{"gene":"LGI1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1998,"finding":"LGI1 encodes a ~60 kDa protein containing leucine-rich repeats; the gene is rearranged and its expression is absent in glioblastoma cell lines and significantly reduced in malignant gliomas, establishing it as a candidate tumor suppressor at 10q24.","method":"Positional cloning, immunohistochemistry, expression analysis in glioblastoma cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — positional cloning and expression assays, single lab, multiple cell lines and tumor samples","pmids":["9879993"],"is_preprint":false},{"year":2002,"finding":"Mutations in LGI1 (including premature stop codons) segregate with autosomal dominant lateral temporal epilepsy (EPT/ADLTE), and LGI1 protein is expressed ubiquitously in neuronal cell bodies of the brain.","method":"Mutation analysis in epilepsy families, immunohistochemistry","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic segregation in two families, immunohistochemical confirmation of neuronal expression","pmids":["11978770"],"is_preprint":false},{"year":2005,"finding":"Wild-type LGI1 is a secreted protein; ADPEAF-linked mutations cause either failure of secretion or protein instability, establishing loss of secretion as the pathogenic mechanism for this epilepsy.","method":"Transfection of HEK293T cells, secretion assay for wild-type and mutant LGI1 constructs","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro secretion assay with multiple mutants, replicated across multiple subsequent studies","pmids":["15857855"],"is_preprint":false},{"year":2006,"finding":"ADAM22, a transmembrane protein whose mutation causes seizures, serves as a receptor for secreted LGI1. LGI1 binding to ADAM22 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices; ADPEAF-causing mutant LGI1 fails to bind ADAM22.","method":"Co-immunoprecipitation, electrophysiology in rat hippocampal slices, binding assay with mutant LGI1","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal binding assays, functional electrophysiology, mutagenesis confirmation, replicated by multiple subsequent studies","pmids":["16990550"],"is_preprint":false},{"year":2006,"finding":"LGI1 is a novel subunit of presynaptic Kv1.1-containing channel complexes in hippocampal axon terminals, where it selectively prevents N-type inactivation mediated by the Kvβ1 subunit; ADLTE-associated LGI1 mutants fail to prevent this inactivation, resulting in channels with rapid inactivation kinetics.","method":"Biochemical co-purification/proteomics of Kv1.1 complexes from rat brain, electrophysiology, analysis of disease mutants","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-purification with mass spectrometry, electrophysiological characterization of mutant effects, multiple orthogonal methods in one study","pmids":["16504945"],"is_preprint":false},{"year":2006,"finding":"LGI1 is expressed as two isoforms (~60 and ~65 kDa) that reside in different subcellular compartments; the long isoform is secreted while the short isoform is retained intracellularly. ADLTE mutants of the long form are retained in the ER and Golgi. Secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells.","method":"Subcellular fractionation, immunocytochemistry, secretion assays in transfected cells, cell surface binding assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, ICC, binding assay), single lab but consistent with broader literature","pmids":["17067999"],"is_preprint":false},{"year":2008,"finding":"LGI1 binds to ADAM22, ADAM23, and ADAM11, but not ADAM12, establishing that ADAM22 is not the sole receptor for LGI1 and that the LGI-ADAM interaction system involves multiple ADAM family members.","method":"Immunoprecipitation and mass spectrometric analysis from mouse brain, quantitative cell-ELISA binding assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP/MS from brain tissue plus quantitative cell-ELISA, single lab, consistent with genetic epistasis data","pmids":["18974846"],"is_preprint":false},{"year":2009,"finding":"ADAM23 is identified as the primary high-affinity LGI1-binding protein in an unbiased brain screen. LGI1 binding to ADAM23 promotes neurite outgrowth; ADAM23-null neurons show reduced dendritic arborization and ADAM23-null mice exhibit spontaneous seizures and decreased seizure thresholds.","method":"Unbiased brain binding screen, neurite outgrowth assays in wild-type vs. ADAM23-/- neurons, in vivo seizure monitoring","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased binding screen, genetic loss-of-function with multiple phenotypic readouts, consistent with complementary studies","pmids":["19796686"],"is_preprint":false},{"year":2010,"finding":"LGI1-/- mice develop lethal epilepsy rescued specifically by neuronal LGI1 transgene but not LGI3. Extracellularly secreted LGI1 organizes a transsynaptic protein complex linking presynaptic ADAM23/Kv1 channels and postsynaptic ADAM22/AMPA receptor scaffolds; loss of LGI1 selectively reduces AMPA receptor-mediated synaptic transmission in hippocampus.","method":"Genetic knockout and transgenic rescue, co-immunoprecipitation of transsynaptic complex, electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic rescue experiment, biochemical complex characterization, electrophysiology, multiple orthogonal methods","pmids":["20133599"],"is_preprint":false},{"year":2010,"finding":"LGI1 functions as a specific Nogo receptor 1 (NgR1) ligand that antagonizes myelin-based growth inhibition. NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.","method":"Neuronal growth assays on myelin substrates, growth cone collapse assay, pulldown/co-immunoprecipitation of NgR1-ADAM22 complex","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional growth assays with defined substrate, co-IP of receptor complex, single lab","pmids":["20463223"],"is_preprint":false},{"year":2012,"finding":"LGI1 regulates postnatal pruning of retinal axons in the visual relay thalamus; mutant truncated LGI1 (836delC) blocks retinogeniculate axon pruning and arrests normal single-fiber strengthening, while excess wild-type LGI1 accelerates both processes.","method":"Transgenic mouse models expressing mutant or wild-type LGI1, retinogeniculate synapse electrophysiology and anatomical analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple transgenic lines with reciprocal effects, electrophysiological and anatomical readouts, complementary heterozygous deletion","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 interaction, and reversibly reduce synaptic AMPA receptor clusters in hippocampal neurons. Disruption of the LGI1-ADAM22 interaction alone (by soluble ADAM22 ectodomain) is sufficient to reduce synaptic AMPA receptors. LGI1 knockout mice show greatly reduced hippocampal AMPA receptor levels.","method":"ELISA, co-immunoprecipitation, rat hippocampal neuron cultures, LGI1 knockout mouse analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ELISA, co-IP, cell culture, KO mice), mechanistic rescue experiments, single lab with comprehensive approach","pmids":["24227725"],"is_preprint":false},{"year":2014,"finding":"Selective deletion of LGI1 in glutamatergic pyramidal neurons (Emx1-Cre or CaMKIIα-Cre) causes spontaneous seizures, whereas deletion in GABAergic parvalbumin interneurons does not alter seizure thresholds, establishing that LGI1 secreted from excitatory neurons is required for epilepsy prevention.","method":"Conditional knockout mice with cell-type specific Cre drivers, EEG monitoring, convulsant seizure threshold testing","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell-type specific conditional knockouts with clear differential phenotypes, replicated across Cre lines","pmids":["25234641"],"is_preprint":false},{"year":2015,"finding":"LGI1 acts as a paracrine signal from both pre- and postsynaptic neurons, functioning specifically through ADAM22 to set postsynaptic strength. ADAM22 maintains excitatory synapses through PDZ domain interactions. In the absence of LGI1, the mature scaffolding protein PSD-95 cannot modulate synaptic transmission, but SAP102 function is unaffected, revealing that LGI1-ADAM22 coordinates synapse maturation by regulating PSD-95 function.","method":"Hippocampal slice electrophysiology, molecular replacement with ADAM22 mutants, viral expression constructs in LGI1-null neurons","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic dissection with multiple domain mutants, electrophysiological validation, mechanistic specificity for PSD-95 vs SAP102","pmids":["26178195"],"is_preprint":false},{"year":2016,"finding":"LGI1 deficiency (>50% down-regulation) causes posttranscriptional reduction of axonal Kv1.1 and Kv1.2 channel density at the axon initial segment of hippocampal CA3 neurons, reducing D-type potassium current and intrinsic excitability control; recombinant