{"gene":"LGI2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2005,"finding":"LGI2 (specifically a 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 into 293T cells, secretion assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct secretion assay in cultured cells, single lab, single method","pmids":["15857855"],"is_preprint":false},{"year":2011,"finding":"LGI2 is neuronally secreted and interacts with metalloproteinase-lacking members of the ADAM family (ADAM22/ADAM23), acting on these neuronal receptors involved in synapse remodeling; a protein-truncating mutation in LGI2 prevents both secretion and ADAM interaction, causing remitting focal epilepsy in Lagotto Romagnolo dogs.","method":"Genome-wide association, identification of truncating mutation, secretion assay, ADAM interaction assay, canine genetic model","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional assays (secretion + ADAM binding), replicated with disease mutation, ortholog model","pmids":["21829378"],"is_preprint":false},{"year":2010,"finding":"Wild-type LGI2 is secreted to the extracellular medium in glycosylated form; mutations at positions structurally homologous to epilepsy-causing LGI1 mutations cause secretion failure and accumulation in the endoplasmic reticulum, establishing a shared molecular pathogenesis mechanism.","method":"Transfection-based secretion assay, subcellular localization (ER accumulation), 3D structural modeling of EAR domain mutations","journal":"BMC biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct secretion and localization assays with multiple mutants, single lab","pmids":["20863412"],"is_preprint":false},{"year":2023,"finding":"LGI2 interacts with axonal ADAM23 and, together with LGI3, is required for the accumulation and stability of juxtaparanodal Kv1 potassium channel complexes in myelinated axons; this LGI2/LGI3-ADAM23 interaction regulates the refractory period and enables high-frequency burst firing of action potentials.","method":"Genetic knockout mice, immunohistochemistry, electrophysiology, peripheral nerve dissection, Co-IP/interaction assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — KO mouse model with defined cellular phenotype (Kv1 mislocalization), electrophysiological readout, multiple orthogonal methods","pmids":["36828548"],"is_preprint":false},{"year":2024,"finding":"LGI2 is expressed by inferior olivary neurons as a presynaptic secreted protein and works in concert with C1QL1 and CRTAC1 to specify the mature connectivity pattern of excitatory synapses onto cerebellar Purkinje cells during postnatal development.","method":"Mouse developmental expression analysis, genetic and molecular dissection of presynaptic secreted proteins, in vivo mouse cerebellar circuit analysis","journal":"Nature neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse model with circuit-level readout, single study","pmids":["39658623"],"is_preprint":false},{"year":2025,"finding":"Lgi2 is expressed primarily in GABAergic interneurons of the mouse hippocampus, with expression peaking during juvenility (P14); Lgi2 ablation in mice provokes ictal-like epileptiform activity in hippocampal slice cultures and causes deficits in spatial reversal learning and cognitive flexibility in adults.","method":"In situ hybridization/expression analysis, LGI2-deficient mouse model, hippocampal slice electrophysiology, behavioral testing","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with electrophysiological and behavioral phenotypes, single lab","pmids":["41177215"],"is_preprint":false},{"year":2019,"finding":"LGI2 is expressed in parvalbumin-positive basket cells and identified as a unique presynaptic molecular contributor to somatic GABAergic synapses; mutations in LGI2 are implicated in epilepsy syndromes.","method":"Review/synthesis of expression and genetic data; direct experimental basis cited from prior studies","journal":"Frontiers in molecular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 — review synthesis, no new primary experiment reported","pmids":["31297048"],"is_preprint":false}],"current_model":"LGI2 is a neuronally secreted glycoprotein expressed primarily in GABAergic interneurons that acts extracellularly by binding to ADAM22/ADAM23 receptors on neurons; this interaction is required for the clustering and stability of juxtaparanodal Kv1 potassium channel complexes in myelinated axons (regulating refractory period and high-frequency firing), for specifying excitatory synapse identity on cerebellar Purkinje cells, and for suppressing epileptiform network activity during postnatal brain development — with disease-causing truncations preventing secretion and ADAM interaction, thereby causing remitting focal epilepsy."