0.143347,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18989,"output_tokens":5358,"usd":0.114447,"stage2_stop_reason":"end_turn"},"total_usd":0.257794,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Xenopus oocyte expression + whole-cell patch-clamp; transgenic mouse model with in vivo EEG and neuronal recording\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with functional assay in oocytes replicated in transgenic mouse model with direct neuronal recording\",\n      \"pmids\": [\"11166117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Triple-labeled fluorescent immunocytochemistry in human MS tissue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization in human tissue, replicated across multiple MS cases, but single method (immunocytochemistry)\",\n      \"pmids\": [\"15148385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp electrophysiology in HEK293 cells; subcellular localization analysis\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — heterologous expression with patch-clamp and localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"15028761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, membrane biotinylation, whole-cell patch-clamp, beta1/beta2 chimeric subunit analysis in transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (Co-IP, biochemical surface expression, electrophysiology, mutagenesis) in a single rigorous study\",\n      \"pmids\": [\"14761957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology in mammalian neuronal expression system, direct comparison of Nav1.2 vs Nav1.6\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro electrophysiology with direct head-to-head comparison of the two channels in neuronal cells, single lab but multiple voltage-clamp protocols\",\n      \"pmids\": [\"15760941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Calmodulin binding assay (variant found in autism family screening)\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single binding assay, single report, no functional electrophysiology follow-up\",\n      \"pmids\": [\"12610651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-expression in heterologous cells with patch-clamp electrophysiology; confocal microscopy of neuronal localization; FGF14 N-terminus deletion constructs\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology and direct imaging with mutagenesis, two orthogonal methods, single lab\",\n      \"pmids\": [\"19465131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Affinity purification from brain + mass spectrometry; co-immunoprecipitation in heterologous cells; confocal microscopy; patch-clamp electrophysiology\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (affinity purification/MS, Co-IP, imaging, electrophysiology), single lab\",\n      \"pmids\": [\"25724910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mass spectrometry identification of phosphosite, complemented by electrophysiology and surface expression assays, single lab multiple methods\",\n      \"pmids\": [\"25615535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp of hippocampal neurons and heterologous Nav1.2; CaMKII activity assay in brain lysates; pharmacological CaMKII inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology in both neurons and heterologous cells plus biochemical CaMKII activity assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28137877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell voltage-clamp electrophysiology in heterologous expression system; immunohistochemistry; compartmental computational neuron modeling\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro electrophysiology of 11 variants with computational modeling, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28256214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence co-localization in mouse brain sections at postnatal day 15; multiple interneuron marker antibodies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct immunofluorescence localization with multiple cell-type markers, single lab, single method\",\n      \"pmids\": [\"28784306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional and constitutive Scn2a knockout mouse models; in vivo EEG recording; ethosuximide pharmacology; cell-type-specific Cre-mediated deletion; immunohistochemistry\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via conditional cell-type-specific knockouts with in vivo EEG, multiple mouse lines, pharmacological validation\",\n      \"pmids\": [\"30175250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Scn2a knockout in mice; whole-cell patch-clamp of pyramidal neurons; dendritic recordings; cell-autonomous sparse deletion; synaptic plasticity assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-autonomous conditional KO with direct dendritic electrophysiology and plasticity measurements, multiple approaches\",\n      \"pmids\": [\"31230762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Voltage-clamp electrophysiology in HEK cells; Xenopus oocyte expression; Nav-beta4 peptide resurgent current assay; surface expression measurement\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with multiple assay types (conventional, resurgent, gating pore) in two expression systems, single lab\",\n      \"pmids\": [\"31558572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis in neonatal and adult Nav1.2 splice isoforms; whole-cell voltage-clamp in transfected cells; compartmental neuron modeling\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological comparison of variants in two isoforms with computational modeling, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31995133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Knock-in mouse model expressing only adult Nav1.2 isoform; whole-cell patch-clamp of cortical pyramidal neurons; in vivo seizure threshold