{"gene":"LGI2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2005,"finding":"LGI2 (including the splice form LGI2B) is secreted into the extracellular medium following transfection into 293T cells, demonstrating that secretion is a conserved feature of the LGI protein family.","method":"Transfection of 293T cells followed by detection of secreted protein in culture medium","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct secretion assay in cell culture, single lab, single method but clear functional readout","pmids":["15857855"],"is_preprint":false},{"year":2011,"finding":"LGI2 is neuronally secreted, and a protein-truncating mutation in LGI2 prevents secretion. Wild-type LGI2 interacts with metalloproteinase-lacking ADAM family receptors (ADAM22/ADAM23), and the truncation mutation abolishes this ADAM interaction. LGI2 acts at least in part through the same ADAM receptors as LGI1.","method":"Genome-wide association mapping, identification of truncating mutation, secretion assays, ADAM interaction assays (canine model with Lagotto Romagnolo breed)","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic mapping, secretion assay, interaction assay), replicated finding for secretion, canine ortholog with strong mechanistic parallel to LGI1","pmids":["21829378"],"is_preprint":false},{"year":2010,"finding":"Wild-type LGI2 is secreted to the extracellular medium in glycosylated form. Several LGI2 mutant proteins corresponding to non-synonymous SNPs (affecting the signal peptide, leucine-rich repeats, and EAR propeller domain) are secretion-deficient and accumulate in the endoplasmic reticulum. Mutations at structurally homologous positions in the EAR domain have the same effect on secretion in LGI1 and LGI2.","method":"Transfection-based secretion assays, subcellular localization experiments, 3D structural modeling of EAR domain","journal":"BMC biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct secretion and localization assays with mutagenesis, single lab, two orthogonal methods (secretion assay + localization)","pmids":["20863412"],"is_preprint":false},{"year":2023,"finding":"LGI2 (together with LGI3) interacts with axonal ADAM23 to regulate the accumulation and stability of juxtaparanodal Kv1 (Shaker-type potassium channel) complexes in myelinated axons. This LGI2/LGI3-ADAM23 interaction is required for normal Kv1 clustering at the juxtaparanode, and loss of ADAM23 disrupts Kv1 complexes. Juxtaparanodal Kv1 complexes regulated by this pathway affect the refractory period and enable high-frequency burst firing of action potentials.","method":"Genetic knockout of ADAM23, peripheral nerve dissection, immunohistochemistry, electrophysiology (refractory period measurement)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, multiple orthogonal methods (IHC, electrophysiology), direct mechanistic pathway established","pmids":["36828548"],"is_preprint":false},{"year":2025,"finding":"Lgi2 is expressed mainly in GABAergic interneurons in the mouse hippocampus, with expression low neonatally but increasing during juvenility (P14). Lgi2 ablation in mice provokes ictal-like activity in hippocampal slice cultures, and adult LGI2-deficient mice show deficits in spatial reversal learning and impaired cognitive flexibility.","method":"In situ hybridization/expression analysis, Lgi2 knockout mice, electrophysiological recordings in hippocampal slice cultures, behavioral testing","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype (ictal activity) and behavioral readout, single lab, multiple orthogonal methods","pmids":["41177215"],"is_preprint":false},{"year":2024,"finding":"LGI2 is expressed presynaptically by inferior olivary neurons and, together with C1QL1 and CRTAC1, works in concert to specify the mature connectivity pattern (synaptic molecular identity) of climbing fiber inputs onto cerebellar Purkinje cells during postnatal development.","method":"Mouse postnatal developmental expression analysis, genetic dissection of presynaptic secreted protein contributions to synapse specificity","journal":"Nature neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined presynaptic expression with functional epistasis in circuit specification, single study, multiple proteins tested in concert","pmids":["39658623"],"is_preprint":false},{"year":2019,"finding":"LGI2 is expressed in parvalbumin-positive basket cells and identified as a unique presynaptic molecular contributor to GABAergic synapses on the soma of cortical/hippocampal neurons; mutations in LGI2 are implicated in epilepsy syndromes.","method":"Review citing experimental localization and genetic data from prior studies","journal":"Frontiers in molecular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper citing prior experimental data, no new direct experiment described in abstract","pmids":["31297048"],"is_preprint":false}],"current_model":"LGI2 