{"gene":"LGI1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1998,"finding":"LGI1 encodes a ~60 kDa secreted protein containing leucine-rich repeats (LRR); the gene is rearranged and its expression is absent in glioblastoma cell lines and malignant gliomas, identifying it as a candidate tumor suppressor.","method":"Positional cloning, translocation mapping, Northern blot/expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — original cloning paper with structural characterization, single lab","pmids":["9879993"],"is_preprint":false},{"year":2002,"finding":"Mutations in LGI1 (including premature stop codons) cause autosomal dominant partial epilepsy with auditory features (ADPEAF/ADLTE), establishing LGI1 as a non-ion-channel epilepsy gene; mouse Lgi1 expression is predominantly neuronal in temporal lobe regions.","method":"Resequencing of candidate genes in ADPEAF families, immunohistochemistry in mouse brain","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — foundational gene discovery paper, replicated across multiple families, >400 citations","pmids":["11810107"],"is_preprint":false},{"year":2002,"finding":"LGI1 mutations introducing premature stop codons (loss of function) segregate with autosomal dominant lateral temporal epilepsy; LGI1 protein is expressed in neuronal cell compartments throughout the brain.","method":"Mutation analysis in ADLTE families, immunohistochemistry","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — independent replication in separate families confirming LOF mechanism","pmids":["11978770"],"is_preprint":false},{"year":2005,"finding":"LGI1 is a secreted protein; ADPEAF-associated mutations (missense and truncating) reduce or abolish secretion of LGI1 from transfected 293T cells, demonstrating loss-of-function as the pathogenic mechanism.","method":"Transfection of wild-type and mutant LGI1 into 293T cells, conditioned medium analysis, Western blot","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro secretion assay with multiple mutants, replicated by multiple subsequent labs","pmids":["15857855"],"is_preprint":false},{"year":2006,"finding":"LGI1 binds ADAM22 (a postsynaptic transmembrane protein) as its receptor; this interaction enhances AMPA receptor-mediated synaptic transmission in hippocampal slices; ADPEAF-mutant LGI1 fails to bind ADAM22; ADAM22 is anchored to the postsynaptic density via stargazin-containing scaffolds.","method":"Co-immunoprecipitation, electrophysiology in hippocampal slices (rat brain), HEK293 cell binding assays, mutant analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, seminal paper, >300 citations, replicated broadly","pmids":["16990550"],"is_preprint":false},{"year":2006,"finding":"Lgi1 assembles into presynaptic Kv1.1-containing potassium channel complexes (with Kv1.4 and Kvβ1) in hippocampal axonal terminals, and selectively prevents N-type (Kvβ1-mediated) inactivation; ADLTE-mutant Lgi1 fails to inhibit inactivation, resulting in channels with rapid inactivation kinetics.","method":"Immunoprecipitation/mass spectrometry from rat brain, electrophysiology, co-expression in HEK cells, mutant analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 — biochemical complex purification + functional electrophysiology + mutagenesis, >240 citations","pmids":["16504945"],"is_preprint":false},{"year":2006,"finding":"LGI1 is expressed as two protein isoforms (~60 and ~65 kDa) in human brain; the long isoform is secreted, whereas the short isoform is retained intracellularly; ADLTE mutants of the long form are retained in the ER and Golgi; secreted LGI1 binds specifically to the cell surface of differentiated PC12 cells.","method":"Western blot, subcellular fractionation, immunofluorescence of transfected cells, cell surface binding assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods establishing secretion, localization, and surface binding","pmids":["17067999"],"is_preprint":false},{"year":2008,"finding":"LGI1 binds to ADAM22, ADAM23, and ADAM11 with distinct affinities; LGI4 also binds these ADAMs; binding was characterized by quantitative cell-ELISA and immunoprecipitation/mass spectrometry from mouse brain.","method":"Immunoprecipitation + mass spectrometry, quantitative cell-ELISA","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 — reciprocal IP + MS from native brain tissue, quantitative binding assay","pmids":["18974846"],"is_preprint":false},{"year":2009,"finding":"LGI1 interacts with synaptic vesicle proteins synaptotagmin, synaptophysin, syntaxin 1A, clathrin heavy chain 1, syntaxin binding protein 1, and ADAM23, implicating LGI1 in synaptic vesicle function in neurons.","method":"Co-immunoprecipitation of GFP-tagged LGI1 from human brain lysates + mass spectrometry + Western blot confirmation","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP + MS + Western validation, single lab, human brain tissue","pmids":["19387870"],"is_preprint":false},{"year":2010,"finding":"Extracellular secreted LGI1 links presynaptic ADAM23 to postsynaptic ADAM22, forming a transsynaptic protein complex that includes presynaptic Kv1 potassium channels and postsynaptic AMPA receptor scaffolds; loss of LGI1 (knockout mice) causes lethal epilepsy, disrupts this synaptic connection, and selectively reduces AMPA receptor-mediated synaptic transmission in hippocampus.","method":"LGI1 knockout mice, LGI1 transgene rescue, co-immunoprecipitation from brain, electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — KO + transgene rescue + biochemistry + electrophysiology, multiple orthogonal methods, >240 citations","pmids":["20133599"],"is_preprint":false},{"year":2010,"finding":"LGI1 is a specific ligand for Nogo receptor 1 (NgR1) that antagonizes myelin-based growth inhibition and myelin-induced growth cone collapse; NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.","method":"Neurite outgrowth assay, growth cone collapse assay, co-immunoprecipitation, binding assays","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays + Co-IP, single lab, novel binding partner identified","pmids":["20463223"],"is_preprint":false},{"year":2010,"finding":"LGI1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability with enhanced excitatory synaptic transmission (increased glutamate release), providing mechanistic basis for seizure phenotype.","method":"Mouse chromosome engineering (null mutation), EEG, electrophysiology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined electrophysiological phenotype","pmids":["20130004"],"is_preprint":false},{"year":2010,"finding":"LGI1 is identified as the primary autoantigen in limbic encephalitis previously attributed to voltage-gated potassium channels (VGKC); LGI1 interacts with presynaptic ADAM23 and postsynaptic ADAM22; patient antibodies recognize LGI1 and reactivity is abrogated by immunoabsorption with LGI1-expressing cells and absent in Lgi1-null mouse brain.","method":"Immunoprecipitation + mass spectrometry, HEK293 cell-based assay, immunoabsorption, immunostaining of Lgi1-null mice","journal":"The Lancet. Neurology","confidence":"High","confidence_rationale":"Tier 1-2 — IP/MS identification + null mouse confirmation + immunoabsorption, >700 citations","pmids":["20580615"],"is_preprint":false},{"year":2010,"finding":"Homozygous deletion of LGI1 causes hypomyelination of axons in both peripheral (sciatic nerve, Schwann cells) and central nervous systems, establishing a role for LGI1 in myelination.","method":"Electron microscopy of sciatic nerve, histological analysis of CNS in Lgi1 null mice","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 — KO mice with EM ultrastructural phenotype, single lab","pmids":["20857514"],"is_preprint":false},{"year":2012,"finding":"LGI1 regulates postnatal pruning of retinogeniculate synapses; ADLTE-associated truncated mutant LGI1 blocks retinogeniculate axon pruning and arrests normal postnatal single fiber strengthening, whereas excess wild-type LGI1 accelerates pruning.","method":"Transgenic mice expressing mutant or excess wild-type LGI1, retinogeniculate axon tracing, electrophysiology","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic mouse models with defined anatomical and electrophysiological phenotypes","pmids":["22262888"],"is_preprint":false},{"year":2013,"finding":"LGI1 autoantibodies from limbic encephalitis patients target the EPTP repeat