testing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse with direct neuronal electrophysiology and in vivo seizure assay, multiple phenotypic readouts\",\n      \"pmids\": [\"25378553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic crosses between Scn2aQ54 transgenic and two independent Kcnq2 mutant mouse lines; in vivo seizure monitoring and survival analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis confirmed with two independent Kcnq2 alleles, clear double-mutant phenotype\",\n      \"pmids\": [\"16464983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Transgenic alteration of Cacna1g expression in Scn2aQ54 mice; in vivo seizure frequency monitoring\",\n      \"journal\": \"Epilepsia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with transgenic lines in both directions, single lab\",\n      \"pmids\": [\"27112236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Scn2a knockout in granule cells; patch-clamp recording; GABA release measurement; olfactory behavioral assay\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with direct electrophysiology, neurotransmitter release measurement, and behavioral readout\",\n      \"pmids\": [\"30125271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Scn2a+/- mice; whole-cell patch-clamp; LTP recording in hippocampal slices; behavioral tests (Morris water maze, fear conditioning)\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — heterozygous KO with direct neuronal electrophysiology, LTP, and behavioral assays, single lab multiple methods\",\n      \"pmids\": [\"31249508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell transcriptomics paired with whole-cell patch-clamp recordings; conditional SCN2A deletion in OLs; lineage marker analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-cell transcriptomics combined with direct electrophysiology and conditional gene deletion, multiple orthogonal approaches\",\n      \"pmids\": [\"34496232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"ASO intracerebroventricular delivery in transgenic mouse model; seizure monitoring; behavioral testing; lifespan analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function rescue with ASO with multiple behavioral and electrophysiological endpoints, clear mechanistic link\",\n      \"pmids\": [\"34850743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-generated mouse model; patch-clamp in heterologous cells, neuronal cultures, and brain slices; cell-type specific analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR knock-in mouse with electrophysiology in multiple systems (heterologous, neuronal culture, brain slice), single lab with orthogonal approaches\",\n      \"pmids\": [\"34156984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis; whole-cell patch-clamp in HEK293T cells co-expressing beta1 and beta2 subunits; comparison of neonatal and adult splice isoforms\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with isoform comparison and multiple voltage-clamp protocols, single lab, mechanistically rigorous\",\n      \"pmids\": [\"34287911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Ank2 knockout in neocortical neurons; whole-cell patch-clamp dendritic recordings; immunofluorescence co-localization; comparison with Scn2a+/- phenotypes\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with direct dendritic electrophysiology and imaging, phenotypic comparison across two gene models, single lab multiple methods\",\n      \"pmids\": [\"38290518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Scn2a haploinsufficiency in granule cells; VOR measurement in humans and mice; cerebellar electrophysiology; CRISPR-activator rescue\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with direct synaptic electrophysiology, behavioral VOR measurement, and CRISPR rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"38412857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Scn2a-deficient mouse model; microglial ablation with PLX3397; confocal imaging of synaptic markers; electrophysiology; human cerebral organoids with SCN2A mutation; complement pathway analysis\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with pharmacological rescue, extended to human organoid model, multiple orthogonal methods including electrophysiology and imaging\",\n      \"pmids\": [\"38499656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Molecular dynamics simulation; patch-clamp electrophysiology; dynamic action potential clamp; site-directed mutagenesis of N1662 and Q1494 residues\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-function study combining molecular dynamics with mutagenesis at two residues and functional validation by electrophysiology, multiple orthogonal approaches\",\n      \"pmids\": [\"38939966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"AAV-delivered CRISPRa in Scn2a+/- mice; whole-cell patch-clamp of neocortical pyramidal cells; chemoconvulsant seizure threshold assay; human iPSC-derived neuron electrophysiology\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo AAV-CRISPRa rescue with direct electrophysiology in mice and human iPSC neurons, multiple endpoints, cross-species validation\",\n      \"pmids\": [\"40963013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp electrophysiology in HEK293T and COS-7 cells; pharmacological receptor antagonist controls; site-directed mutagenesis of IV-S6 domain residues\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with mutagenesis of drug binding site, receptor-independence confirmed in sigma-1 negative cells, single lab\",\n      \"pmids\": [\"23139844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Two-electrode voltage-clamp in Xenopus oocytes expressing Nav1.2 with beta1 subunit\",\n      \"journal\": \"Anesthesia and analgesia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro electrophysiology but single lab, single