is a secreted, glycosylated protein expressed predominantly in GABAergic interneurons and select excitatory neurons (e.g., inferior olivary neurons) that acts extracellularly by binding to metalloproteinase-lacking ADAM family receptors (principally ADAM22/ADAM23); this LGI2–ADAM23 interaction is required for the clustering and stability of juxtaparanodal Kv1 potassium channel complexes in myelinated axons (regulating the refractory period), and LGI2 also cooperates with other secreted proteins to specify synapse identity on cerebellar Purkinje cells; loss-of-function mutations that prevent LGI2 secretion or abolish ADAM binding cause epileptiform activity and behavioral deficits in model organisms."},"narrative":{"mechanistic_narrative":"LGI2 is a secreted, glycosylated neuronal protein that organizes axonal and synaptic connectivity in the nervous system by acting extracellularly on metalloproteinase-lacking ADAM family receptors [PMID:21829378, PMID:36828548]. It is secreted into the extracellular medium in glycosylated form, and its secretion depends on correct folding of its leucine-rich repeat and EAR propeller domains; non-synonymous mutations affecting the signal peptide, LRR, or EAR domain render the protein secretion-deficient and cause it to accumulate in the endoplasmic reticulum, with structurally homologous EAR mutations producing the same defect in LGI1 [PMID:15857855, PMID:20863412]. Once secreted, LGI2 binds the metalloproteinase-lacking ADAM receptors ADAM22/ADAM23, and a protein-truncating mutation that blocks secretion also abolishes this ADAM interaction, placing LGI2 in the same receptor pathway as LGI1 [PMID:21829378]. Through its interaction with axonal ADAM23, LGI2 (with LGI3) controls the accumulation and stability of juxtaparanodal Kv1 (Shaker-type) potassium channel complexes in myelinated axons, thereby regulating the action-potential refractory period and high-frequency burst firing [PMID:36828548]. LGI2 is expressed predominantly in GABAergic interneurons, and its ablation in mice provokes ictal-like activity in hippocampal slices and impairs spatial reversal learning and cognitive flexibility [PMID:41177215]; it is also expressed presynaptically by inferior olivary neurons, where it acts together with C1QL1 and CRTAC1 to specify the mature climbing fiber synaptic connectivity onto cerebellar Purkinje cells [PMID:39658623].","teleology":[{"year":2005,"claim":"Establishing whether LGI2 is secreted defined the basic mode of action of the protein, showing it acts in the extracellular space like other LGI family members.","evidence":"Transfection of 293T cells and detection of LGI2 (and splice form LGI2B) in culture medium","pmids":["15857855"],"confidence":"Medium","gaps":["No receptor or extracellular partner identified at this stage","Native neuronal secretion not yet demonstrated"]},{"year":2010,"claim":"Mapping which domains are required for secretion clarified how disease-associated mutations disrupt LGI2 function at the level of trafficking rather than activity.","evidence":"Transfection-based secretion and subcellular localization assays with mutagenesis of signal peptide, LRR, and EAR domains, plus 3D modeling of the EAR domain","pmids":["20863412"],"confidence":"Medium","gaps":["Does not establish the extracellular binding partner","Structural model not experimentally resolved"]},{"year":2011,"claim":"Identifying the ADAM22/ADAM23 interaction and a secretion-blocking truncating mutation placed LGI2 in a defined receptor pathway shared with LGI1 and linked it to neurological disease.","evidence":"GWAS mapping and identification of a truncating mutation in a canine (Lagotto Romagnolo) model, with secretion and ADAM interaction assays","pmids":["21829378"],"confidence":"High","gaps":["Downstream effect of ADAM binding not yet defined","Functional consequence at axons/synapses not established"]},{"year":2023,"claim":"Linking LGI2-ADAM23 signaling to juxtaparanodal Kv1 channel clustering defined the cellular consequence of the interaction and its impact on axonal excitability.","evidence":"ADAM23 genetic knockout, peripheral nerve immunohistochemistry, and electrophysiological refractory-period measurements","pmids":["36828548"],"confidence":"High","gaps":["Relative contributions of LGI2 versus LGI3 not resolved","Mechanism of Kv1 recruitment downstream of ADAM23 unknown"]},{"year":2024,"claim":"Demonstrating presynaptic LGI2 expression in inferior olivary neurons and combinatorial action with C1QL1/CRTAC1 extended its role from axonal channel clustering to circuit-level synapse specification.","evidence":"Mouse postnatal developmental expression analysis and genetic dissection of presynaptic secreted protein contributions to climbing fiber-Purkinje cell connectivity","pmids":["39658623"],"confidence":"Medium","gaps":["Receptor