domain of LGI1, specifically inhibit LGI1-ADAM22/23 interactions, and reversibly reduce synaptic AMPA receptor clusters in rat hippocampal neurons; disruption of LGI1-ADAM22 interaction alone (via soluble ADAM22 ectodomain) reduces synaptic AMPA receptors; LGI1 knockout mouse shows greatly reduced AMPA receptors in hippocampal dentate gyrus.","method":"ELISA arrays, cell-based inhibition assays, immunofluorescence of rat hippocampal neurons, LGI1 KO mouse analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, patient antibodies + genetic model + neuronal culture, >260 citations","pmids":["24227725"],"is_preprint":false},{"year":2014,"finding":"LGI1 deletion restricted to glutamatergic pyramidal neurons (Emx1-Cre or CaMKIIα-Cre conditional knockouts) is sufficient to generate seizures; deletion in GABAergic parvalbumin interneurons does not produce spontaneous seizures or increased seizure susceptibility, establishing that LGI1 secreted from excitatory neurons is required for circuit homeostasis.","method":"Conditional knockout mice using cell-type-specific Cre drivers, EEG, behavioral analysis","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis using multiple Cre lines with clear cell-type-specific phenotypic readouts","pmids":["25234641"],"is_preprint":false},{"year":2015,"finding":"LGI1 acts as a paracrine signal from both pre- and postsynaptic neurons, acting specifically through ADAM22 to set postsynaptic strength; ADAM22 maintains excitatory synapses through PDZ domain interactions; in the absence of LGI1, PSD-95 (but not SAP102) cannot modulate synaptic transmission, indicating that LGI1-ADAM22 coordinates synapse maturation by regulating PSD-95 functional incorporation.","method":"Organotypic slice electrophysiology, lentiviral knockdown, rescue experiments with domain mutants of ADAM22, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — electrophysiology + molecular rescue + domain mutant analysis, multiple orthogonal methods","pmids":["26178195"],"is_preprint":false},{"year":2016,"finding":"Four secretion-positive LGI1 missense mutations (T380A, R407C, S473L, R474Q) causing ADLTE do not impair protein secretion but significantly impair LGI1 interaction with ADAM22 and ADAM23 receptors on the cell surface, identifying a second extracellular loss-of-function mechanism.","method":"Transfection of mutant LGI1 in cultured cells, secretion assay, immunofluorescence, co-immunoprecipitation, 3D protein modeling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1-2 — secretion assay + co-IP + cell surface immunofluorescence, multiple mutants tested","pmids":["27760137"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of the human LGI1-ADAM22 complex reveals a 2:2 heterotetrameric assembly; the hydrophobic pocket of the EPTP domain of LGI1 binds the metalloprotease-like domain of ADAM22; the LRR and EPTP domains mediate LGI1-LGI1 dimerization; a pathogenic mutation R474Q disrupts higher-order LGI1-ADAM22 assembly in vitro and in a mouse model without affecting secretion or direct ADAM22 binding.","method":"X-ray crystallography, mutagenesis, co-immunoprecipitation, mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional mutagenesis and in vivo validation","pmids":["29670100"],"is_preprint":false},{"year":2018,"finding":"Patient-derived IgG against LGI1 disrupts LGI1 binding to both ADAM23 (presynaptic) and ADAM22 (postsynaptic); antibody epitopes map to both LRR and EPTP domains; infusion of patient IgG into mouse ventricles decreases synaptic levels of Kv1.1 (presynaptically, preceding AMPA receptor changes) and AMPA receptors, causes neuronal hyperexcitability, impairs long-term potentiation, and produces reversible memory deficits.","method":"Live confocal imaging of hippocampal slices, patch-clamp electrophysiology, field potential LTP recordings, mouse cerebroventricular IgG transfer, behavioral testing (novel object recognition)","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1-2 — patient IgG transfer in vivo + multiple electrophysiological readouts + behavior, >180 citations","pmids":["30346486"],"is_preprint":false},{"year":2019,"finding":"ADAM22 and ADAM23 modulate trafficking of LGI1: they promote ER export and surface expression of LGI1, co-transport LGI1 in axonal vesicles (live-cell imaging), and are required for LGI1 enrichment at the axon initial segment (AIS); ADLTE missense mutations S473L and R474Q prevent LGI1 association with ADAM22 and its enrichment at the AIS.","method":"Rat hippocampal neuron culture, immunofluorescence, live-cell imaging, co-immunoprecipitation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — live imaging + co-IP + immunofluorescence with multiple mutants, multiple orthogonal methods","pmids":["30598502"],"is_preprint":false},{"year":2020,"finding":"CSF-derived patient monoclonal antibodies against LGI1 recognize either the LRR or EPTP domain; LRR-specific mAbs bind ADAM22/23-docked LGI1 and induce internalization of the LGI1-ADAM22/23 complex in HEK293T cells and live hippocampal neurons; EPTP-specific mAbs inhibit LGI1 docking to ADAM22/23; both domain-specific mAbs abrogate LTP and LRR-directed mAbs with higher binding strength induce memory impairment after intrahippocampal injection.","method":"Monoclonal antibody generation from patient B cells, live cell-based assay, internalization assay, intrahippocampal injection in rodents, LTP recording, behavioral testing","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1-2 — patient-derived mAbs + in vivo injection + electrophysiology + behavior, multiple orthogonal methods","pmids":["32437528"],"is_preprint":false},{"year":2020,"finding":"CSF-derived monoclonal LGI1 autoantibodies (IgG1, IgG2, IgG4 isotypes) increase intrinsic cellular excitability and glutamatergic synaptic transmission in hippocampal CA3 neurons in slice cultures; 7/26 antibodies blocked LGI1-ADAM22 interaction in vitro, while all antibodies promoted excitability regardless of ADAM22-blocking activity.","method":"Antibody cloning from CSF ASCs and B cells, patch-clamp electrophysiology in hippocampal slice cultures, in vitro LGI1-ADAM22 competition assay","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 1-2 — electrophysiology with patient-derived mAbs in slice culture, multiple antibodies tested","pmids":["31900946"],"is_preprint":false},{"year":2020,"finding":"Subacute reduction of LGI1 expression by shRNA in hippocampal slices increases dentate granule cell excitability and low-frequency facilitation of mossy fiber-CA3 neurotransmission; this effect is occluded by Kv1 family blocker α-dendrotoxin, implicating Kv1.1 as the mediating channel; LGI1 knockdown in neuronal primary culture also increases network activity.","method":"shRNA knockdown in ex vivo hippocampal slices and primary neuronal cultures, patch-clamp electrophysiology, pharmacological occlusion with α-dendrotoxin","journal":"Epilepsia","confidence":"High","confidence_rationale":"Tier 1-2 — KD + pharmacological dissection of mechanism, two experimental systems","pmids":["33104247"],"is_preprint":false},{"year":2021,"finding":"LGI1-ADAM22 governs transsynaptic nanoalignment by instructing PSD-95 family MAGUKs to organize a transsynaptic protein network including NMDA/AMPA receptors, Kv1 channels, and LRRTM4-Neurexin adhesion molecules; ADAM22 knock-in mice lacking the ADAM22-MAGUK interaction exhibit lethal hippocampal epilepsy, less-condensed PSD-95 nanodomains, disordered nanoalignment, and decreased excitatory synaptic transmission; forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in non-neuronal cells.","method":"ADAM22 knock-in mice (MAGUK-binding domain deleted), super-resolution microscopy, electrophysiology, reconstitution in non-neuronal cells, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — KI mice + reconstitution + super-resolution imaging + electrophysiology, multiple orthogonal methods","pmids":["33397806"],"is_preprint":false},{"year":2021,"finding":"14-3-3 proteins bind phosphorylated ADAM22 (dual phosphorylation by PKA) and protect the LGI1-ADAM22 complex from endocytosis-dependent degradation; PKA activation by forskolin increases ADAM22 levels; ~50% of normal LGI1 levels and ~10% of normal ADAM22 levels are sufficient to prevent lethal epilepsy in hypomorphic mice.","method":"Genetic and structural analysis, hypomorphic mouse series, in vitro