expression system\",\n      \"pmids\": [\"24557103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Gene-trap Scn2a-deficient mice; brain region-specific Cre-mediated deletion; EEG/EMG sleep analysis; patch-clamp of SCN neurons; RNA sequencing\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with direct neuronal electrophysiology and transcriptomics, single lab, links Nav1.2 to SCN firing and sleep\",\n      \"pmids\": [\"35301122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Scn2aK1422E knock-in mice; whole-cell patch-clamp of cortical neurons and slices; calcium imaging; compartmental neuron modeling; in vivo EEG\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model with direct neuronal patch-clamp, calcium imaging, and computational modeling, multiple orthogonal methods\",\n      \"pmids\": [\"35417922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Patient iPSC-derived early-stage cortical neurons; patch-clamp electrophysiology; Western blot; RT-PCR; single-cell transcriptomics\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived neurons with electrophysiology, protein quantification, and transcriptomics, distinguishes ID vs epilepsy variants mechanistically\",\n      \"pmids\": [\"37010102\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCN2A encodes the voltage-gated sodium channel Nav1.2, which initiates and propagates action potentials in excitatory neurons and select interneurons; Nav1.2 is scaffolded to the axon initial segment and dendritic membrane via ankyrin-B, regulated by CaMKII (which enhances persistent current and depolarizes inactivation) and GSK3β (which phosphorylates T1966 in the C-terminal tail to suppress surface expression and channel activity), and modulated by FGF12 and FGF14 at the axon initial segment; fast inactivation depends critically on a hydrogen bond between N1662 and Q1494; gain-of-function variants that increase persistent or resurgent current, slow inactivation, or expand ion permeability cause neonatal/infantile-onset epileptic encephalopathy, while loss-of-function variants cause reduced neuronal excitability, impaired dendritic backpropagation, synaptic depression, and LTP deficits associated with autism spectrum disorder and intellectual disability; haploinsufficiency specifically in excitatory neurons drives absence-like seizures, while Nav1.2 in cerebellar granule cells is required for LTP and VOR gain modulation, and Nav1.2 in oligodendrocyte precursors is required for their spiking and maturation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#13, #20]. Channel function is shaped by accessory and regulatory partners: the beta1 subunit enhances surface expression in an ankyrinG-dependent manner [#3], FGF12 and FGF14 form complexes at the axon initial segment and modulate current density and gating [#6, #7], and ankyrin-B scaffolds Nav1.2 to the dendritic membrane such that ANK2 haploinsufficiency phenocopies Scn2a loss [#25]. Nav1.2 activity is further tuned by phosphorylation, with CaMKII enhancing persistent current and depolarizing inactivation [#9] and GSK3beta phosphorylating C-terminal T1966 to suppress surface expression and current [#8]. Fast inactivation depends on a hydrogen bond between N1662 and Q1494 [#28], and a developmentally regulated neonatal splice isoform is intrinsically less excitable than the adult isoform, conferring early-life seizure protection [#16]. Disease variants segregate mechanistically: gain-of-function variants that slow inactivation and increase persistent, resurgent, or aberrant ion permeability cause early-onset epileptic encephalopathy [#0, #14, #33], whereas loss-of-function variants that reduce current, protein level, or excitability cause autism and intellectual disability phenotypes [#10, #14, #34], with haploinsufficiency in excitatory neurons driving absence-like seizures and synaptic deficits [#12, #23]. Nav1.2 function extends across cell types beyond cortical excitatory neurons, including cerebellar granule cells where it supports LTP and VOR plasticity [#26], olfactory bulb granule cells [#19], and spiking oligodendrocyte precursors required for their maturation [#21]. 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 [#22, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"S4-S5 linker mutant in Xenopus oocytes plus transgenic mice with EEG and CA1 recording\",\n      \"pmids\": [\"11166117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address developmental timing of vulnerability\", \"Single engineered mutation rather than patient variants\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified calmodulin as a binding partner of Nav1.2 via an autism-associated variant reducing calcium-calmodulin affinity.\",\n      \"evidence\": \"Calmodulin binding assay of the R1902C variant\",\n      \"pmids\": [\"12610651\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional electrophysiology follow-up\", \"Single binding assay, single report\", \"Physiological consequence of altered CaM binding unestablished\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, biotinylation, patch-clamp and chimera/mutant analysis in transfected cells; R102X dominant-negative analysis in HEK293\",\n      \"pmids\": [\"14761957\", \"15028761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"beta1-ankyrinG mechanism not tested in neurons\", \"Native scaffold composition at AIS not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished Nav1.2 biophysics from Nav1.6, showing more depolarized activation, greater inactivation accumulation, and smaller persistent current, rationalizing channel-specific roles.