LGI1 restores Kv1 channel density and D-current.","method":"Electrophysiology (D-type current recording), immunofluorescence, recombinant LGI1 application, LGI1 knockout and heterozygous mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — recombinant protein application, genetic depletion, electrophysiological readout, posttranscriptional mechanism established","pmids":["28673977"],"is_preprint":false},{"year":2016,"finding":"LGI1 acts presynaptically as a negative modulator of excitatory synaptic transmission during early postnatal development; LGI1 deficiency causes increased presynaptic glutamate release without altering postsynaptic AMPA receptor activity, leading to hyperexcitable networks before seizure onset.","method":"Electrophysiology in hippocampal slices from Lgi1-/- mice at pre-seizure stages, postsynaptic AMPA receptor recording, morphological analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — pre-seizure developmental analysis, dissection of pre vs postsynaptic mechanisms, genetic model","pmids":["26878798"],"is_preprint":false},{"year":2016,"finding":"LGI1 missense mutations S473L and R474Q (secretion-positive) fail to interact with ADAM22 and ADAM23 on the cell surface, establishing a second loss-of-function mechanism (impaired receptor binding) distinct from secretion failure.","method":"Immunofluorescence, co-immunoprecipitation with cell-surface ADAM22/23, 3D protein modeling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP and immunofluorescence with multiple secretion-competent mutants, consistent with crystal structure data","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 LGI1's C-terminal EPTP domain binds to the metalloprotease-like domain of ADAM22; LGI1's LRR and EPTP domains mediate LGI1-LGI1 dimerization. Pathogenic R474Q mutation disrupts the LGI1-LGI1 interface and the higher-order assembly in vitro and in a mouse epilepsy model.","method":"X-ray crystallography, in vitro binding assays, knock-in mouse model for R474Q mutation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and in vivo knock-in mouse model","pmids":["29670100"],"is_preprint":false},{"year":2018,"finding":"Patient-derived LGI1 IgG antibodies prevent LGI1 binding to both ADAM23 and ADAM22; epitopes reside in the LRR1 and EPTP1 domains. In mice infused with patient IgG, Kv1.1 and AMPA receptor synaptic levels decrease (Kv1.1 effects precede AMPA effects), causing neuronal hyperexcitability, increased glutamatergic transmission, impaired LTP, and reversible memory deficits.","method":"Epitope mapping with LGI1 domain constructs, cerebroventricular patient IgG infusion in mice, confocal analysis, patch-clamp electrophysiology, LTP recording, behavioral memory testing","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — patient-derived IgG passive transfer model, multiple orthogonal readouts (biochemical, electrophysiological, behavioral), reversal upon IgG withdrawal","pmids":["30346486"],"is_preprint":false},{"year":2019,"finding":"ADAM22 and ADAM23 modulate LGI1 trafficking: they promote ER export and expression of LGI1 at the neuronal cell surface, and co-transport with LGI1 in axonal vesicles. LGI1 is recruited to the axon initial segment where it colocalizes with ADAM22 and Kv1 channels; ADLTE mutations S473L and R474Q prevent LGI1 association with ADAM22 and enrichment at the AIS.","method":"Hippocampal neuron cultures, immunofluorescence, live-cell axonal transport imaging, expression of ADLTE mutants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live-cell imaging, immunofluorescence, disease mutant analysis, multiple orthogonal methods in single lab","pmids":["30598502"],"is_preprint":false},{"year":2020,"finding":"Patient-derived monoclonal LGI1 antibodies (mAbs) segregate into two populations targeting either the LRR or EPTP domains with distinct properties: LRR-specific mAbs bind brain sections and induce internalization of the LGI1-ADAM22/23 complex in neurons; EPTP-specific mAbs inhibit LGI1 docking to ADAM22/23 but show less brain binding. Both types abolish LTP induction; LRR-directed high-affinity mAbs induce memory impairment after hippocampal injection.","method":"Generation of patient-derived mAbs from peripheral B cells, live cell-based assays, intrahippocampal injection in rodents, LTP recording, behavioral testing","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — patient mAbs with domain-specific mechanistic dissection, in vivo injection with electrophysiological and behavioral outcomes, multiple orthogonal methods","pmids":["32437528"],"is_preprint":false},{"year":2020,"finding":"CSF-derived monoclonal LGI1 antibodies from patients increase intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures; both ADAM22-competing and non-competing antibodies produce this effect, demonstrating that LGI1 antibodies alone are sufficient to promote neuronal hyperexcitability.","method":"Cloning of antibodies from CSF B cells/ASCs, application to hippocampal slice cultures, patch-clamp electrophysiology","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — monoclonal antibody application to defined neuronal preparation, electrophysiological readout, two mechanistic classes tested","pmids":["31900946"],"is_preprint":false},{"year":2021,"finding":"LGI1-ADAM22 instructs PSD-95 family MAGUKs to organize transsynaptic protein networks including NMDA/AMPA receptors, Kv1 channels, and LRRTM4-Neurexin adhesion molecules. ADAM22 knock-in mice lacking the ADAM22-MAGUK interaction develop lethal epilepsy with less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission. Without ADAM22-MAGUK interaction, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Forced co-expression of ADAM22 and PSD-95 reconstitutes nano-condensates in non-neuronal cells.","method":"ADAM22 knock-in mouse (MAGUK interaction-deficient), super-resolution microscopy, electrophysiology, reconstitution in non-neuronal cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knock-in genetic model, reconstitution in non-neuronal cells, super-resolution structural analysis, electrophysiology, multiple orthogonal methods","pmids":["33397806"],"is_preprint":false},{"year":2021,"finding":"PKA-mediated dual phosphorylation of ADAM22 promotes high-affinity binding to dimerized 14-3-3 proteins, protecting LGI1-ADAM22 complexes from endocytosis-dependent degradation. Forskolin-induced PKA activation increases ADAM22 levels. Approximately 50% of normal LGI1 levels and only ~10% of ADAM22 levels are sufficient to prevent lethal epilepsy in hypomorphic mice.","method":"Genetic analysis of hypomorphic mice, structural analysis of 14-3-3/ADAM22 interaction, PKA activation experiments with forskolin","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic hypomorphic series with quantitative threshold determination, structural and biochemical PTM characterization, pharmacological validation","pmids":["34910912"],"is_preprint":false},{"year":2020,"finding":"Subacute shRNA-mediated reduction of LGI1 in hippocampus increases dentate granule cell excitability and low-frequency facilitation of mossy fiber to CA3 transmission; α-dendrotoxin (Kv1 blocker) occludes this effect, implicating Kv1.1 as the downstream effector.","method":"shRNA knockdown in hippocampal slices and neuronal cultures, electrophysiology, pharmacological occlusion with α-dendrotoxin","journal":"Epilepsia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA KD with pharmacological occlusion experiment, single lab","pmids":["33104247"],"is_preprint":false},{"year":2022,"finding":"An LRR domain-specific (but not EPTP domain-specific) patient-derived monoclonal LGI1 antibody increases intrinsic excitability of CA3 pyramidal neurons correlated with reduced sensitivity to a selective Kv1.1 channel blocker, demonstrating that LRR-domain antibodies modulate neuronal excitability via Kv1.1.","method":"Domain-specific patient mAb application to organotypic hippocampal cultures, patch-clamp electrophysiology, pharmacological Kv1.1 block","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific mAbs with electrophysiological dissection and pharmacological validation, single lab","pmids":["36078121"],"is_preprint":false},{"year":2004,"finding":"Reintroduction of LGI1 into LGI1-null glioma cell lines (T98G, A172) significantly reduces cell proliferation, inhibits invasion in Matrigel assays, and reduces anchorage-independent growth, demonstrating a functional role in suppressing malignant phenotypes via ERK1/2 pathway inhibition.","method":"Retroviral/stable transfection of LGI1 into null glioma cell lines, proliferation assays, Matrigel invasion assays, soft agar colony assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in multiple null cell lines with multiple phenotypic readouts, single lab","pmids":["12821932"],"is_preprint":false},{"year":2004,"finding":"LGI1 