phosphorylation and binding assays, pharmacological PKA activation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — structural analysis + genetic hypomorphic series + biochemical assays, multiple methods","pmids":["34910912"],"is_preprint":false},{"year":2022,"finding":"LGI1 is enriched in excitatory and inhibitory synaptic contact sites (most densely in CA3 hippocampus), is secreted from both somatodendritic and axonal compartments, and occurs in oligodendrocytic, neuro-oligodendrocytic, and astro-microglial protein complexes; proteomics reveals LGI1-Kv1-MAGUK complexes but does not identify LGI1 complexes with postsynaptic glutamate receptors.","method":"Patient-derived recombinant monoclonal antibody-based immunofluorescence, co-immunoprecipitation + mass spectrometry from mouse brain","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — patient mAb-based IF + proteomic interactome from native tissue, single lab","pmids":["35727946"],"is_preprint":false},{"year":2022,"finding":"An LRR-domain-specific LGI1 autoantibody (but not an EPTP-domain-specific mAb) increases intrinsic excitability of CA3 pyramidal neurons and reduces sensitivity to the selective Kv1.1 channel blocker, indicating that LRR mAbs modulate Kv1.1 channel function to promote neuronal excitability.","method":"Patient-derived recombinant monoclonal antibodies applied to organotypic rat hippocampal slice cultures, patch-clamp electrophysiology, pharmacological Kv1.1 blockade","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — electrophysiology with domain-specific mAbs + pharmacological dissection, single lab","pmids":["36078121"],"is_preprint":false}],"current_model":"LGI1 is a secreted glycoprotein that forms a transsynaptic ligand–receptor complex by binding presynaptic ADAM23 and postsynaptic ADAM22; ADAM22 in turn anchors PSD-95/MAGUK scaffolds to organize transsynaptic nanoalignment, regulate AMPA receptor-mediated synaptic transmission, and maintain Kv1 potassium channel function, while LGI1 also assembles directly into presynaptic Kv1.1-containing complexes to suppress Kvβ1-mediated N-type inactivation; loss of LGI1 function—through secretion-blocking mutations, extracellular ADAM-binding mutations, or autoantibody-mediated internalization/disruption—reduces synaptic AMPA receptors and dysregulates Kv1.1, lowering seizure threshold and causing limbic encephalitis-associated memory impairment, with complex stability further regulated by PKA-dependent phosphorylation of ADAM22 and 14-3-3 binding."},"narrative":{"teleology":[{"year":1998,"claim":"Cloning of LGI1 established its identity as a leucine-rich repeat–containing secreted protein lost in glioblastomas, initially framing it as a candidate tumor suppressor before its neuronal role was recognized.","evidence":"Positional cloning and translocation mapping of the t(10;19) breakpoint in glioblastoma cell lines, Northern blot expression analysis","pmids":["9879993"],"confidence":"Medium","gaps":["Tumor-suppressor function was never confirmed in vivo","Expression outside brain was not deeply characterized"]},{"year":2002,"claim":"Discovery that LGI1 loss-of-function mutations cause ADPEAF reframed the gene from a tumor suppressor to the first non-ion-channel epilepsy gene, raising the question of how a secreted protein controls seizure threshold.","evidence":"Resequencing of candidate genes in multiple ADPEAF/ADLTE families identifying truncating and missense mutations, replicated independently","pmids":["11810107","11978770"],"confidence":"High","gaps":["Mechanism by which LGI1 loss produces seizures was unknown","Whether mutations act through haploinsufficiency or dominant-negative effects was unresolved"]},{"year":2005,"claim":"Demonstrating that ADPEAF mutations block LGI1 secretion from cells established loss-of-function (impaired extracellular availability) as the shared pathogenic mechanism, directing the search toward extracellular receptors.","evidence":"Transfection of wild-type and mutant LGI1 into 293T cells with conditioned medium analysis","pmids":["15857855"],"confidence":"High","gaps":["The receptor for secreted LGI1 was unknown","Whether some mutations might act by a mechanism other than impaired secretion was not addressed"]},{"year":2006,"claim":"Identification of ADAM22 as the postsynaptic receptor for LGI1 and of presynaptic Kv1.1/Kvβ1 complexes as a second LGI1 binding partner revealed two distinct effector arms—AMPA receptor regulation and Kv1 channel inactivation gating—explaining how a single secreted protein controls both synaptic strength and intrinsic excitability.","evidence":"Co-immunoprecipitation from rat brain, electrophysiology in hippocampal slices and HEK cells, mass spectrometry, mutant analysis","pmids":["16990550","16504945"],"confidence":"High","gaps":["Whether ADAM23 serves as a presynaptic receptor bridging to ADAM22 was not yet established","Structural basis of binding was unknown","Relative contribution of Kv1 vs AMPA receptor arm to seizures was undetermined"]},{"year":2010,"claim":"Knockout mouse studies and identification of LGI1 as the autoantigen in limbic encephalitis (previously attributed to 'VGKC antibodies') unified the genetic and autoimmune mechanisms: LGI1 bridges presynaptic ADAM23 to postsynaptic ADAM22 to maintain both AMPA receptor signaling and Kv1 function, and either genetic loss or antibody-mediated disruption is pathogenic.","evidence":"LGI1 KO mice with lethal epilepsy, transgene rescue, IP/MS from brain, patient serum immunoprecipitation, HEK cell-based assays, immunostaining of Lgi1-null brain","pmids":["20133599","20580615","20130004"],"confidence":"High","gaps":["Cell-type-specific requirement for LGI1 was unclear","Precise epitopes and pathogenic mechanisms of patient antibodies were not resolved","Myelination role from KO phenotype needed further characterization"]},{"year":2013,"claim":"Mapping autoantibody epitopes to the EPTP domain and showing that disrupting LGI1–ADAM22 interaction alone (by soluble ADAM22 ectodomain) is sufficient to reduce synaptic AMPA receptor clusters established that the LGI1–ADAM22 interaction is the critical node for maintaining postsynaptic receptor density.","evidence":"ELISA domain mapping, cell-based inhibition assays, immunofluorescence of rat hippocampal neurons, LGI1 KO mouse dentate gyrus analysis","pmids":["24227725"],"confidence":"High","gaps":["Whether antibodies also act through Kv1 channels was not tested","Reversibility in vivo was not established"]},{"year":2016,"claim":"Discovery that certain ADLTE mutations (T380A, R407C, S473L, R474Q) are secreted normally but fail to bind ADAM22/23 identified a second class of extracellular loss-of-function mechanism distinct from secretion defects, demonstrating that receptor engagement is an independent vulnerable step.","evidence":"Secretion assays, co-immunoprecipitation, cell surface immunofluorescence, 3D protein modeling with multiple mutants","pmids":["27760137"],"confidence":"High","gaps":["Structural explanation for how each mutation disrupts binding was lacking"]},{"year":2018,"claim":"The crystal structure of the LGI1–ADAM22 2:2 heterotetramer revealed the molecular interface (EPTP hydrophobic pocket engaging ADAM22 metalloprotease-like domain) and showed that pathogenic mutation R474Q disrupts higher-order assembly rather than direct binding, explaining how some mutations are secretion- and binding-competent yet pathogenic.","evidence":"X-ray crystallography, mutagenesis, co-immunoprecipitation, mouse model validation","pmids":["29670100"],"confidence":"High","gaps":["Structure of full transsynaptic ADAM23–LGI1–LGI1–ADAM22 complex was not determined","Structural basis of LGI1 interaction with Kv1 channels remained unknown"]},{"year":2018,"claim":"In vivo transfer of patient IgG demonstrated that LGI1 autoantibodies reduce presynaptic Kv1.1 levels before AMPA receptor loss, impair LTP, and cause reversible memory deficits, establishing a temporal hierarchy of pathogenic effects and linking autoimmune disruption directly to cognitive symptoms.","evidence":"Cerebroventricular IgG infusion in mice, live confocal imaging of hippocampal slices, patch-clamp electrophysiology, LTP recording, novel object recognition","pmids":["30346486"],"confidence":"High","gaps":["Whether Kv1.1 loss is the primary driver of excitability or secondary to complex