mediating the synapse-specification function not defined","Molecular interplay with C1QL1/CRTAC1 not mechanistically resolved"]},{"year":2025,"claim":"Cell-type-resolved expression and knockout phenotyping established LGI2 as a GABAergic-interneuron protein whose loss causes epileptiform activity and cognitive deficits, connecting molecular function to organismal phenotype.","evidence":"Expression analysis, Lgi2 knockout mice, hippocampal slice electrophysiology, and behavioral testing","pmids":["41177215"],"confidence":"Medium","gaps":["Causal link between ictal activity and the specific ADAM/Kv1 pathway not directly established","Circuit mechanism for cognitive flexibility deficits unknown"]},{"year":null,"claim":"How LGI2's two roles — juxtaparanodal Kv1 channel stabilization and presynaptic synapse-identity specification — are coordinated at the molecular level, and which receptors mediate each, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural data on the LGI2-ADAM complex","Mechanism coupling ADAM binding to Kv1 clustering undefined","Receptor for the synapse-specification function not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]}],"complexes":[],"partners":["ADAM23","ADAM22","C1QL1","CRTAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N0V4","full_name":"Leucine-rich repeat LGI family member 2","aliases":["LGI1-like protein 2","Leucine-rich glioma-inactivated protein 2"],"length_aa":545,"mass_kda":62.3,"function":"Required for the development of soma-targeting inhibitory GABAergic synapses made by parvalbumin-positive basket cells","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8N0V4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LGI2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LGI2","total_profiled":1310},"omim":[{"mim_id":"608303","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 4; LGI4","url":"https://www.omim.org/entry/608303"},{"mim_id":"608302","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 3; LGI3","url":"https://www.omim.org/entry/608302"},{"mim_id":"608301","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 2; LGI2","url":"https://www.omim.org/entry/608301"},{"mim_id":"600512","title":"EPILEPSY, FAMILIAL TEMPORAL LOBE, 1; ETL1","url":"https://www.omim.org/entry/600512"},{"mim_id":"115450","title":"CASEIN, ALPHA; CSN1","url":"https://www.omim.org/entry/115450"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Centrosome","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":120.3}],"url":"https://www.proteinatlas.org/search/LGI2"},"hgnc":{"alias_symbol":["KIAA1916","FLJ10675"],"prev_symbol":[]},"alphafold":{"accession":"Q8N0V4","domains":[{"cath_id":"3.80.10.10","chopping":"38-213","consensus_level":"medium","plddt":91.9527,"start":38,"end":213},{"cath_id":"2.120.10.80","chopping":"216-228_320-541","consensus_level":"medium","plddt":96.1662,"start":216,"end":541},{"cath_id":"2.40.128","chopping":"230-317","consensus_level":"medium","plddt":95.3603,"start":230,"end":317}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N0V4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N0V4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N0V4-F1-predicted_aligned_error_v6.png","plddt_mean":91.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LGI2","jax_strain_url":"https://www.jax.org/strain/search?query=LGI2"},"sequence":{"accession":"Q8N0V4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N0V4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N0V4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N0V4"}},"corpus_meta":[{"pmid":"15857855","id":"PMC_15857855","title":"ADPEAF 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  \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct secretion assay in cell culture, single lab, single method but clear functional readout\",\n      \"pmids\": [\"15857855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LGI2 is neuronally secreted, and a protein-truncating mutation in LGI2 prevents secretion. Wild-type LGI2 interacts with metalloproteinase-lacking ADAM family receptors (ADAM22/ADAM23), and the truncation mutation abolishes this ADAM interaction. LGI2 acts at least in part through the same ADAM receptors as LGI1.\",\n      \"method\": \"Genome-wide association mapping, identification of truncating mutation, secretion assays, ADAM interaction assays (canine model with Lagotto Romagnolo breed)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic mapping, secretion assay, interaction assay), replicated finding for secretion, canine ortholog with strong mechanistic parallel to LGI1\",\n      \"pmids\": [\"21829378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wild-type LGI2 is secreted to the extracellular medium in glycosylated form. Several LGI2 mutant proteins corresponding to non-synonymous SNPs (affecting the signal peptide, leucine-rich repeats, and EAR propeller domain) are secretion-deficient and accumulate in the endoplasmic reticulum. Mutations at structurally homologous positions in the EAR domain have the same effect on secretion in LGI1 and LGI2.