re-expression in T98G glioma cells downregulates MMP1 and MMP3 gene expression through inhibition of ERK1/2 phosphorylation (not p38) and promotion of AKT phosphorylation leading to Raf1(Ser-259) phosphorylation; pharmacological inhibition of MAPK pathway mimics LGI1 effects, and phorbol ester treatment reverses LGI1-mediated suppression of MMP1/3 and ERK1/2 phosphorylation.","method":"Affymetrix gene chip, pharmacological inhibitors (PD98059, U0126, SB203580), Western blot for ERK1/2 and AKT phosphorylation, phorbol ester treatment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway analysis with multiple pharmacological tools and readouts, single lab","pmids":["15047712"],"is_preprint":false},{"year":2024,"finding":"OPALIN, an oligodendrocyte-specific membrane protein, is identified as an LGI1 receptor on oligodendrocytes via LGI1 affinity chromatography and mass spectrometry. Conditional knockout of OPALIN in the oligodendrocyte lineage causes hypomyelination and white matter abnormalities phenocopying LGI1 deficiency; re-expression of LGI1-binding-deficient OPALIN (K23A/D26A) fails to rescue hypomyelination.","method":"LGI1 affinity chromatography with mouse brain lysates and mass spectrometry, conditional knockout mice, viral rescue with wild-type and mutant OPALIN","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — affinity chromatography/MS for receptor identification, conditional KO phenocopy, binding-deficient mutant rescue failure, multiple orthogonal validations","pmids":["39083419"],"is_preprint":false}],"current_model":"LGI1 is a secreted neuronal glycoprotein that forms a transsynaptic complex by binding presynaptically to ADAM23 (and Kv1.1-containing channel complexes) and postsynaptically to ADAM22 (which anchors PSD-95/MAGUK scaffolds and AMPA receptors); through this transsynaptic nanoalignment, LGI1-ADAM22 enables PSD-95 to potentiate AMPA receptor-mediated synaptic transmission and regulates Kv1 channel density at the axon initial segment to control intrinsic excitability; the LGI1-ADAM22 complex is stabilized by PKA-mediated phosphorylation of ADAM22 and 14-3-3 binding, and in oligodendrocytes LGI1 promotes myelination via the receptor OPALIN, while disease-causing mutations either prevent LGI1 secretion or impair its binding to ADAM22/23, and patient autoantibodies targeting the LRR or EPTP domains disrupt LGI1-ADAM22/23 interactions and/or induce receptor internalization, reducing Kv1.1 and AMPA receptor levels and causing neuronal hyperexcitability, LTP impairment, and memory deficits."},"narrative":{"mechanistic_narrative":"LGI1 is a secreted neuronal glycoprotein that organizes a transsynaptic protein complex controlling synaptic strength and intrinsic neuronal excitability, and whose loss of function causes epilepsy [PMID:15857855, PMID:20133599]. Secreted wild-type LGI1 bridges presynaptic ADAM23/Kv1 channel complexes and postsynaptic ADAM22/AMPA receptor scaffolds, and genetic deletion of LGI1 in mice produces lethal epilepsy that is rescued by neuronal LGI1 but not LGI3 [PMID:20133599]. Through ADAM22, LGI1 instructs PSD-95-family MAGUKs to condense transsynaptic nanodomains that align Kv1 channels, NMDA/AMPA receptors and adhesion molecules, and this ADAM22-MAGUK linkage is required for PSD-95 to potentiate AMPA receptor-mediated transmission [PMID:26178195, PMID:33397806]; the LGI1-ADAM22 complex is further stabilized by PKA-dependent phosphorylation of ADAM22 and 14-3-3 binding that protects it from endocytic degradation [PMID:34910912]. Presynaptically, LGI1 is a subunit of Kv1.1-containing channels and prevents Kvβ1-mediated N-type inactivation, and LGI1 deficiency post-transcriptionally reduces Kv1.1/Kv1.2 density at the axon initial segment, lowering D-type current and raising excitability [PMID:16504945, PMID:28673977]. The crystal structure of the LGI1-ADAM22 complex defines a 2:2 heterotetramer in which the EPTP domain binds the ADAM22 metalloprotease-like domain while the LRR and EPTP domains mediate LGI1 dimerization [PMID:29670100]. Autosomal dominant lateral temporal epilepsy mutations act either by blocking LGI1 secretion or by abolishing ADAM22/23 binding and higher-order assembly without affecting secretion [PMID:15857855, PMID:27760137, PMID:29670100], and limbic encephalitis patient autoantibodies against the LRR or EPTP domains disrupt LGI1-ADAM22/23 interactions or internalize the complex, reducing Kv1.1 and AMPA receptors and producing hyperexcitability, impaired LTP and reversible memory deficits [PMID:30346486, PMID:32437528]. Beyond the nervous system, LGI1 binds the oligodendrocyte receptor OPALIN to promote myelination [PMID:39083419], and was originally identified as a candidate glioma tumor suppressor that, when re-expressed, suppresses proliferation and invasion via ERK1/2 inhibition [PMID:9879993, PMID:12821932].","teleology":[{"year":1998,"claim":"Established LGI1 as a leucine-rich-repeat protein and candidate tumor suppressor, the first functional clue to the gene before its neuronal role was known.","evidence":"Positional cloning and expression analysis in glioblastoma cell lines and gliomas","pmids":["9879993"],"confidence":"Medium","gaps":["No mechanism for tumor suppression defined","Neuronal function not yet addressed"]},{"year":2004,"claim":"Showed LGI1 re-expression suppresses glioma malignancy through MAPK signaling, providing the first mechanistic pathway for its tumor-suppressor activity.","evidence":"Gain-of-function transfection in null glioma lines with proliferation/invasion assays and ERK1/2-AKT pathway analysis","pmids":["12821932","15047712"],"confidence":"Medium","gaps":["Cell-line-based, no in vivo tumor model","Relationship to neuronal ADAM-receptor signaling unclear"]},{"year":2002,"claim":"Linked LGI1 to human disease by showing truncating mutations segregate with autosomal dominant lateral temporal epilepsy, reframing the gene as neurological.","evidence":"Mutation analysis in epilepsy families and brain immunohistochemistry","pmids":["11978770"],"confidence":"Medium","gaps":["Pathogenic mechanism of mutations unknown","Molecular partners undefined"]},{"year":2005,"claim":"Defined secretion failure as a primary pathogenic mechanism, showing wild-type LGI1 is secreted while many ADPEAF mutants are retained or unstable.","evidence":"Secretion assays of wild-type and mutant LGI1 in HEK293T cells","pmids":["15857855"],"confidence":"High","gaps":["Did not identify a receptor or downstream effector","Secretion-competent disease mutants not yet explained"]},{"year":2006,"claim":"Identified the receptor and synaptic output of LGI1 — ADAM22 binding enhances AMPA transmission and disease mutants fail to bind — and revealed LGI1 as a Kv1.1 channel subunit that blocks N-type inactivation.","evidence":"Co-IP, hippocampal slice electrophysiology, Kv1.1 complex co-purification/proteomics and mutant analysis","pmids":["16990550","16504945","17067999"],"confidence":"High","gaps":["Whether ADAM22 was the sole receptor unresolved","Pre- vs postsynaptic site of action unclear"]},{"year":2009,"claim":"Expanded the receptor repertoire to multiple ADAM family members and established ADAM23 as the high-affinity partner regulating neurite outgrowth and seizure threshold.","evidence":"IP/MS from brain, unbiased binding screen, neurite assays in ADAM23-/- neurons, in vivo seizure monitoring","pmids":["18974846","19796686"],"confidence":"High","gaps":["Distinct roles of ADAM22 vs ADAM23 not separated","Mechanism of outgrowth promotion undefined"]},{"year":2010,"claim":"Demonstrated in vivo that LGI1 organizes a transsynaptic complex linking presynaptic ADAM23/Kv1 to postsynaptic ADAM22/AMPA scaffolds, with knockout causing lethal epilepsy rescued specifically by neuronal LGI1.","evidence":"LGI1 knockout/transgenic rescue, transsynaptic complex co-IP, electrophysiology","pmids":["20133599"],"confidence":"High","gaps":["Molecular details of scaffold organization not resolved","Cell types secreting functional LGI1 not defined"]},{"year":2010,"claim":"Reported an additional ligand role for LGI1 as an NgR1 antagonist of myelin growth inhibition, with NgR1-ADAM22 forming a receptor complex.","evidence":"Myelin substrate growth assays, growth cone collapse, co-IP of NgR1-ADAM22","pmids":["20463223"],"confidence":"Medium","gaps":["Relationship of NgR1 axis to synaptic functions unclear","Single-lab finding"]},{"year":2012,"claim":"Showed LGI1 dose bidirectionally controls developmental retinogeniculate axon pruning and single-fiber strengthening, extending its role to circuit refinement.","evidence":"Mutant and overexpression transgenic mice, retinogeniculate electrophysiology and anatomy","pmids":["22262888"],"confidence":"High","gaps":["Receptor mediating pruning effect not identified","Link to ADAM22/23 transsynaptic complex not tested"]},{"year":2014,"claim":"Localized