destabilization was not resolved","Chronic in vivo effects beyond 2 weeks were not studied"]},{"year":2020,"claim":"Patient-derived monoclonal antibodies with distinct domain specificity (LRR vs EPTP) operate through different pathomechanisms—LRR mAbs internalize the intact LGI1–ADAM complex while EPTP mAbs block docking—yet both impair LTP, demonstrating convergent synaptic pathology from diverse antibody populations; pharmacological occlusion experiments confirmed Kv1.1 as the mediating channel for LGI1 knockdown–induced excitability changes.","evidence":"Patient-derived mAbs in HEK293T internalization assays, intrahippocampal injection in rodents with behavioral and electrophysiological readouts, shRNA knockdown in hippocampal slices with α-dendrotoxin occlusion","pmids":["32437528","31900946","33104247"],"confidence":"High","gaps":["Relative pathogenic weight of internalization vs blocking mechanisms in patients in vivo was not determined","Whether non-ADAM22-blocking antibodies act entirely through Kv1 was not established"]},{"year":2021,"claim":"The LGI1–ADAM22 complex was shown to govern transsynaptic nanoalignment by instructing PSD-95 nanodomain condensation; PKA-dependent phosphorylation of ADAM22 recruits 14-3-3 proteins that protect the complex from endocytic degradation, and as little as ~50% of normal LGI1 is sufficient to prevent lethal epilepsy, defining the threshold and regulatory logic of the pathway.","evidence":"ADAM22 knock-in mice lacking MAGUK-binding domain, super-resolution microscopy, reconstitution in non-neuronal cells, hypomorphic mouse allelic series, in vitro phosphorylation and 14-3-3 binding assays","pmids":["33397806","34910912"],"confidence":"High","gaps":["Whether PKA regulation is activity-dependent at synapses is unknown","How LGI1–ADAM22 nanodomains are spatially organized relative to presynaptic release sites needs further super-resolution characterization"]},{"year":null,"claim":"Key unresolved questions include the structure of the full transsynaptic ADAM23–LGI1–LGI1–ADAM22 complex, the structural basis of LGI1 interaction with Kv1 channels, whether the Kv1 and AMPA receptor arms are independently or coordinately regulated during synaptic plasticity, and the functional significance of LGI1 complexes in non-neuronal cells (oligodendrocytes, astrocytes).","evidence":"","pmids":[],"confidence":"Low","gaps":["No full transsynaptic complex structure","Kv1–LGI1 structural interface undefined","Functional role of LGI1 in glia is minimally characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[4,9,15,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,24,25]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,6,9,15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6,21]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,5,9,17,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,17,25,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,12,20,22]}],"complexes":["LGI1-ADAM22-ADAM23 transsynaptic complex","Kv1.1/Kv1.4/Kvβ1-LGI1 presynaptic complex","LGI1-ADAM22-PSD-95/MAGUK postsynaptic complex"],"partners":["ADAM22","ADAM23","ADAM11","KCNA1","KCNAB1","DLG4","RTN4R"],"other_free_text":[]},"mechanistic_narrative":"LGI1 is a secreted neuronal glycoprotein that organizes excitatory synaptic architecture and controls seizure threshold by forming a transsynaptic ligand–receptor bridge between presynaptic ADAM23 and postsynaptic ADAM22. The LGI1–ADAM22 complex anchors PSD-95/MAGUK scaffolds to establish transsynaptic nanoalignment, regulate AMPA receptor–mediated synaptic transmission, and coordinate synapse maturation and pruning; the complex is stabilized by PKA-dependent phosphorylation of ADAM22 and 14-3-3 binding [PMID:20133599, PMID:33397806, PMID:34910912]. LGI1 also assembles into presynaptic Kv1.1/Kvβ1 potassium channel complexes, where it suppresses Kvβ1-mediated N-type inactivation to control neuronal excitability [PMID:16504945, PMID:33104247]. Loss-of-function mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF) through impaired secretion or disrupted ADAM22/23 binding, while autoantibodies targeting LGI1 cause limbic encephalitis by internalizing or blocking the LGI1–ADAM complex, reducing synaptic AMPA receptors and Kv1.1 levels, and producing reversible memory deficits [PMID:11810107, PMID:20580615, PMID:30346486]."},"prefetch_data":{"uniprot":{"accession":"O95970","full_name":"Leucine-rich glioma-inactivated protein 1","aliases":["Epitempin-1"],"length_aa":557,"mass_kda":63.8,"function":"Regulates voltage-gated potassium channels assembled from KCNA1, KCNA4 and KCNAB1. It slows down channel inactivation by precluding channel closure mediated by the KCNAB1 subunit. Ligand for ADAM22 that positively regulates synaptic transmission mediated by AMPA-type glutamate receptors (By similarity). Plays a role in suppressing the production of MMP1/3 through the phosphatidylinositol 3-kinase/ERK pathway. 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encephalitis.","date":"2020","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/32799011","citation_count":20,"is_preprint":false},{"pmid":"16533756","id":"PMC_16533756","title":"Expression studies in gliomas and glial cells do not support a tumor suppressor role for LGI1.","date":"2006","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16533756","citation_count":20,"is_preprint":false},{"pmid":"14643004","id":"PMC_14643004","title":"No evidence for a seriously increased malignancy risk in LGI1-caused epilepsy.","date":"2003","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/14643004","citation_count":20,"is_preprint":false},{"pmid":"34967933","id":"PMC_34967933","title":"The LGI1 protein: molecular structure, physiological functions and disruption-related seizures.","date":"2021","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/34967933","citation_count":19,"is_preprint":false},{"pmid":"34953167","id":"PMC_34953167","title":"Objective sleep profile in LGI1/CASPR2 autoimmunity.","date":"2022","source":"Sleep","url":"https://pubmed.ncbi.nlm.nih.gov/34953167","citation_count":19,"is_preprint":false},{"pmid":"32417596","id":"PMC_32417596","title":"Novel findings of HLA association with anti-LGI1 encephalitis: HLA-DRB1*03:01 and HLA-DQB1*02:01.","date":"2020","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/32417596","citation_count":19,"is_preprint":false},{"pmid":"27760137","id":"PMC_27760137","title":"Secretion-Positive LGI1 Mutations Linked to Lateral Temporal Epilepsy Impair Binding to ADAM22 and ADAM23 Receptors.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27760137","citation_count":19,"is_preprint":false},{"pmid":"30103974","id":"PMC_30103974","title":"Distinction between anti-VGKC-complex seropositive patients with and without anti-LGI1/CASPR2 antibodies.","date":"2018","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30103974","citation_count":19,"is_preprint":false},{"pmid":"35727946","id":"PMC_35727946","title":"Patient-derived antibodies reveal the subcellular distribution and heterogeneous interactome of LGI1.","date":"2022","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35727946","citation_count":17,"is_preprint":false},{"pmid":"8219362","id":"PMC_8219362","title":"The Etl-1 gene encodes a nuclear protein differentially expressed during early mouse development.","date":"1993","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/8219362","citation_count":17,"is_preprint":false},{"pmid":"19387870","id":"PMC_19387870","title":"Mass spectrometry identifies LGI1-interacting proteins that are involved in synaptic vesicle function in the human brain.","date":"2009","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/19387870","citation_count":17,"is_preprint":false},{"pmid":"33104247","id":"PMC_33104247","title":"LGI1 downregulation increases neuronal circuit excitability.","date":"2020","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/33104247","citation_count":16,"is_preprint":false},{"pmid":"18355961","id":"PMC_18355961","title":"Analysis of LGI1 promoter sequence, PDYN and GABBR1 polymorphisms in sporadic and familial lateral temporal lobe epilepsy.","date":"2008","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/18355961","citation_count":16,"is_preprint":false},{"pmid":"25346110","id":"PMC_25346110","title":"Homozygous Deletion of the LGI1 Gene in Mice Leads to Developmental Abnormalities Resulting in Cortical Dysplasia.","date":"2014","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/25346110","citation_count":15,"is_preprint":false},{"pmid":"34910912","id":"PMC_34910912","title":"14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34910912","citation_count":15,"is_preprint":false},{"pmid":"36078121","id":"PMC_36078121","title":"An Epitope-Specific LGI1-Autoantibody Enhances Neuronal Excitability by Modulating Kv1.1 Channel.