\",\n      \"method\": \"Transfection-based secretion assays, subcellular localization experiments, 3D structural modeling of EAR domain\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct secretion and localization assays with mutagenesis, single lab, two orthogonal methods (secretion assay + localization)\",\n      \"pmids\": [\"20863412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGI2 (together with LGI3) interacts with axonal ADAM23 to regulate the accumulation and stability of juxtaparanodal Kv1 (Shaker-type potassium channel) complexes in myelinated axons. This LGI2/LGI3-ADAM23 interaction is required for normal Kv1 clustering at the juxtaparanode, and loss of ADAM23 disrupts Kv1 complexes. Juxtaparanodal Kv1 complexes regulated by this pathway affect the refractory period and enable high-frequency burst firing of action potentials.\",\n      \"method\": \"Genetic knockout of ADAM23, peripheral nerve dissection, immunohistochemistry, electrophysiology (refractory period measurement)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, multiple orthogonal methods (IHC, electrophysiology), direct mechanistic pathway established\",\n      \"pmids\": [\"36828548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lgi2 is expressed mainly in GABAergic interneurons in the mouse hippocampus, with expression low neonatally but increasing during juvenility (P14). Lgi2 ablation in mice provokes ictal-like activity in hippocampal slice cultures, and adult LGI2-deficient mice show deficits in spatial reversal learning and impaired cognitive flexibility.\",\n      \"method\": \"In situ hybridization/expression analysis, Lgi2 knockout mice, electrophysiological recordings in hippocampal slice cultures, behavioral testing\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype (ictal activity) and behavioral readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41177215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGI2 is expressed presynaptically by inferior olivary neurons and, together with C1QL1 and CRTAC1, works in concert to specify the mature connectivity pattern (synaptic molecular identity) of climbing fiber inputs onto cerebellar Purkinje cells during postnatal development.\",\n      \"method\": \"Mouse postnatal developmental expression analysis, genetic dissection of presynaptic secreted protein contributions to synapse specificity\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined presynaptic expression with functional epistasis in circuit specification, single study, multiple proteins tested in concert\",\n      \"pmids\": [\"39658623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LGI2 is expressed in parvalbumin-positive basket cells and identified as a unique presynaptic molecular contributor to GABAergic synapses on the soma of cortical/hippocampal neurons; mutations in LGI2 are implicated in epilepsy syndromes.\",\n      \"method\": \"Review citing experimental localization and genetic data from prior studies\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper citing prior experimental data, no new direct experiment described in abstract\",\n      \"pmids\": [\"31297048\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGI2 is a secreted, glycosylated protein expressed predominantly in GABAergic interneurons and select excitatory neurons (e.g., inferior olivary neurons) that acts extracellularly by binding to metalloproteinase-lacking ADAM family receptors (principally ADAM22/ADAM23); this LGI2–ADAM23 interaction is required for the clustering and stability of juxtaparanodal Kv1 potassium channel complexes in myelinated axons (regulating the refractory period), and LGI2 also cooperates with other secreted proteins to specify synapse identity on cerebellar Purkinje cells; loss-of-function mutations that prevent LGI2 secretion or abolish ADAM binding cause epileptiform activity and behavioral deficits in model organisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LGI2 is a secreted, glycosylated neuronal protein that organizes axonal and synaptic connectivity in the nervous system by acting extracellularly on metalloproteinase-lacking ADAM family receptors [#1, #3]. It is secreted into the extracellular medium in glycosylated form, and its secretion depends on correct folding of its leucine-rich repeat and EAR propeller domains; non-synonymous mutations affecting the signal peptide, LRR, or EAR domain render the protein secretion-deficient and cause it to accumulate in the endoplasmic reticulum, with structurally homologous EAR mutations producing the same defect in LGI1 [#0, #2]. Once secreted, LGI2 binds the metalloproteinase-lacking