the protective source of LGI1 to glutamatergic neurons, since deletion there but not in PV interneurons caused seizures.","evidence":"Cell-type-specific conditional knockouts with EEG and seizure threshold testing","pmids":["25234641"],"confidence":"High","gaps":["Pre- vs postsynaptic mechanism in excitatory neurons not separated"]},{"year":2015,"claim":"Defined the postsynaptic logic of LGI1-ADAM22 signaling: it enables mature PSD-95, but not SAP102, to modulate synaptic strength, identifying a MAGUK-specific maturation switch.","evidence":"Slice electrophysiology with ADAM22 domain mutants and viral replacement in LGI1-null neurons","pmids":["26178195"],"confidence":"High","gaps":["Structural basis of ADAM22-MAGUK coupling unknown","How PSD-95 is selectively engaged unresolved"]},{"year":2013,"claim":"Established the autoimmune mechanism of limbic encephalitis by showing EPTP-targeting autoantibodies block LGI1-ADAM22/23 binding and reversibly reduce synaptic AMPA receptors.","evidence":"ELISA, co-IP, hippocampal neuron cultures, LGI1 knockout analysis","pmids":["24227725"],"confidence":"High","gaps":["Effect on Kv1.1 not yet examined","In vivo behavioral consequences untested"]},{"year":2016,"claim":"Resolved the post-transcriptional and presynaptic arms of LGI1 function, showing it maintains AIS Kv1 channel density/D-current and negatively modulates presynaptic glutamate release before seizures, and identified secretion-competent mutants that fail receptor binding as a second loss-of-function class.","evidence":"D-type current recordings with recombinant LGI1, pre-seizure slice electrophysiology, and co-IP/modeling of S473L and R474Q mutants","pmids":["28673977","26878798","27760137"],"confidence":"High","gaps":["Molecular machinery setting Kv1 density at the AIS undefined","How presynaptic and postsynaptic roles are coordinated unclear"]},{"year":2018,"claim":"Provided the atomic and in vivo basis of complex assembly — a 2:2 LGI1-ADAM22 heterotetramer with LGI1 dimerization — and demonstrated that disrupting LGI1 binding/internalization underlies both genetic and autoimmune disease.","evidence":"X-ray crystallography with R474Q knock-in mouse, and patient-IgG passive transfer with electrophysiology and behavior","pmids":["29670100","30346486"],"confidence":"High","gaps":["Higher-order assembly stoichiometry in vivo not fully defined","Trafficking determinants of the complex not addressed"]},{"year":2019,"claim":"Showed ADAM22/23 reciprocally control LGI1 trafficking — promoting ER export, surface expression, axonal co-transport and AIS recruitment — explaining how the complex is delivered to functional sites.","evidence":"Live-cell axonal transport imaging and immunofluorescence with ADLTE mutants in hippocampal neurons","pmids":["30598502"],"confidence":"High","gaps":["Vesicular trafficking machinery not identified","Single-lab imaging study"]},{"year":2020,"claim":"Dissected autoantibody mechanisms into domain-specific classes: LRR-directed antibodies internalize the complex and impair memory via Kv1.1, while EPTP-directed antibodies block ADAM22/23 docking, with both abolishing LTP.","evidence":"Patient-derived monoclonal antibodies, cell-based assays, intrahippocampal injection, LTP and behavior, plus CSF-derived mAb slice electrophysiology and pharmacological Kv1.1 block","pmids":["32437528","31900946","36078121"],"confidence":"High","gaps":["Relative contribution of each antibody class in patients unknown","Long-term structural consequences of internalization undefined"]},{"year":2021,"claim":"Established that LGI1-ADAM22 instructs PSD-95-family MAGUKs to condense transsynaptic nanodomains, and that PKA phosphorylation/14-3-3 binding stabilizes the complex against degradation, with quantitative thresholds for epilepsy prevention.","evidence":"ADAM22-MAGUK-deficient knock-in mice, super-resolution microscopy, non-neuronal reconstitution, and structural/biochemical PTM analysis with hypomorphic mouse series","pmids":["33397806","34910912"],"confidence":"High","gaps":["Physiological signals driving PKA-dependent stabilization in vivo unclear","How nanodomain condensation translates to channel/receptor density unresolved"]},{"year":2024,"claim":"Extended LGI1 signaling beyond neurons by identifying OPALIN as its oligodendrocyte receptor required for myelination, with binding-deficient OPALIN failing to rescue hypomyelination.","evidence":"LGI1 affinity chromatography/MS, conditional OPALIN knockout phenocopy, binding-deficient mutant rescue","pmids":["39083419"],"confidence":"High","gaps":["Downstream OPALIN signaling in oligodendrocytes undefined","Whether ADAM receptors participate in the myelination axis unknown"]},{"year":null,"claim":"How the multiple LGI1 receptor axes (ADAM22/23 synaptic, NgR1, OPALIN myelination) are integrated and differentially deployed across cell types and development remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking synaptic, axon-guidance and myelination functions","Signal-transduction events downstream of LGI1 binding largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,7,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,14,23]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,8,28]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular 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markers","url":"https://pubmed.ncbi.nlm.nih.gov/35003396","citation_count":25,"is_preprint":false},{"pmid":"11907806","id":"PMC_11907806","title":"Physical and functional characterization of the human LGI1 gene and its possible role in glioma development.","date":"2001","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/11907806","citation_count":25,"is_preprint":false},{"pmid":"30253786","id":"PMC_30253786","title":"LGI1 expression and human brain asymmetry: insights from patients with LGI1-antibody encephalitis.","date":"2018","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/30253786","citation_count":24,"is_preprint":false},{"pmid":"17681454","id":"PMC_17681454","title":"Absence of mutations in the LGI1 receptor ADAM22 gene in autosomal dominant lateral temporal epilepsy.","date":"2007","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/17681454","citation_count":24,"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":22,"is_preprint":false},{"pmid":"22262888","id":"PMC_22262888","title":"Epilepsy gene LGI1 regulates postnatal developmental remodeling of retinogeniculate synapses.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22262888","citation_count":22,"is_preprint":false},{"pmid":"21504429","id":"PMC_21504429","title":"Low penetrance and effect on protein secretion of LGI1 mutations causing autosomal dominant lateral temporal epilepsy.","date":"2011","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/21504429","citation_count":22,"is_preprint":false},{"pmid":"30724344","id":"PMC_30724344","title":"Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies.","date":"2019","source":"Developmental medicine and child neurology","url":"https://pubmed.ncbi.nlm.nih.gov/30724344","citation_count":22,"is_preprint":false},{"pmid":"12942323","id":"PMC_12942323","title":"Expression of the LGI1 gene product in astrocytic gliomas: downregulation with malignant progression.","date":"2003","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12942323","citation_count":21,"is_preprint":false},{"pmid":"16518856","id":"PMC_16518856","title":"Increased expression of LGI1 gene triggers growth inhibition and apoptosis of neuroblastoma cells.","date":"2006","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16518856","citation_count":21,"is_preprint":false},{"pmid":"10920229","id":"PMC_10920229","title":"Identification of the promoter, genomic structure, and mouse ortholog of LGI1.","date":"2000","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/10920229","citation_count":21,"is_preprint":false},{"pmid":"22496201","id":"PMC_22496201","title":"LGI1 microdeletion in autosomal dominant lateral temporal epilepsy.","date":"2012","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/22496201","citation_count":21,"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":20,"is_preprint":false},{"pmid":"32799011","id":"PMC_32799011","title":"Serum and CSF cytokine levels mirror different neuroimmunological mechanisms in patients with LGI1 and Caspr2 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":"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":"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":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":"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":18,"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":17,"is_preprint":false},{"pmid":"21569517","id":"PMC_21569517","title":"The temporal and spatial expression pattern of the LGI1 epilepsy predisposition gene during mouse embryonic cranial development.","date":"2011","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21569517","citation_count":17,"is_preprint":false},{"pmid":"39820999","id":"PMC_39820999","title":"Efgartigimod treatment for therapy-refractory autoimmune encephalitis with coexistent NMDAR and LGI1 antibodies: a case report and literature review.","date":"2025","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/39820999","citation_count":17,"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":16,"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":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":"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":"39083419","id":"PMC_39083419","title":"OPALIN is an LGI1 receptor promoting oligodendrocyte differentiation.