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36078121","citation_count":15,"is_preprint":false},{"pmid":"36591253","id":"PMC_36591253","title":"The diagnosis of anti-LGI1 encephalitis varies with the type of immunodetection assay and sample examined.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36591253","citation_count":15,"is_preprint":false},{"pmid":"38981871","id":"PMC_38981871","title":"Resolution of anti-LGI1-associated autoimmune encephalitis in a patient after treatment with efgartigimod.","date":"2024","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38981871","citation_count":14,"is_preprint":false},{"pmid":"37591767","id":"PMC_37591767","title":"Electrolyte Imbalance in Anti-LGI1 Encephalitis: It Is Not All in Your Head.","date":"2023","source":"Neurology(R) neuroimmunology & neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/37591767","citation_count":14,"is_preprint":false},{"pmid":"37264220","id":"PMC_37264220","title":"Comparison of quantitative FDG-PET and MRI in anti-LGI1 autoimmune encephalitis.","date":"2023","source":"Neuroradiology","url":"https://pubmed.ncbi.nlm.nih.gov/37264220","citation_count":14,"is_preprint":false},{"pmid":"25194489","id":"PMC_25194489","title":"LGI1: from zebrafish to human epilepsy.","date":"2014","source":"Progress in brain research","url":"https://pubmed.ncbi.nlm.nih.gov/25194489","citation_count":14,"is_preprint":false},{"pmid":"32560097","id":"PMC_32560097","title":"Psychiatric Manifestation of Anti-LGI1 Encephalitis.","date":"2020","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32560097","citation_count":13,"is_preprint":false},{"pmid":"29771820","id":"PMC_29771820","title":"Effect of LGI1 antibody-positive IgG on hippocampal neuron survival: a preliminary study.","date":"2018","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/29771820","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53124,"output_tokens":6937,"usd":0.131714},"stage2":{"model":"claude-opus-4-6","input_tokens":10615,"output_tokens":3412,"usd":0.207563},"total_usd":0.339277,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"LGI1 encodes a ~60 kDa secreted protein containing leucine-rich repeats (LRR); the gene is rearranged and its expression is absent in glioblastoma cell lines and malignant gliomas, identifying it as a candidate tumor suppressor.\",\n      \"method\": \"Positional cloning, translocation mapping, Northern blot/expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — original cloning paper with structural characterization, single lab\",\n      \"pmids\": [\"9879993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mutations in LGI1 (including premature stop codons) cause autosomal dominant partial epilepsy with auditory features (ADPEAF/ADLTE), establishing LGI1 as a non-ion-channel epilepsy gene; mouse Lgi1 expression is predominantly neuronal in temporal lobe regions.\",\n      \"method\": \"Resequencing of candidate genes in ADPEAF families, immunohistochemistry in mouse brain\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational gene discovery paper, replicated across multiple families, >400 citations\",\n      \"pmids\": [\"11810107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"LGI1 mutations introducing premature stop codons (loss of function) segregate with autosomal dominant lateral temporal epilepsy; LGI1 protein is expressed in neuronal cell compartments throughout the brain.\",\n      \"method\": \"Mutation analysis in ADLTE families, immunohistochemistry\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent replication in separate families confirming LOF mechanism\",\n      \"pmids\": [\"11978770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LGI1 is a secreted protein; ADPEAF-associated mutations (missense and truncating) reduce or abolish secretion of LGI1 from transfected 293T cells, demonstrating loss-of-function as the pathogenic mechanism.\",\n      \"method\": \"Transfection of wild-type and mutant LGI1 into 293T cells, conditioned medium analysis, Western blot\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro secretion assay with multiple mutants, replicated by multiple subsequent labs\",\n      \"pmids\": [\"15857855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LGI1 binds ADAM22 (a postsynaptic transmembrane protein) as its receptor; this interaction enhances AMPA receptor-mediated synaptic transmission in hippocampal slices; ADPEAF-mutant LGI1 fails to bind ADAM22; ADAM22 is anchored to the postsynaptic density via stargazin-containing scaffolds.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology in hippocampal slices (rat brain), HEK293 cell binding assays, mutant analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, seminal paper, >300 citations, replicated broadly\",\n      \"pmids\": [\"16990550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Lgi1 assembles into presynaptic Kv1.1-containing potassium channel complexes (with Kv1.4 and Kvβ1) in hippocampal axonal terminals, and selectively prevents N-type (Kvβ1-mediated) inactivation; ADLTE-mutant Lgi1 fails to inhibit inactivation, resulting in channels with rapid inactivation kinetics.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry from rat brain, electrophysiology, co-expression in HEK cells, mutant analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical complex purification + functional electrophysiology + mutagenesis, >240 citations\",\n      \"pmids\": [\"16504945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LGI1 is expressed as two protein isoforms (~60 and ~65 kDa) in human brain; the long isoform is secreted, whereas the short isoform is retained intracellularly; ADLTE mutants of the long form are retained in the ER and Golgi; secreted LGI1 binds specifically to the cell surface of differentiated PC12 cells.\",\n      \"method\": \"Western blot, subcellular fractionation, immunofluorescence of transfected cells, cell surface binding assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods establishing secretion, localization, and surface binding\",\n      \"pmids\": [\"17067999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LGI1 binds to ADAM22, ADAM23, and ADAM11 with distinct affinities; LGI4 also binds these ADAMs; binding was characterized by quantitative cell-ELISA and immunoprecipitation/mass spectrometry from mouse brain.\",\n      \"method\": \"Immunoprecipitation + mass spectrometry, quantitative cell-ELISA\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal IP + MS from native brain tissue, quantitative binding assay\",\n      \"pmids\": [\"18974846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LGI1 interacts with synaptic vesicle proteins synaptotagmin, synaptophysin, syntaxin 1A, clathrin heavy chain 1, syntaxin binding protein 1, and ADAM23, implicating LGI1 in synaptic vesicle function in neurons.\",\n      \"method\": \"Co-immunoprecipitation of GFP-tagged LGI1 from human brain lysates + mass spectrometry + Western blot confirmation\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP + MS + Western validation, single lab, human brain tissue\",\n      \"pmids\": [\"19387870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Extracellular secreted LGI1 links presynaptic ADAM23 to postsynaptic ADAM22, forming a transsynaptic protein complex that includes presynaptic Kv1 potassium channels and postsynaptic AMPA receptor scaffolds; loss of LGI1 (knockout mice) causes lethal epilepsy, disrupts this synaptic connection, and selectively reduces AMPA receptor-mediated synaptic transmission in hippocampus.\",\n      \"method\": \"LGI1 knockout mice, LGI1 transgene rescue, co-immunoprecipitation from brain, electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO + transgene rescue + biochemistry + electrophysiology, multiple orthogonal methods, >240 citations\",\n      \"pmids\": [\"20133599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LGI1 is a specific ligand for Nogo receptor 1 (NgR1) that antagonizes myelin-based growth inhibition and myelin-induced growth cone collapse; NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.