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that LGI2 is a secreted protein resolved whether LGI family members beyond LGI1 function extracellularly, positioning LGI2 as a potential signaling ligand rather than an intracellular factor.","evidence":"Secretion assay after transfection of LGI2B splice form into 293T cells","pmids":["15857855"],"confidence":"Medium","gaps":["Secretion shown only in heterologous 293T cells, not in neurons","Receptor or binding partner unknown","Functional consequence of secretion not tested"]},{"year":2010,"claim":"Demonstrating that EAR-domain mutations homologous to epilepsy-causing LGI1 variants block LGI2 secretion and cause ER retention established a shared pathogenic mechanism across the LGI family.","evidence":"Secretion assays and subcellular localization of multiple LGI2 mutants in transfected cells, 3D structural modeling","pmids":["20863412"],"confidence":"Medium","gaps":["No disease-causing LGI2 mutations in humans confirmed at this point","ADAM receptor interaction not yet tested for LGI2","Neuronal relevance of secretion failure not assessed in vivo"]},{"year":2011,"claim":"Identifying a truncating LGI2 mutation that abolishes both secretion and ADAM22/ADAM23 interaction as the cause of remitting focal epilepsy in dogs established LGI2 as a functional ligand for ADAM receptors and directly linked its loss to epileptogenesis.","evidence":"Genome-wide association in Lagotto Romagnolo dogs, truncating mutation identified, secretion and ADAM interaction assays with wild-type vs. mutant protein","pmids":["21829378"],"confidence":"High","gaps":["No human LGI2-epilepsy mutations reported","Downstream signaling events at ADAM receptors not characterized","Neural circuit mechanism of epilepsy not defined"]},{"year":2023,"claim":"Showing that LGI2 interaction with axonal ADAM23 is required for juxtaparanodal Kv1 channel clustering and high-frequency firing defined a specific cell-biological function — axonal ion channel organization — beyond synaptic remodeling.","evidence":"LGI2 knockout mice, immunohistochemistry for Kv1 channel mislocalization, electrophysiology measuring refractory period and burst firing, co-immunoprecipitation","pmids":["36828548"],"confidence":"High","gaps":["Relative contributions of LGI2 vs. LGI3 to Kv1 clustering not fully separable","Structural basis of LGI2-ADAM23 interaction unresolved","Whether Kv1 mislocalization contributes to epilepsy phenotype not tested"]},{"year":2024,"claim":"Identifying LGI2 as a presynaptic secreted factor from inferior olivary neurons that specifies excitatory synapse identity on Purkinje cells expanded its role from axonal organization to synapse-type specification in cerebellar circuits.","evidence":"Mouse developmental expression analysis and in vivo cerebellar circuit dissection, molecular epistasis with C1QL1 and CRTAC1","pmids":["39658623"],"confidence":"Medium","gaps":["Single study; independent replication needed","ADAM receptor involvement at climbing fiber synapses not confirmed","Whether LGI2 cerebellar function relates to epilepsy phenotype unknown"]},{"year":2025,"claim":"Demonstrating that LGI2 is expressed in hippocampal GABAergic interneurons with a juvenile peak and that its ablation causes epileptiform discharges and cognitive inflexibility identified the cell type and developmental window through which LGI2 suppresses network hyperexcitability.","evidence":"In situ hybridization, LGI2-deficient mouse hippocampal slice electrophysiology, behavioral testing for spatial reversal learning","pmids":["41177215"],"confidence":"Medium","gaps":["Mechanism by which interneuron-secreted LGI2 suppresses excitability not defined","Whether cognitive deficits are secondary to developmental epileptiform activity or reflect an independent function","Single lab; human relevance not established"]},{"year":null,"claim":"The downstream signaling events triggered by LGI2-ADAM22/ADAM23 binding that mediate channel clustering, synapse specification, and epilepsy suppression remain undefined, and no human Mendelian epilepsy mutations in LGI2 have been reported.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of LGI2-ADAM complex","Intracellular signaling cascade downstream of ADAM engagement unknown","Human genetic validation lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,3,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2,4]},{"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":[3,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["ADAM22","ADAM23","LGI3","C1QL1","CRTAC1"],"other_free_text":[]},"mechanistic_narrative":"LGI2 is a neuronally secreted glycoprotein that functions as an extracellular ligand for ADAM22/ADAM23 receptors to organize synaptic and axonal architecture during postnatal brain development. LGI2 is secreted in glycosylated form and binds ADAM22/ADAM23; disease-causing truncations prevent both secretion and receptor interaction, causing retention in the endoplasmic reticulum [PMID:21829378, PMID:20863412]. Through its interaction with axonal ADAM23, LGI2 (together with LGI3) is required for the clustering and stability of juxtaparanodal Kv1 potassium channel complexes in myelinated axons, thereby regulating the refractory period and enabling high-frequency burst firing [PMID:36828548]. Expressed predominantly in GABAergic interneurons with peak expression during juvenile development, LGI2 suppresses epileptiform network activity; its loss causes ictal-like discharges in hippocampal circuits and deficits in cognitive flexibility, and a truncating mutation in canine LGI2 causes remitting focal epilepsy [PMID:41177215, PMID:21829378]."},"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 mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15857855","citation_count":133,"is_preprint":false},{"pmid":"21829378","id":"PMC_21829378","title":"LGI2 truncation causes a remitting focal epilepsy in dogs.