ADAM receptors ADAM22/ADAM23, and a protein-truncating mutation that blocks secretion also abolishes this ADAM interaction, placing LGI2 in the same receptor pathway as LGI1 [#1]. Through its interaction with axonal ADAM23, LGI2 (with LGI3) controls the accumulation and stability of juxtaparanodal Kv1 (Shaker-type) potassium channel complexes in myelinated axons, thereby regulating the action-potential refractory period and high-frequency burst firing [#3]. LGI2 is expressed predominantly in GABAergic interneurons, and its ablation in mice provokes ictal-like activity in hippocampal slices and impairs spatial reversal learning and cognitive flexibility [#4]; it is also expressed presynaptically by inferior olivary neurons, where it acts together with C1QL1 and CRTAC1 to specify the mature climbing fiber synaptic connectivity onto cerebellar Purkinje cells [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing whether LGI2 is secreted defined the basic mode of action of the protein, showing it acts in the extracellular space like other LGI family members.\",\n      \"evidence\": \"Transfection of 293T cells and detection of LGI2 (and splice form LGI2B) in culture medium\",\n      \"pmids\": [\"15857855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or extracellular partner identified at this stage\", \"Native neuronal secretion not yet demonstrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping which domains are required for secretion clarified how disease-associated mutations disrupt LGI2 function at the level of trafficking rather than activity.\",\n      \"evidence\": \"Transfection-based secretion and subcellular localization assays with mutagenesis of signal peptide, LRR, and EAR domains, plus 3D modeling of the EAR domain\",\n      \"pmids\": [\"20863412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish the extracellular binding partner\", \"Structural model not experimentally resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying the ADAM22/ADAM23 interaction and a secretion-blocking truncating mutation placed LGI2 in a defined receptor pathway shared with LGI1 and linked it to neurological disease.\",\n      \"evidence\": \"GWAS mapping and identification of a truncating mutation in a canine (Lagotto Romagnolo) model, with secretion and ADAM interaction assays\",\n      \"pmids\": [\"21829378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effect of ADAM binding not yet defined\", \"Functional consequence at axons/synapses not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linking LGI2-ADAM23 signaling to juxtaparanodal Kv1 channel clustering defined the cellular consequence of the interaction and its impact on axonal excitability.\",\n      \"evidence\": \"ADAM23 genetic knockout, peripheral nerve immunohistochemistry, and electrophysiological refractory-period measurements\",\n      \"pmids\": [\"36828548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of LGI2 versus LGI3 not resolved\", \"Mechanism of Kv1 recruitment downstream of ADAM23 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating presynaptic LGI2 expression in inferior olivary neurons and combinatorial action with C1QL1/CRTAC1 extended its role from axonal channel clustering to circuit-level synapse specification.\",\n      \"evidence\": \"Mouse postnatal developmental expression analysis and genetic dissection of presynaptic secreted protein contributions to climbing fiber-Purkinje cell connectivity\",\n      \"pmids\": [\"39658623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the synapse-specification function not defined\", \"Molecular interplay with C1QL1/CRTAC1 not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cell-type-resolved expression and knockout phenotyping established LGI2 as a GABAergic-interneuron protein whose loss causes epileptiform activity and cognitive deficits, connecting molecular function to organismal phenotype.\",\n      \"evidence\": \"Expression analysis, Lgi2 knockout mice, hippocampal slice electrophysiology, and behavioral testing\",\n      \"pmids\": [\"41177215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between ictal activity and the specific ADAM/Kv1 pathway not directly established\", \"Circuit mechanism for cognitive flexibility deficits unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LGI2's two roles — juxtaparanodal Kv1 channel stabilization and presynaptic synapse-identity specification — are coordinated at the molecular level, and which receptors mediate each, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural data on the LGI2-ADAM complex\", \"Mechanism coupling ADAM binding to Kv1 clustering undefined\", \"Receptor for the synapse-specification function not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ADAM23\", \"ADAM22\", \"C1QL1\", \"CRTAC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}