\",\n      \"method\": \"Neurite outgrowth assay, growth cone collapse assay, co-immunoprecipitation, binding assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays + Co-IP, single lab, novel binding partner identified\",\n      \"pmids\": [\"20463223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LGI1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability with enhanced excitatory synaptic transmission (increased glutamate release), providing mechanistic basis for seizure phenotype.\",\n      \"method\": \"Mouse chromosome engineering (null mutation), EEG, electrophysiology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined electrophysiological phenotype\",\n      \"pmids\": [\"20130004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LGI1 is identified as the primary autoantigen in limbic encephalitis previously attributed to voltage-gated potassium channels (VGKC); LGI1 interacts with presynaptic ADAM23 and postsynaptic ADAM22; patient antibodies recognize LGI1 and reactivity is abrogated by immunoabsorption with LGI1-expressing cells and absent in Lgi1-null mouse brain.\",\n      \"method\": \"Immunoprecipitation + mass spectrometry, HEK293 cell-based assay, immunoabsorption, immunostaining of Lgi1-null mice\",\n      \"journal\": \"The Lancet. Neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — IP/MS identification + null mouse confirmation + immunoabsorption, >700 citations\",\n      \"pmids\": [\"20580615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Homozygous deletion of LGI1 causes hypomyelination of axons in both peripheral (sciatic nerve, Schwann cells) and central nervous systems, establishing a role for LGI1 in myelination.\",\n      \"method\": \"Electron microscopy of sciatic nerve, histological analysis of CNS in Lgi1 null mice\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with EM ultrastructural phenotype, single lab\",\n      \"pmids\": [\"20857514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LGI1 regulates postnatal pruning of retinogeniculate synapses; ADLTE-associated truncated mutant LGI1 blocks retinogeniculate axon pruning and arrests normal postnatal single fiber strengthening, whereas excess wild-type LGI1 accelerates pruning.\",\n      \"method\": \"Transgenic mice expressing mutant or excess wild-type LGI1, retinogeniculate axon tracing, electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse models with defined anatomical and electrophysiological phenotypes\",\n      \"pmids\": [\"22262888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LGI1 autoantibodies from limbic encephalitis patients target the EPTP repeat domain of LGI1, specifically inhibit LGI1-ADAM22/23 interactions, and reversibly reduce synaptic AMPA receptor clusters in rat hippocampal neurons; disruption of LGI1-ADAM22 interaction alone (via soluble ADAM22 ectodomain) reduces synaptic AMPA receptors; LGI1 knockout mouse shows greatly reduced AMPA receptors in hippocampal dentate gyrus.\",\n      \"method\": \"ELISA arrays, cell-based inhibition assays, immunofluorescence of rat hippocampal neurons, LGI1 KO mouse analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, patient antibodies + genetic model + neuronal culture, >260 citations\",\n      \"pmids\": [\"24227725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LGI1 deletion restricted to glutamatergic pyramidal neurons (Emx1-Cre or CaMKIIα-Cre conditional knockouts) is sufficient to generate seizures; deletion in GABAergic parvalbumin interneurons does not produce spontaneous seizures or increased seizure susceptibility, establishing that LGI1 secreted from excitatory neurons is required for circuit homeostasis.\",\n      \"method\": \"Conditional knockout mice using cell-type-specific Cre drivers, EEG, behavioral analysis\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using multiple Cre lines with clear cell-type-specific phenotypic readouts\",\n      \"pmids\": [\"25234641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LGI1 acts as a paracrine signal from both pre- and postsynaptic neurons, acting specifically through ADAM22 to set postsynaptic strength; ADAM22 maintains excitatory synapses through PDZ domain interactions; in the absence of LGI1, PSD-95 (but not SAP102) cannot modulate synaptic transmission, indicating that LGI1-ADAM22 coordinates synapse maturation by regulating PSD-95 functional incorporation.\",\n      \"method\": \"Organotypic slice electrophysiology, lentiviral knockdown, rescue experiments with domain mutants of ADAM22, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — electrophysiology + molecular rescue + domain mutant analysis, multiple orthogonal methods\",\n      \"pmids\": [\"26178195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Four secretion-positive LGI1 missense mutations (T380A, R407C, S473L, R474Q) causing ADLTE do not impair protein secretion but significantly impair LGI1 interaction with ADAM22 and ADAM23 receptors on the cell surface, identifying a second extracellular loss-of-function mechanism.\",\n      \"method\": \"Transfection of mutant LGI1 in cultured cells, secretion assay, immunofluorescence, co-immunoprecipitation, 3D protein modeling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — secretion assay + co-IP + cell surface immunofluorescence, multiple mutants tested\",\n      \"pmids\": [\"27760137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of the human LGI1-ADAM22 complex reveals a 2:2 heterotetrameric assembly; the hydrophobic pocket of the EPTP domain of LGI1 binds the metalloprotease-like domain of ADAM22; the LRR and EPTP domains mediate LGI1-LGI1 dimerization; a pathogenic mutation R474Q disrupts higher-order LGI1-ADAM22 assembly in vitro and in a mouse model without affecting secretion or direct ADAM22 binding.\",\n      \"method\": \"X-ray crystallography, mutagenesis, co-immunoprecipitation, mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional mutagenesis and in vivo validation\",\n      \"pmids\": [\"29670100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Patient-derived IgG against LGI1 disrupts LGI1 binding to both ADAM23 (presynaptic) and ADAM22 (postsynaptic); antibody epitopes map to both LRR and EPTP domains; infusion of patient IgG into mouse ventricles decreases synaptic levels of Kv1.1 (presynaptically, preceding AMPA receptor changes) and AMPA receptors, causes neuronal hyperexcitability, impairs long-term potentiation, and produces reversible memory deficits.\",\n      \"method\": \"Live confocal imaging of hippocampal slices, patch-clamp electrophysiology, field potential LTP recordings, mouse cerebroventricular IgG transfer, behavioral testing (novel object recognition)\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — patient IgG transfer in vivo + multiple electrophysiological readouts + behavior, >180 citations\",\n      \"pmids\": [\"30346486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM22 and ADAM23 modulate trafficking of LGI1: they promote ER export and surface expression of LGI1, co-transport LGI1 in axonal vesicles (live-cell imaging), and are required for LGI1 enrichment at the axon initial segment (AIS); ADLTE missense mutations S473L and R474Q prevent LGI1 association with ADAM22 and its enrichment at the AIS.\",\n      \"method\": \"Rat hippocampal neuron culture, immunofluorescence, live-cell imaging, co-immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live imaging + co-IP + immunofluorescence with multiple mutants, multiple orthogonal methods\",\n      \"pmids\": [\"30598502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSF-derived patient monoclonal antibodies against LGI1 recognize either the LRR or EPTP domain; LRR-specific mAbs bind ADAM22/23-docked LGI1 and induce internalization of the LGI1-ADAM22/23 complex in HEK293T cells and live hippocampal neurons; EPTP-specific mAbs inhibit LGI1 docking to ADAM22/23; both domain-specific mAbs abrogate LTP and LRR-directed mAbs with higher binding strength induce memory impairment after intrahippocampal injection.