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39083419","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":"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":"39193150","id":"PMC_39193150","title":"Innovation and optimization in autoimmune encephalitis trials: the design and rationale for the Phase 3, randomized study of satralizumab in patients with NMDAR-IgG-antibody-positive or LGI1-IgG-antibody-positive autoimmune encephalitis (CIELO).","date":"2024","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39193150","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55500,"output_tokens":7330,"usd":0.138225,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16572,"output_tokens":5668,"usd":0.11228,"stage2_stop_reason":"end_turn"},"total_usd":0.250505,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"LGI1 encodes a ~60 kDa protein containing leucine-rich repeats; the gene is rearranged and its expression is absent in glioblastoma cell lines and significantly reduced in malignant gliomas, establishing it as a candidate tumor suppressor at 10q24.\",\n      \"method\": \"Positional cloning, immunohistochemistry, expression analysis in glioblastoma cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — positional cloning and expression assays, single lab, multiple cell lines and tumor samples\",\n      \"pmids\": [\"9879993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mutations in LGI1 (including premature stop codons) segregate with autosomal dominant lateral temporal epilepsy (EPT/ADLTE), and LGI1 protein is expressed ubiquitously in neuronal cell bodies of the brain.\",\n      \"method\": \"Mutation analysis in epilepsy families, immunohistochemistry\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic segregation in two families, immunohistochemical confirmation of neuronal expression\",\n      \"pmids\": [\"11978770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Wild-type LGI1 is a secreted protein; ADPEAF-linked mutations cause either failure of secretion or protein instability, establishing loss of secretion as the pathogenic mechanism for this epilepsy.\",\n      \"method\": \"Transfection of HEK293T cells, secretion assay for wild-type and mutant LGI1 constructs\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro secretion assay with multiple mutants, replicated across multiple subsequent studies\",\n      \"pmids\": [\"15857855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM22, a transmembrane protein whose mutation causes seizures, serves as a receptor for secreted LGI1. LGI1 binding to ADAM22 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices; ADPEAF-causing mutant LGI1 fails to bind ADAM22.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology in rat hippocampal slices, binding assay with mutant LGI1\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal binding assays, functional electrophysiology, mutagenesis confirmation, replicated by multiple subsequent studies\",\n      \"pmids\": [\"16990550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LGI1 is a novel subunit of presynaptic Kv1.1-containing channel complexes in hippocampal axon terminals, where it selectively prevents N-type inactivation mediated by the Kvβ1 subunit; ADLTE-associated LGI1 mutants fail to prevent this inactivation, resulting in channels with rapid inactivation kinetics.\",\n      \"method\": \"Biochemical co-purification/proteomics of Kv1.1 complexes from rat brain, electrophysiology, analysis of disease mutants\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-purification with mass spectrometry, electrophysiological characterization of mutant effects, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16504945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LGI1 is expressed as two isoforms (~60 and ~65 kDa) that reside in different subcellular compartments; the long isoform is secreted while the short isoform is retained intracellularly. ADLTE mutants of the long form are retained in the ER and Golgi. Secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells.\",\n      \"method\": \"Subcellular fractionation, immunocytochemistry, secretion assays in transfected cells, cell surface binding assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, ICC, binding assay), single lab but consistent with broader literature\",\n      \"pmids\": [\"17067999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LGI1 binds to ADAM22, ADAM23, and ADAM11, but not ADAM12, establishing that ADAM22 is not the sole receptor for LGI1 and that the LGI-ADAM interaction system involves multiple ADAM family members.\",\n      \"method\": \"Immunoprecipitation and mass spectrometric analysis from mouse brain, quantitative cell-ELISA binding assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP/MS from brain tissue plus quantitative cell-ELISA, single lab, consistent with genetic epistasis data\",\n      \"pmids\": [\"18974846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM23 is identified as the primary high-affinity LGI1-binding protein in an unbiased brain screen. LGI1 binding to ADAM23 promotes neurite outgrowth; ADAM23-null neurons show reduced dendritic arborization and ADAM23-null mice exhibit spontaneous seizures and decreased seizure thresholds.\",\n      \"method\": \"Unbiased brain binding screen, neurite outgrowth assays in wild-type vs. ADAM23-/- neurons, in vivo seizure monitoring\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased binding screen, genetic loss-of-function with multiple phenotypic readouts, consistent with complementary studies\",\n      \"pmids\": [\"19796686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LGI1-/- mice develop lethal epilepsy rescued specifically by neuronal LGI1 transgene but not LGI3. Extracellularly secreted LGI1 organizes a transsynaptic protein complex linking presynaptic ADAM23/Kv1 channels and postsynaptic ADAM22/AMPA receptor scaffolds; loss of LGI1 selectively reduces AMPA receptor-mediated synaptic transmission in hippocampus.\",\n      \"method\": \"Genetic knockout and transgenic rescue, co-immunoprecipitation of transsynaptic complex, 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 / Strong — genetic rescue experiment, biochemical complex characterization, electrophysiology, multiple orthogonal methods\",\n      \"pmids\": [\"20133599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LGI1 functions as a specific Nogo receptor 1 (NgR1) ligand that antagonizes myelin-based growth inhibition. NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.\",\n      \"method\": \"Neuronal growth assays on myelin substrates, growth cone collapse assay, pulldown/co-immunoprecipitation of NgR1-ADAM22 complex\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional growth assays with defined substrate, co-IP of receptor complex, single lab\",\n      \"pmids\": [\"20463223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LGI1 regulates postnatal pruning of retinal axons in the visual relay thalamus; mutant truncated LGI1 (836delC) blocks retinogeniculate axon pruning and arrests normal single-fiber strengthening, while excess wild-type LGI1 accelerates both processes.\",\n      \"method\": \"Transgenic mouse models expressing mutant or wild-type LGI1, retinogeniculate synapse electrophysiology and anatomical analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple transgenic lines with reciprocal effects, electrophysiological and anatomical readouts, complementary heterozygous deletion\",\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 interaction, and reversibly reduce synaptic AMPA receptor clusters in hippocampal neurons. Disruption of the LGI1-ADAM22 interaction alone (by soluble ADAM22 ectodomain) is sufficient to reduce synaptic AMPA receptors. LGI1 knockout mice show greatly reduced hippocampal AMPA receptor levels.