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21829378","citation_count":85,"is_preprint":false},{"pmid":"23713523","id":"PMC_23713523","title":"LGI proteins in the nervous system.","date":"2013","source":"ASN neuro","url":"https://pubmed.ncbi.nlm.nih.gov/23713523","citation_count":70,"is_preprint":false},{"pmid":"12023020","id":"PMC_12023020","title":"The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucine-rich repeat proteins.","date":"2002","source":"FEBS 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cultured cells, single lab, single method\",\n      \"pmids\": [\"15857855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LGI2 is neuronally secreted and interacts with metalloproteinase-lacking members of the ADAM family (ADAM22/ADAM23), acting on these neuronal receptors involved in synapse remodeling; a protein-truncating mutation in LGI2 prevents both secretion and ADAM interaction, causing remitting focal epilepsy in Lagotto Romagnolo dogs.\",\n      \"method\": \"Genome-wide association, identification of truncating mutation, secretion assay, ADAM interaction assay, canine genetic model\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional assays (secretion + ADAM binding), replicated with disease mutation, ortholog model\",\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; mutations at positions structurally homologous to epilepsy-causing LGI1 mutations cause secretion failure and accumulation in the endoplasmic reticulum, establishing a shared molecular pathogenesis mechanism.\",\n      \"method\": \"Transfection-based secretion assay, subcellular localization (ER accumulation), 3D structural modeling of EAR domain mutations\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct secretion and localization assays with multiple mutants, single lab\",\n      \"pmids\": [\"20863412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGI2 interacts with axonal ADAM23 and, together with LGI3, is required for the accumulation and stability of juxtaparanodal Kv1 potassium channel complexes in myelinated axons; this LGI2/LGI3-ADAM23 interaction regulates the refractory period and enables high-frequency burst firing of action potentials.\",\n      \"method\": \"Genetic knockout mice, immunohistochemistry, electrophysiology, peripheral nerve dissection, Co-IP/interaction assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KO mouse model with defined cellular phenotype (Kv1 mislocalization), electrophysiological readout, multiple orthogonal methods\",\n      \"pmids\": [\"36828548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGI2 is expressed by inferior olivary neurons as a presynaptic secreted protein and works in concert with C1QL1 and CRTAC1 to specify the mature connectivity pattern of excitatory synapses onto cerebellar Purkinje cells during postnatal development.\",\n      \"method\": \"Mouse developmental expression analysis, genetic and molecular dissection of presynaptic secreted proteins, in vivo mouse cerebellar circuit analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with circuit-level readout, single study\",\n      \"pmids\": [\"39658623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lgi2 is expressed primarily in GABAergic interneurons of the mouse hippocampus, with expression peaking during juvenility (P14); Lgi2 ablation in mice provokes ictal-like epileptiform activity in hippocampal slice cultures and causes deficits in spatial reversal learning and cognitive flexibility in adults.\",\n      \"method\": \"In situ hybridization/expression analysis, LGI2-deficient mouse model, hippocampal slice electrophysiology, behavioral testing\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with electrophysiological and behavioral phenotypes, single lab\",\n      \"pmids\": [\"41177215\"],\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 somatic GABAergic synapses; mutations in LGI2 are implicated in epilepsy syndromes.\",\n      \"method\": \"Review/synthesis of expression and genetic data; direct experimental basis cited from prior studies\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — review synthesis, no new primary experiment reported\",\n      \"pmids\": [\"31297048\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGI2 is a neuronally secreted glycoprotein expressed primarily in GABAergic interneurons that acts extracellularly by binding to ADAM22/ADAM23 receptors on neurons; this interaction is required for the clustering and stability of juxtaparanodal Kv1 potassium channel complexes in myelinated axons (regulating refractory period and high-frequency firing), for specifying excitatory synapse identity on cerebellar Purkinje cells, and for suppressing epileptiform network activity during postnatal brain development — with disease-causing truncations preventing secretion and ADAM interaction, thereby causing remitting focal epilepsy.