\",\n      \"method\": \"Monoclonal antibody generation from patient B cells, live cell-based assay, internalization assay, intrahippocampal injection in rodents, LTP recording, behavioral testing\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — patient-derived mAbs + in vivo injection + electrophysiology + behavior, multiple orthogonal methods\",\n      \"pmids\": [\"32437528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSF-derived monoclonal LGI1 autoantibodies (IgG1, IgG2, IgG4 isotypes) increase intrinsic cellular excitability and glutamatergic synaptic transmission in hippocampal CA3 neurons in slice cultures; 7/26 antibodies blocked LGI1-ADAM22 interaction in vitro, while all antibodies promoted excitability regardless of ADAM22-blocking activity.\",\n      \"method\": \"Antibody cloning from CSF ASCs and B cells, patch-clamp electrophysiology in hippocampal slice cultures, in vitro LGI1-ADAM22 competition assay\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — electrophysiology with patient-derived mAbs in slice culture, multiple antibodies tested\",\n      \"pmids\": [\"31900946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Subacute reduction of LGI1 expression by shRNA in hippocampal slices increases dentate granule cell excitability and low-frequency facilitation of mossy fiber-CA3 neurotransmission; this effect is occluded by Kv1 family blocker α-dendrotoxin, implicating Kv1.1 as the mediating channel; LGI1 knockdown in neuronal primary culture also increases network activity.\",\n      \"method\": \"shRNA knockdown in ex vivo hippocampal slices and primary neuronal cultures, patch-clamp electrophysiology, pharmacological occlusion with α-dendrotoxin\",\n      \"journal\": \"Epilepsia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KD + pharmacological dissection of mechanism, two experimental systems\",\n      \"pmids\": [\"33104247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LGI1-ADAM22 governs transsynaptic nanoalignment by instructing PSD-95 family MAGUKs to organize a transsynaptic protein network including NMDA/AMPA receptors, Kv1 channels, and LRRTM4-Neurexin adhesion molecules; ADAM22 knock-in mice lacking the ADAM22-MAGUK interaction exhibit lethal hippocampal epilepsy, less-condensed PSD-95 nanodomains, disordered nanoalignment, and decreased excitatory synaptic transmission; forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in non-neuronal cells.\",\n      \"method\": \"ADAM22 knock-in mice (MAGUK-binding domain deleted), super-resolution microscopy, electrophysiology, reconstitution in non-neuronal cells, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — KI mice + reconstitution + super-resolution imaging + electrophysiology, multiple orthogonal methods\",\n      \"pmids\": [\"33397806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"14-3-3 proteins bind phosphorylated ADAM22 (dual phosphorylation by PKA) and protect the LGI1-ADAM22 complex from endocytosis-dependent degradation; PKA activation by forskolin increases ADAM22 levels; ~50% of normal LGI1 levels and ~10% of normal ADAM22 levels are sufficient to prevent lethal epilepsy in hypomorphic mice.\",\n      \"method\": \"Genetic and structural analysis, hypomorphic mouse series, in vitro phosphorylation and binding assays, pharmacological PKA activation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural analysis + genetic hypomorphic series + biochemical assays, multiple methods\",\n      \"pmids\": [\"34910912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LGI1 is enriched in excitatory and inhibitory synaptic contact sites (most densely in CA3 hippocampus), is secreted from both somatodendritic and axonal compartments, and occurs in oligodendrocytic, neuro-oligodendrocytic, and astro-microglial protein complexes; proteomics reveals LGI1-Kv1-MAGUK complexes but does not identify LGI1 complexes with postsynaptic glutamate receptors.\",\n      \"method\": \"Patient-derived recombinant monoclonal antibody-based immunofluorescence, co-immunoprecipitation + mass spectrometry from mouse brain\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient mAb-based IF + proteomic interactome from native tissue, single lab\",\n      \"pmids\": [\"35727946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"An LRR-domain-specific LGI1 autoantibody (but not an EPTP-domain-specific mAb) increases intrinsic excitability of CA3 pyramidal neurons and reduces sensitivity to the selective Kv1.1 channel blocker, indicating that LRR mAbs modulate Kv1.1 channel function to promote neuronal excitability.\",\n      \"method\": \"Patient-derived recombinant monoclonal antibodies applied to organotypic rat hippocampal slice cultures, patch-clamp electrophysiology, pharmacological Kv1.1 blockade\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology with domain-specific mAbs + pharmacological dissection, single lab\",\n      \"pmids\": [\"36078121\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGI1 is a secreted glycoprotein that forms a transsynaptic ligand–receptor complex by binding presynaptic ADAM23 and postsynaptic ADAM22; ADAM22 in turn anchors PSD-95/MAGUK scaffolds to organize transsynaptic nanoalignment, regulate AMPA receptor-mediated synaptic transmission, and maintain Kv1 potassium channel function, while LGI1 also assembles directly into presynaptic Kv1.1-containing complexes to suppress Kvβ1-mediated N-type inactivation; loss of LGI1 function—through secretion-blocking mutations, extracellular ADAM-binding mutations, or autoantibody-mediated internalization/disruption—reduces synaptic AMPA receptors and dysregulates Kv1.1, lowering seizure threshold and causing limbic encephalitis-associated memory impairment, with complex stability further regulated by PKA-dependent phosphorylation of ADAM22 and 14-3-3 binding.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LGI1 is a secreted neuronal glycoprotein that organizes excitatory synaptic architecture and controls seizure threshold by forming a transsynaptic ligand–receptor bridge between presynaptic ADAM23 and postsynaptic ADAM22. The LGI1–ADAM22 complex anchors PSD-95/MAGUK scaffolds to establish transsynaptic nanoalignment, regulate AMPA receptor–mediated synaptic transmission, and coordinate synapse maturation and pruning; the complex is stabilized by PKA-dependent phosphorylation of ADAM22 and 14-3-3 binding [PMID:20133599, PMID:33397806, PMID:34910912]. LGI1 also assembles into presynaptic Kv1.1/Kvβ1 potassium channel complexes, where it suppresses Kvβ1-mediated N-type inactivation to control neuronal excitability [PMID:16504945, PMID:33104247]. Loss-of-function mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF) through impaired secretion or disrupted ADAM22/23 binding, while autoantibodies targeting LGI1 cause limbic encephalitis by internalizing or blocking the LGI1–ADAM complex, reducing synaptic AMPA receptors and Kv1.1 levels, and producing reversible memory deficits [PMID:11810107, PMID:20580615, PMID:30346486].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Cloning of LGI1 established its identity as a leucine-rich repeat–containing secreted protein lost in glioblastomas, initially framing it as a candidate tumor suppressor before its neuronal role was recognized.\",\n      \"evidence\": \"Positional cloning and translocation mapping of the t(10;19) breakpoint in glioblastoma cell lines, Northern blot expression analysis\",\n      \"pmids\": [\"9879993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tumor-suppressor function was never confirmed in vivo\", \"Expression outside brain was not deeply characterized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery that LGI1 loss-of-function mutations cause ADPEAF reframed the gene from a tumor suppressor to the first non-ion-channel epilepsy gene, raising the question of how a secreted protein controls seizure threshold.\",\n      \"evidence\": \"Resequencing of candidate genes in multiple ADPEAF/ADLTE families identifying truncating and missense mutations, replicated independently\",\n      \"pmids\": [\"11810107\", \"11978770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which LGI1 loss produces seizures was unknown\", \"Whether mutations act through haploinsufficiency or dominant-negative effects was unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that ADPEAF mutations block LGI1 secretion from cells established loss-of-function (impaired extracellular availability) as the shared pathogenic mechanism, directing the search toward extracellular receptors.