\",\n      \"evidence\": \"Head-to-head whole-cell patch-clamp in mouse spinal sensory neurons\",\n      \"pmids\": [\"15760941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional division of labor in intact axon not addressed\", \"Single neuronal expression system\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic crosses of Scn2aQ54 with two independent Kcnq2 mutant lines, seizure and survival analysis\",\n      \"pmids\": [\"16464983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of channel interaction not defined\", \"Limited to engineered alleles\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed FGF14 isoforms target to the axon initial segment and regulate Nav1.2 current, with the FGF14 N-terminus required for localization and modulation.\",\n      \"evidence\": \"Heterologous co-expression patch-clamp, confocal imaging, N-terminal deletion constructs\",\n      \"pmids\": [\"19465131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface with Nav1.2 not mapped\", \"Isoform-specific physiological role in vivo not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that the neonatal Nav1.2 splice isoform is intrinsically less excitable, providing seizure protection during early brain development.\",\n      \"evidence\": \"Knock-in mice expressing only adult isoform with cortical patch-clamp and seizure threshold testing\",\n      \"pmids\": [\"25378553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of isoform excitability difference not defined\", \"Regulation of the developmental splice switch unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assay/MS, surface labeling, siRNA, and patch-clamp; affinity purification/MS, Co-IP, imaging and electrophysiology\",\n      \"pmids\": [\"25615535\", \"25724910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling these kinases in vivo not defined\", \"Interplay between GSK3, CaMKII and FGF regulation not integrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Neuronal and heterologous patch-clamp with CaMKII assays; 11-variant electrophysiology with computational modeling; interneuron immunofluorescence\",\n      \"pmids\": [\"28137877\", \"28256214\", \"28784306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Variant classification rests on heterologous systems and modeling\", \"In vivo CaMKII contribution to human disease not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional and constitutive Scn2a knockouts, EEG, ethosuximide pharmacology, immunohistochemistry\",\n      \"pmids\": [\"30175250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Circuit basis of spike-and-wave discharges not fully mapped\", \"Trigger for axonal redistribution unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cell-autonomous conditional Scn2a KO with dendritic recordings; Scn2a+/- mice with LTP and behavioral assays\",\n      \"pmids\": [\"31230762\", \"31249508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between dendritic excitability loss and behavioral deficits not fully causal\", \"Reversibility in adults addressed only later\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined biophysical signatures separating gain- from loss-of-function variants, including resurgent and gating pore currents.\",\n      \"evidence\": \"Voltage-clamp in HEK and oocytes with Nav-beta4 resurgent and surface expression assays for R1882Q and R853Q\",\n      \"pmids\": [\"31558572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal consequences of gating pore current not measured\", \"Heterologous-system limitations\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that EOEE variant dysfunction is amplified in the neonatal isoform, explaining the early-onset phenotype.\",\n      \"evidence\": \"Variant electrophysiology in neonatal and adult isoforms with compartmental modeling\",\n      \"pmids\": [\"31995133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation in isoform-specific models lacking\", \"Limited variant set\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"30125271\", \"34496232\", \"34156984\", \"34850743\", \"34287911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Nav1.2 in OL maturation not defined\", \"ASO durability and translatability not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"35301122\", \"35417922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SCN role rests on region-specific deletion, not pure SCN\", \"Ion-permeability mechanism studied in one variant\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Patient iPSC-derived cortical neurons with patch-clamp, Western blot, RT-PCR and single-cell transcriptomics\",\n      \"pmids\": [\"37010102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Early-stage neurons may not capture mature phenotypes\", \"Genotype-phenotype generalization across variants limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"38939966\", \"38290518\", \"38412857\", \"38499656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger linking Nav1.2 loss to complement activation not defined\", \"Generality of microglial pruning across brain regions unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated allele-upregulating CRISPRa rescues electrophysiological and seizure phenotypes in adolescent haploinsufficient mice and in human iPSC neurons, providing a gene-dosage therapeutic strategy.\",\n      \"evidence\": \"AAV-delivered CRISPRa in Scn2a+/- mice with cortical patch-clamp and chemoconvulsant assays plus iPSC-neuron electrophysiology\",\n      \"pmids\": [\"40963013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety and durability not established\", \"Applicability to gain-of-function disease not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 4, 14, 33]},\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [0, 4, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 6, 7, 12, 19, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13, 19, 20, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 10, 14, 33, 34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SCN1B\", \"FGF12\", \"FGF14\", \"ANK2\", \"ANK3\", \"CALM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}