\",\n      \"method\": \"ELISA, co-immunoprecipitation, rat hippocampal neuron cultures, LGI1 knockout mouse analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ELISA, co-IP, cell culture, KO mice), mechanistic rescue experiments, single lab with comprehensive approach\",\n      \"pmids\": [\"24227725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Selective deletion of LGI1 in glutamatergic pyramidal neurons (Emx1-Cre or CaMKIIα-Cre) causes spontaneous seizures, whereas deletion in GABAergic parvalbumin interneurons does not alter seizure thresholds, establishing that LGI1 secreted from excitatory neurons is required for epilepsy prevention.\",\n      \"method\": \"Conditional knockout mice with cell-type specific Cre drivers, EEG monitoring, convulsant seizure threshold testing\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell-type specific conditional knockouts with clear differential phenotypes, replicated across Cre lines\",\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, functioning specifically through ADAM22 to set postsynaptic strength. ADAM22 maintains excitatory synapses through PDZ domain interactions. In the absence of LGI1, the mature scaffolding protein PSD-95 cannot modulate synaptic transmission, but SAP102 function is unaffected, revealing that LGI1-ADAM22 coordinates synapse maturation by regulating PSD-95 function.\",\n      \"method\": \"Hippocampal slice electrophysiology, molecular replacement with ADAM22 mutants, viral expression constructs in LGI1-null neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic dissection with multiple domain mutants, electrophysiological validation, mechanistic specificity for PSD-95 vs SAP102\",\n      \"pmids\": [\"26178195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LGI1 deficiency (>50% down-regulation) causes posttranscriptional reduction of axonal Kv1.1 and Kv1.2 channel density at the axon initial segment of hippocampal CA3 neurons, reducing D-type potassium current and intrinsic excitability control; recombinant LGI1 restores Kv1 channel density and D-current.\",\n      \"method\": \"Electrophysiology (D-type current recording), immunofluorescence, recombinant LGI1 application, LGI1 knockout and heterozygous mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — recombinant protein application, genetic depletion, electrophysiological readout, posttranscriptional mechanism established\",\n      \"pmids\": [\"28673977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LGI1 acts presynaptically as a negative modulator of excitatory synaptic transmission during early postnatal development; LGI1 deficiency causes increased presynaptic glutamate release without altering postsynaptic AMPA receptor activity, leading to hyperexcitable networks before seizure onset.\",\n      \"method\": \"Electrophysiology in hippocampal slices from Lgi1-/- mice at pre-seizure stages, postsynaptic AMPA receptor recording, morphological analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pre-seizure developmental analysis, dissection of pre vs postsynaptic mechanisms, genetic model\",\n      \"pmids\": [\"26878798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LGI1 missense mutations S473L and R474Q (secretion-positive) fail to interact with ADAM22 and ADAM23 on the cell surface, establishing a second loss-of-function mechanism (impaired receptor binding) distinct from secretion failure.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation with cell-surface ADAM22/23, 3D protein modeling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and immunofluorescence with multiple secretion-competent mutants, consistent with crystal structure data\",\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 LGI1's C-terminal EPTP domain binds to the metalloprotease-like domain of ADAM22; LGI1's LRR and EPTP domains mediate LGI1-LGI1 dimerization. Pathogenic R474Q mutation disrupts the LGI1-LGI1 interface and the higher-order assembly in vitro and in a mouse epilepsy model.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, knock-in mouse model for R474Q mutation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and in vivo knock-in mouse model\",\n      \"pmids\": [\"29670100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Patient-derived LGI1 IgG antibodies prevent LGI1 binding to both ADAM23 and ADAM22; epitopes reside in the LRR1 and EPTP1 domains. In mice infused with patient IgG, Kv1.1 and AMPA receptor synaptic levels decrease (Kv1.1 effects precede AMPA effects), causing neuronal hyperexcitability, increased glutamatergic transmission, impaired LTP, and reversible memory deficits.\",\n      \"method\": \"Epitope mapping with LGI1 domain constructs, cerebroventricular patient IgG infusion in mice, confocal analysis, patch-clamp electrophysiology, LTP recording, behavioral memory testing\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — patient-derived IgG passive transfer model, multiple orthogonal readouts (biochemical, electrophysiological, behavioral), reversal upon IgG withdrawal\",\n      \"pmids\": [\"30346486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM22 and ADAM23 modulate LGI1 trafficking: they promote ER export and expression of LGI1 at the neuronal cell surface, and co-transport with LGI1 in axonal vesicles. LGI1 is recruited to the axon initial segment where it colocalizes with ADAM22 and Kv1 channels; ADLTE mutations S473L and R474Q prevent LGI1 association with ADAM22 and enrichment at the AIS.\",\n      \"method\": \"Hippocampal neuron cultures, immunofluorescence, live-cell axonal transport imaging, expression of ADLTE mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging, immunofluorescence, disease mutant analysis, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"30598502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Patient-derived monoclonal LGI1 antibodies (mAbs) segregate into two populations targeting either the LRR or EPTP domains with distinct properties: LRR-specific mAbs bind brain sections and induce internalization of the LGI1-ADAM22/23 complex in neurons; EPTP-specific mAbs inhibit LGI1 docking to ADAM22/23 but show less brain binding. Both types abolish LTP induction; LRR-directed high-affinity mAbs induce memory impairment after hippocampal injection.\",\n      \"method\": \"Generation of patient-derived mAbs from peripheral B cells, live cell-based assays, intrahippocampal injection in rodents, LTP recording, behavioral testing\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — patient mAbs with domain-specific mechanistic dissection, in vivo injection with electrophysiological and behavioral outcomes, multiple orthogonal methods\",\n      \"pmids\": [\"32437528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSF-derived monoclonal LGI1 antibodies from patients increase intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures; both ADAM22-competing and non-competing antibodies produce this effect, demonstrating that LGI1 antibodies alone are sufficient to promote neuronal hyperexcitability.\",\n      \"method\": \"Cloning of antibodies from CSF B cells/ASCs, application to hippocampal slice cultures, patch-clamp electrophysiology\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — monoclonal antibody application to defined neuronal preparation, electrophysiological readout, two mechanistic classes tested\",\n      \"pmids\": [\"31900946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LGI1-ADAM22 instructs PSD-95 family MAGUKs to organize transsynaptic protein networks including NMDA/AMPA receptors, Kv1 channels, and LRRTM4-Neurexin adhesion molecules. ADAM22 knock-in mice lacking the ADAM22-MAGUK interaction develop lethal epilepsy with less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission. Without ADAM22-MAGUK interaction, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Forced co-expression of ADAM22 and PSD-95 reconstitutes nano-condensates in non-neuronal cells.\",\n      \"method\": \"ADAM22 knock-in mouse (MAGUK interaction-deficient), super-resolution microscopy, electrophysiology, reconstitution in non-neuronal cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knock-in genetic model, reconstitution in non-neuronal cells, super-resolution structural analysis, electrophysiology, multiple orthogonal methods\",\n      \"pmids\": [\"33397806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKA-mediated dual phosphorylation of ADAM22 promotes high-affinity binding to dimerized 14-3-3 proteins, protecting LGI1-ADAM22 complexes from endocytosis-dependent degradation. Forskolin-induced PKA activation increases ADAM22 levels. Approximately 50% of normal LGI1 levels and only ~10% of ADAM22 levels are sufficient to prevent lethal epilepsy in hypomorphic mice.