\",\n      \"evidence\": \"Transfection of wild-type and mutant LGI1 into 293T cells with conditioned medium analysis\",\n      \"pmids\": [\"15857855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor for secreted LGI1 was unknown\", \"Whether some mutations might act by a mechanism other than impaired secretion was not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of ADAM22 as the postsynaptic receptor for LGI1 and of presynaptic Kv1.1/Kvβ1 complexes as a second LGI1 binding partner revealed two distinct effector arms—AMPA receptor regulation and Kv1 channel inactivation gating—explaining how a single secreted protein controls both synaptic strength and intrinsic excitability.\",\n      \"evidence\": \"Co-immunoprecipitation from rat brain, electrophysiology in hippocampal slices and HEK cells, mass spectrometry, mutant analysis\",\n      \"pmids\": [\"16990550\", \"16504945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM23 serves as a presynaptic receptor bridging to ADAM22 was not yet established\", \"Structural basis of binding was unknown\", \"Relative contribution of Kv1 vs AMPA receptor arm to seizures was undetermined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Knockout mouse studies and identification of LGI1 as the autoantigen in limbic encephalitis (previously attributed to 'VGKC antibodies') unified the genetic and autoimmune mechanisms: LGI1 bridges presynaptic ADAM23 to postsynaptic ADAM22 to maintain both AMPA receptor signaling and Kv1 function, and either genetic loss or antibody-mediated disruption is pathogenic.\",\n      \"evidence\": \"LGI1 KO mice with lethal epilepsy, transgene rescue, IP/MS from brain, patient serum immunoprecipitation, HEK cell-based assays, immunostaining of Lgi1-null brain\",\n      \"pmids\": [\"20133599\", \"20580615\", \"20130004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific requirement for LGI1 was unclear\", \"Precise epitopes and pathogenic mechanisms of patient antibodies were not resolved\", \"Myelination role from KO phenotype needed further characterization\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping autoantibody epitopes to the EPTP domain and showing that disrupting LGI1–ADAM22 interaction alone (by soluble ADAM22 ectodomain) is sufficient to reduce synaptic AMPA receptor clusters established that the LGI1–ADAM22 interaction is the critical node for maintaining postsynaptic receptor density.\",\n      \"evidence\": \"ELISA domain mapping, cell-based inhibition assays, immunofluorescence of rat hippocampal neurons, LGI1 KO mouse dentate gyrus analysis\",\n      \"pmids\": [\"24227725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether antibodies also act through Kv1 channels was not tested\", \"Reversibility in vivo was not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that certain ADLTE mutations (T380A, R407C, S473L, R474Q) are secreted normally but fail to bind ADAM22/23 identified a second class of extracellular loss-of-function mechanism distinct from secretion defects, demonstrating that receptor engagement is an independent vulnerable step.\",\n      \"evidence\": \"Secretion assays, co-immunoprecipitation, cell surface immunofluorescence, 3D protein modeling with multiple mutants\",\n      \"pmids\": [\"27760137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural explanation for how each mutation disrupts binding was lacking\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The crystal structure of the LGI1–ADAM22 2:2 heterotetramer revealed the molecular interface (EPTP hydrophobic pocket engaging ADAM22 metalloprotease-like domain) and showed that pathogenic mutation R474Q disrupts higher-order assembly rather than direct binding, explaining how some mutations are secretion- and binding-competent yet pathogenic.\",\n      \"evidence\": \"X-ray crystallography, mutagenesis, co-immunoprecipitation, mouse model validation\",\n      \"pmids\": [\"29670100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full transsynaptic ADAM23–LGI1–LGI1–ADAM22 complex was not determined\", \"Structural basis of LGI1 interaction with Kv1 channels remained unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"In vivo transfer of patient IgG demonstrated that LGI1 autoantibodies reduce presynaptic Kv1.1 levels before AMPA receptor loss, impair LTP, and cause reversible memory deficits, establishing a temporal hierarchy of pathogenic effects and linking autoimmune disruption directly to cognitive symptoms.\",\n      \"evidence\": \"Cerebroventricular IgG infusion in mice, live confocal imaging of hippocampal slices, patch-clamp electrophysiology, LTP recording, novel object recognition\",\n      \"pmids\": [\"30346486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Kv1.1 loss is the primary driver of excitability or secondary to complex destabilization was not resolved\", \"Chronic in vivo effects beyond 2 weeks were not studied\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Patient-derived monoclonal antibodies with distinct domain specificity (LRR vs EPTP) operate through different pathomechanisms—LRR mAbs internalize the intact LGI1–ADAM complex while EPTP mAbs block docking—yet both impair LTP, demonstrating convergent synaptic pathology from diverse antibody populations; pharmacological occlusion experiments confirmed Kv1.1 as the mediating channel for LGI1 knockdown–induced excitability changes.\",\n      \"evidence\": \"Patient-derived mAbs in HEK293T internalization assays, intrahippocampal injection in rodents with behavioral and electrophysiological readouts, shRNA knockdown in hippocampal slices with α-dendrotoxin occlusion\",\n      \"pmids\": [\"32437528\", \"31900946\", \"33104247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative pathogenic weight of internalization vs blocking mechanisms in patients in vivo was not determined\", \"Whether non-ADAM22-blocking antibodies act entirely through Kv1 was not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The LGI1–ADAM22 complex was shown to govern transsynaptic nanoalignment by instructing PSD-95 nanodomain condensation; PKA-dependent phosphorylation of ADAM22 recruits 14-3-3 proteins that protect the complex from endocytic degradation, and as little as ~50% of normal LGI1 is sufficient to prevent lethal epilepsy, defining the threshold and regulatory logic of the pathway.\",\n      \"evidence\": \"ADAM22 knock-in mice lacking MAGUK-binding domain, super-resolution microscopy, reconstitution in non-neuronal cells, hypomorphic mouse allelic series, in vitro phosphorylation and 14-3-3 binding assays\",\n      \"pmids\": [\"33397806\", \"34910912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PKA regulation is activity-dependent at synapses is unknown\", \"How LGI1–ADAM22 nanodomains are spatially organized relative to presynaptic release sites needs further super-resolution characterization\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structure of the full transsynaptic ADAM23–LGI1–LGI1–ADAM22 complex, the structural basis of LGI1 interaction with Kv1 channels, whether the Kv1 and AMPA receptor arms are independently or coordinately regulated during synaptic plasticity, and the functional significance of LGI1 complexes in non-neuronal cells (oligodendrocytes, astrocytes).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full transsynaptic complex structure\", \"Kv1–LGI1 structural interface undefined\", \"Functional role of LGI1 in glia is minimally characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [4, 9, 15, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 24, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 6, 9, 15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 5, 9, 17, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 17, 25, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 12, 20, 22]}\n    ],\n    \"complexes\": [\n      \"LGI1-ADAM22-ADAM23 transsynaptic complex\",\n      \"Kv1.1/Kv1.4/Kvβ1-LGI1 presynaptic complex\",\n      \"LGI1-ADAM22-PSD-95/MAGUK postsynaptic complex\"\n    ],\n    \"partners\": [\n      \"ADAM22\",\n      \"ADAM23\",\n      \"ADAM11\",\n      \"KCNA1\",\n      \"KCNAB1\",\n      \"DLG4\",\n      \"RTN4R\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}