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LGI2 is a neuronally secreted glycoprotein that functions as an extracellular ligand for ADAM22/ADAM23 receptors to organize synaptic and axonal architecture during postnatal brain development. LGI2 is secreted in glycosylated form and binds ADAM22/ADAM23; disease-causing truncations prevent both secretion and receptor interaction, causing retention in the endoplasmic reticulum [PMID:21829378, PMID:20863412]. Through its interaction with axonal ADAM23, LGI2 (together with LGI3) is required for the clustering and stability of juxtaparanodal Kv1 potassium channel complexes in myelinated axons, thereby regulating the refractory period and enabling high-frequency burst firing [PMID:36828548]. Expressed predominantly in GABAergic interneurons with peak expression during juvenile development, LGI2 suppresses epileptiform network activity; its loss causes ictal-like discharges in hippocampal circuits and deficits in cognitive flexibility, and a truncating mutation in canine LGI2 causes remitting focal epilepsy [PMID:41177215, PMID:21829378].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that LGI2 is a secreted protein resolved whether LGI family members beyond LGI1 function extracellularly, positioning LGI2 as a potential signaling ligand rather than an intracellular factor.\",\n      \"evidence\": \"Secretion assay after transfection of LGI2B splice form into 293T cells\",\n      \"pmids\": [\"15857855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Secretion shown only in heterologous 293T cells, not in neurons\", \"Receptor or binding partner unknown\", \"Functional consequence of secretion not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that EAR-domain mutations homologous to epilepsy-causing LGI1 variants block LGI2 secretion and cause ER retention established a shared pathogenic mechanism across the LGI family.\",\n      \"evidence\": \"Secretion assays and subcellular localization of multiple LGI2 mutants in transfected cells, 3D structural modeling\",\n      \"pmids\": [\"20863412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No disease-causing LGI2 mutations in humans confirmed at this point\", \"ADAM receptor interaction not yet tested for LGI2\", \"Neuronal relevance of secretion failure not assessed in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying a truncating LGI2 mutation that abolishes both secretion and ADAM22/ADAM23 interaction as the cause of remitting focal epilepsy in dogs established LGI2 as a functional ligand for ADAM receptors and directly linked its loss to epileptogenesis.\",\n      \"evidence\": \"Genome-wide association in Lagotto Romagnolo dogs, truncating mutation identified, secretion and ADAM interaction assays with wild-type vs. mutant protein\",\n      \"pmids\": [\"21829378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No human LGI2-epilepsy mutations reported\", \"Downstream signaling events at ADAM receptors not characterized\", \"Neural circuit mechanism of epilepsy not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that LGI2 interaction with axonal ADAM23 is required for juxtaparanodal Kv1 channel clustering and high-frequency firing defined a specific cell-biological function — axonal ion channel organization — beyond synaptic remodeling.\",\n      \"evidence\": \"LGI2 knockout mice, immunohistochemistry for Kv1 channel mislocalization, electrophysiology measuring refractory period and burst firing, co-immunoprecipitation\",\n      \"pmids\": [\"36828548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of LGI2 vs. LGI3 to Kv1 clustering not fully separable\", \"Structural basis of LGI2-ADAM23 interaction unresolved\", \"Whether Kv1 mislocalization contributes to epilepsy phenotype not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying LGI2 as a presynaptic secreted factor from inferior olivary neurons that specifies excitatory synapse identity on Purkinje cells expanded its role from axonal organization to synapse-type specification in cerebellar circuits.\",\n      \"evidence\": \"Mouse developmental expression analysis and in vivo cerebellar circuit dissection, molecular epistasis with C1QL1 and CRTAC1\",\n      \"pmids\": [\"39658623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study; independent replication needed\", \"ADAM receptor involvement at climbing fiber synapses not confirmed\", \"Whether LGI2 cerebellar function relates to epilepsy phenotype unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that LGI2 is expressed in hippocampal GABAergic interneurons with a juvenile peak and that its ablation causes epileptiform discharges and cognitive inflexibility identified the cell type and developmental window through which LGI2 suppresses network hyperexcitability.\",\n      \"evidence\": \"In situ hybridization, LGI2-deficient mouse hippocampal slice electrophysiology, behavioral testing for spatial reversal learning\",\n      \"pmids\": [\"41177215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which interneuron-secreted LGI2 suppresses excitability not defined\", \"Whether cognitive deficits are secondary to developmental epileptiform activity or reflect an independent function\", \"Single lab; human relevance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The downstream signaling events triggered by LGI2-ADAM22/ADAM23 binding that mediate channel clustering, synapse specification, and epilepsy suppression remain undefined, and no human Mendelian epilepsy mutations in LGI2 have been reported.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of LGI2-ADAM complex\", \"Intracellular signaling cascade downstream of ADAM engagement unknown\", \"Human genetic validation lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ADAM22\", \"ADAM23\", \"LGI3\", \"C1QL1\", \"CRTAC1\"],\n    \"other_free_text\": []\n  }\n}\n```"}