\",\n      \"method\": \"Genetic analysis of hypomorphic mice, structural analysis of 14-3-3/ADAM22 interaction, PKA activation experiments with forskolin\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic hypomorphic series with quantitative threshold determination, structural and biochemical PTM characterization, pharmacological validation\",\n      \"pmids\": [\"34910912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Subacute shRNA-mediated reduction of LGI1 in hippocampus increases dentate granule cell excitability and low-frequency facilitation of mossy fiber to CA3 transmission; α-dendrotoxin (Kv1 blocker) occludes this effect, implicating Kv1.1 as the downstream effector.\",\n      \"method\": \"shRNA knockdown in hippocampal slices and neuronal cultures, electrophysiology, pharmacological occlusion with α-dendrotoxin\",\n      \"journal\": \"Epilepsia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA KD with pharmacological occlusion experiment, single lab\",\n      \"pmids\": [\"33104247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"An LRR domain-specific (but not EPTP domain-specific) patient-derived monoclonal LGI1 antibody increases intrinsic excitability of CA3 pyramidal neurons correlated with reduced sensitivity to a selective Kv1.1 channel blocker, demonstrating that LRR-domain antibodies modulate neuronal excitability via Kv1.1.\",\n      \"method\": \"Domain-specific patient mAb application to organotypic hippocampal cultures, patch-clamp electrophysiology, pharmacological Kv1.1 block\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific mAbs with electrophysiological dissection and pharmacological validation, single lab\",\n      \"pmids\": [\"36078121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Reintroduction of LGI1 into LGI1-null glioma cell lines (T98G, A172) significantly reduces cell proliferation, inhibits invasion in Matrigel assays, and reduces anchorage-independent growth, demonstrating a functional role in suppressing malignant phenotypes via ERK1/2 pathway inhibition.\",\n      \"method\": \"Retroviral/stable transfection of LGI1 into null glioma cell lines, proliferation assays, Matrigel invasion assays, soft agar colony assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in multiple null cell lines with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"12821932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LGI1 re-expression in T98G glioma cells downregulates MMP1 and MMP3 gene expression through inhibition of ERK1/2 phosphorylation (not p38) and promotion of AKT phosphorylation leading to Raf1(Ser-259) phosphorylation; pharmacological inhibition of MAPK pathway mimics LGI1 effects, and phorbol ester treatment reverses LGI1-mediated suppression of MMP1/3 and ERK1/2 phosphorylation.\",\n      \"method\": \"Affymetrix gene chip, pharmacological inhibitors (PD98059, U0126, SB203580), Western blot for ERK1/2 and AKT phosphorylation, phorbol ester treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway analysis with multiple pharmacological tools and readouts, single lab\",\n      \"pmids\": [\"15047712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OPALIN, an oligodendrocyte-specific membrane protein, is identified as an LGI1 receptor on oligodendrocytes via LGI1 affinity chromatography and mass spectrometry. Conditional knockout of OPALIN in the oligodendrocyte lineage causes hypomyelination and white matter abnormalities phenocopying LGI1 deficiency; re-expression of LGI1-binding-deficient OPALIN (K23A/D26A) fails to rescue hypomyelination.\",\n      \"method\": \"LGI1 affinity chromatography with mouse brain lysates and mass spectrometry, conditional knockout mice, viral rescue with wild-type and mutant OPALIN\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — affinity chromatography/MS for receptor identification, conditional KO phenocopy, binding-deficient mutant rescue failure, multiple orthogonal validations\",\n      \"pmids\": [\"39083419\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGI1 is a secreted neuronal glycoprotein that forms a transsynaptic complex by binding presynaptically to ADAM23 (and Kv1.1-containing channel complexes) and postsynaptically to ADAM22 (which anchors PSD-95/MAGUK scaffolds and AMPA receptors); through this transsynaptic nanoalignment, LGI1-ADAM22 enables PSD-95 to potentiate AMPA receptor-mediated synaptic transmission and regulates Kv1 channel density at the axon initial segment to control intrinsic excitability; the LGI1-ADAM22 complex is stabilized by PKA-mediated phosphorylation of ADAM22 and 14-3-3 binding, and in oligodendrocytes LGI1 promotes myelination via the receptor OPALIN, while disease-causing mutations either prevent LGI1 secretion or impair its binding to ADAM22/23, and patient autoantibodies targeting the LRR or EPTP domains disrupt LGI1-ADAM22/23 interactions and/or induce receptor internalization, reducing Kv1.1 and AMPA receptor levels and causing neuronal hyperexcitability, LTP impairment, and memory deficits.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LGI1 is a secreted neuronal glycoprotein that organizes a transsynaptic protein complex controlling synaptic strength and intrinsic neuronal excitability, and whose loss of function causes epilepsy [#2, #8]. Secreted wild-type LGI1 bridges presynaptic ADAM23/Kv1 channel complexes and postsynaptic ADAM22/AMPA receptor scaffolds, and genetic deletion of LGI1 in mice produces lethal epilepsy that is rescued by neuronal LGI1 but not LGI3 [#8]. Through ADAM22, LGI1 instructs PSD-95-family MAGUKs to condense transsynaptic nanodomains that align Kv1 channels, NMDA/AMPA receptors and adhesion molecules, and this ADAM22-MAGUK linkage is required for PSD-95 to potentiate AMPA receptor-mediated transmission [#13, #22]; the LGI1-ADAM22 complex is further stabilized by PKA-dependent phosphorylation of ADAM22 and 14-3-3 binding that protects it from endocytic degradation [#23]. Presynaptically, LGI1 is a subunit of Kv1.1-containing channels and prevents Kvβ1-mediated N-type inactivation, and LGI1 deficiency post-transcriptionally reduces Kv1.1/Kv1.2 density at the axon initial segment, lowering D-type current and raising excitability [#4, #14]. The crystal structure of the LGI1-ADAM22 complex defines a 2:2 heterotetramer in which the EPTP domain binds the ADAM22 metalloprotease-like domain while the LRR and EPTP domains mediate LGI1 dimerization [#17]. Autosomal dominant lateral temporal epilepsy mutations act either by blocking LGI1 secretion or by abolishing ADAM22/23 binding and higher-order assembly without affecting secretion [#2, #16, #17], and limbic encephalitis patient autoantibodies against the LRR or EPTP domains disrupt LGI1-ADAM22/23 interactions or internalize the complex, reducing Kv1.1 and AMPA receptors and producing hyperexcitability, impaired LTP and reversible memory deficits [#18, #20]. Beyond the nervous system, LGI1 binds the oligodendrocyte receptor OPALIN to promote myelination [#28], and was originally identified as a candidate glioma tumor suppressor that, when re-expressed, suppresses proliferation and invasion via ERK1/2 inhibition [#0, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established LGI1 as a leucine-rich-repeat protein and candidate tumor suppressor, the first functional clue to the gene before its neuronal role was known.\",\n      \"evidence\": \"Positional cloning and expression analysis in glioblastoma cell lines and gliomas\",\n      \"pmids\": [\"9879993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism for tumor suppression defined\", \"Neuronal function not yet addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed LGI1 re-expression suppresses glioma malignancy through MAPK signaling, providing the first mechanistic pathway for its tumor-suppressor activity.\",\n      \"evidence\": \"Gain-of-function transfection in null glioma lines with proliferation/invasion assays and ERK1/2-AKT pathway analysis\",\n      \"pmids\": [\"12821932\", \"15047712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-line-based, no in vivo tumor model\", \"Relationship to neuronal ADAM-receptor signaling unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked LGI1 to human disease by showing truncating mutations segregate with autosomal dominant lateral temporal epilepsy, reframing the gene as neurological.\",\n      \"evidence\": \"Mutation analysis in epilepsy families and brain immunohistochemistry\",\n      \"pmids\": [\"11978770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathogenic mechanism of mutations unknown\", \"Molecular partners undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined secretion failure as a primary pathogenic mechanism, showing wild-type LGI1 is secreted while many ADPEAF mutants are retained or unstable.\",\n      \"evidence\": \"Secretion assays of wild-type and mutant LGI1 in HEK293T cells\",\n      \"pmids\": [\"15857855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify a receptor or downstream effector\", \"Secretion-competent disease mutants not yet explained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the receptor and synaptic output of LGI1 — ADAM22 binding enhances AMPA transmission and disease mutants fail to bind — and revealed LGI1 as a Kv1.1 channel subunit that blocks N-type inactivation.\",\n      \"evidence\": \"Co-IP, hippocampal slice electrophysiology, Kv1.1 complex co-purification/proteomics and mutant analysis\",\n      \"pmids\": [\"16990550\", \"16504945\", \"17067999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM22 was the sole receptor unresolved\", \"Pre- vs postsynaptic site of action unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Expanded the receptor repertoire to multiple ADAM family members and established ADAM23 as the high-affinity partner regulating neurite outgrowth and seizure threshold.\",\n      \"evidence\": \"IP/MS from brain, unbiased binding screen, neurite assays in ADAM23-/- neurons, in vivo seizure monitoring\",\n      \"pmids\": [\"18974846\", \"19796686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct roles of ADAM22 vs ADAM23 not separated\", \"Mechanism of outgrowth promotion undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated in vivo that LGI1 organizes a transsynaptic complex linking presynaptic ADAM23/Kv1 to postsynaptic ADAM22/AMPA scaffolds, with knockout causing lethal epilepsy rescued specifically by neuronal LGI1.\",\n      \"evidence\": \"LGI1 knockout/transgenic rescue, transsynaptic complex co-IP, electrophysiology\",\n      \"pmids\": [\"20133599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular details of scaffold organization not resolved\", \"Cell types secreting functional LGI1 not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Reported an additional ligand role for LGI1 as an NgR1 antagonist of myelin growth inhibition, with NgR1-ADAM22 forming a receptor complex.\",\n      \"evidence\": \"Myelin substrate growth assays, growth cone collapse, co-IP of NgR1-ADAM22\",\n      \"pmids\": [\"20463223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship of NgR1 axis to synaptic functions unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed LGI1 dose bidirectionally controls developmental retinogeniculate axon pruning and single-fiber strengthening, extending its role to circuit refinement.\",\n      \"evidence\": \"Mutant and overexpression transgenic mice, retinogeniculate electrophysiology and anatomy\",\n      \"pmids\": [\"22262888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating pruning effect not identified\", \"Link to ADAM22/23 transsynaptic complex not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Localized the protective source of LGI1 to glutamatergic neurons, since deletion there but not in PV interneurons caused seizures.\",\n      \"evidence\": \"Cell-type-specific conditional knockouts with EEG and seizure threshold testing\",\n      \"pmids\": [\"25234641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pre- vs postsynaptic mechanism in excitatory neurons not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the postsynaptic logic of LGI1-ADAM22 signaling: it enables mature PSD-95, but not SAP102, to modulate synaptic strength, identifying a MAGUK-specific maturation switch.\",\n      \"evidence\": \"Slice electrophysiology with ADAM22 domain mutants and viral replacement in LGI1-null neurons\",\n      \"pmids\": [\"26178195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ADAM22-MAGUK coupling unknown\", \"How PSD-95 is selectively engaged unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the autoimmune mechanism of limbic encephalitis by showing EPTP-targeting autoantibodies block LGI1-ADAM22/23 binding and reversibly reduce synaptic AMPA receptors.\",\n      \"evidence\": \"ELISA, co-IP, hippocampal neuron cultures, LGI1 knockout analysis\",\n      \"pmids\": [\"24227725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect on Kv1.1 not yet examined\", \"In vivo behavioral consequences untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the post-transcriptional and presynaptic arms of LGI1 function, showing it maintains AIS Kv1 channel density/D-current and negatively modulates presynaptic glutamate release before seizures, and identified secretion-competent mutants that fail receptor binding as a second loss-of-function class.\",\n      \"evidence\": \"D-type current recordings with recombinant LGI1, pre-seizure slice electrophysiology, and co-IP/modeling of S473L and R474Q mutants\",\n      \"pmids\": [\"28673977\", \"26878798\", \"27760137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery setting Kv1 density at the AIS undefined\", \"How presynaptic and postsynaptic roles are coordinated unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the atomic and in vivo basis of complex assembly — a 2:2 LGI1-ADAM22 heterotetramer with LGI1 dimerization — and demonstrated that disrupting LGI1 binding/internalization underlies both genetic and autoimmune disease.\",\n      \"evidence\": \"X-ray crystallography with R474Q knock-in mouse, and patient-IgG passive transfer with electrophysiology and behavior\",\n      \"pmids\": [\"29670100\", \"30346486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Higher-order assembly stoichiometry in vivo not fully defined\", \"Trafficking determinants of the complex not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed ADAM22/23 reciprocally control LGI1 trafficking — promoting ER export, surface expression, axonal co-transport and AIS recruitment — explaining how the complex is delivered to functional sites.\",\n      \"evidence\": \"Live-cell axonal transport imaging and immunofluorescence with ADLTE mutants in hippocampal neurons\",\n      \"pmids\": [\"30598502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Vesicular trafficking machinery not identified\", \"Single-lab imaging study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Dissected autoantibody mechanisms into domain-specific classes: LRR-directed antibodies internalize the complex and impair memory via Kv1.1, while EPTP-directed antibodies block ADAM22/23 docking, with both abolishing LTP.\",\n      \"evidence\": \"Patient-derived monoclonal antibodies, cell-based assays, intrahippocampal injection, LTP and behavior, plus CSF-derived mAb slice electrophysiology and pharmacological Kv1.1 block\",\n      \"pmids\": [\"32437528\", \"31900946\", \"36078121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each antibody class in patients unknown\", \"Long-term structural consequences of internalization undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that LGI1-ADAM22 instructs PSD-95-family MAGUKs to condense transsynaptic nanodomains, and that PKA phosphorylation/14-3-3 binding stabilizes the complex against degradation, with quantitative thresholds for epilepsy prevention.\",\n      \"evidence\": \"ADAM22-MAGUK-deficient knock-in mice, super-resolution microscopy, non-neuronal reconstitution, and structural/biochemical PTM analysis with hypomorphic mouse series\",\n      \"pmids\": [\"33397806\", \"34910912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals driving PKA-dependent stabilization in vivo unclear\", \"How nanodomain condensation translates to channel/receptor density unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended LGI1 signaling beyond neurons by identifying OPALIN as its oligodendrocyte receptor required for myelination, with binding-deficient OPALIN failing to rescue hypomyelination.\",\n      \"evidence\": \"LGI1 affinity chromatography/MS, conditional OPALIN knockout phenocopy, binding-deficient mutant rescue\",\n      \"pmids\": [\"39083419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream OPALIN signaling in oligodendrocytes undefined\", \"Whether ADAM receptors participate in the myelination axis unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple LGI1 receptor axes (ADAM22/23 synaptic, NgR1, OPALIN myelination) are integrated and differentially deployed across cell types and development remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking synaptic, axon-guidance and myelination functions\", \"Signal-transduction events downstream of LGI1 binding largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 7, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 14, 23]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 8, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 16, 19]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 8, 14, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 22, 23]}\n    ],\n    \"complexes\": [\n      \"LGI1-ADAM22 (2:2 heterotetramer)\",\n      \"presynaptic Kv1.1 channel complex\",\n      \"transsynaptic ADAM23/Kv1 - ADAM22/PSD-95-AMPA complex\"\n    ],\n    \"partners\": [\n      \"ADAM22\",\n      \"ADAM23\",\n      \"ADAM11\",\n      \"KCNA1\",\n      \"DLG4\",\n      \"RTN4R\",\n      \"OPALIN\",\n      \"YWHA (14-3-3)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}