{"gene":"LGI4","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2005,"finding":"LGI4 encodes a secreted, glycosylated leucine-rich repeat protein expressed in Schwann cells. Loss of LGI4 function (via a 225-bp insertion causing aberrant splicing and intracellular retention of the mutant protein) causes delayed axonal sorting and hypomyelination in the peripheral nervous system. siRNA-mediated knockdown of Lgi4 in neuron-Schwann cell cocultures inhibits myelination, and exogenous Lgi4 rescues myelination in claw paw (clp/clp) cultures.","method":"Positional cloning of claw paw mutation, RT-PCR/splicing analysis, siRNA knockdown in neuron-Schwann cell cocultures, exogenous protein rescue assay","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (genetic identification, coculture knockdown, rescue experiment), replicated in subsequent studies","pmids":["16341215"],"is_preprint":false},{"year":2008,"finding":"LGI4 binds directly to ADAM22, ADAM23, and ADAM11. Binding specificity was demonstrated by quantitative cell-ELISA, showing that ADAM22 is not the sole receptor for LGI4, as ADAM11 and ADAM23 also show significant binding to LGI4.","method":"Immunoprecipitation, mass spectrometry, quantitative cell-ELISA binding assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP and cell-ELISA, single lab, two orthogonal methods","pmids":["18974846"],"is_preprint":false},{"year":2010,"finding":"Lgi4 binds directly to Adam22 without requirement for additional membrane-associated factors. Schwann cells are the principal cellular source of Lgi4, while Adam22 is required on axons. This defines a paracrine signaling axis: Schwann cell-secreted Lgi4 binds axonal Adam22 to drive Schwann cell differentiation and peripheral nerve myelination.","method":"Direct binding assay (cell-based), heterotypic Schwann cell-sensory neuron cocultures, cell type-specific conditional knockout mice (Schwann cell-specific Lgi4 ablation; axon-specific Adam22 ablation)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay, cell-type-specific conditional knockouts, paracrine mechanism established with multiple orthogonal methods","pmids":["20220021"],"is_preprint":false},{"year":2010,"finding":"Lgi4 promotes proliferation and differentiation of glial-restricted progenitors throughout the PNS (sensory, sympathetic, and enteric ganglia). Compound-mutant mouse analysis (genetic epistasis) showed that Lgi4 promotes enteric gliogenesis through binding the ADAM22 receptor.","method":"Gene-targeted knockout mice, gene expression profiling, compound-mutant epistasis analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene-targeted KO with defined phenotype, epistasis with Adam22, replicated across multiple ganglia types","pmids":["21068328"],"is_preprint":false},{"year":2014,"finding":"In breast tumor cells, ADAM23-negative cells secrete LGI4, which promotes proliferation and invasion of adjacent ADAM23-positive cells. Ablation of LGI4 in ADAM23-negative cells significantly attenuates ADAM23-positive cell proliferation and invasion, placing LGI4 in a paracrine signaling role in tumor intratumoral heterogeneity.","method":"siRNA ablation of LGI4, cell proliferation and invasion assays, heterotypic co-culture experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotype, single lab, two orthogonal readouts (proliferation and invasion)","pmids":["24662834"],"is_preprint":false},{"year":2017,"finding":"Biallelic loss-of-function mutations in LGI4 in humans cause aberrant splicing and impaired secretion of truncated LGI4 protein, resulting in lack of peripheral nerve myelin (confirmed by transmission electron microscopy of sciatic nerve), consistent with the paracrine LGI4-ADAM22 signaling mechanism.","method":"Whole-exome sequencing, iPSC-based functional secretion assay, transmission electron microscopy of patient sciatic nerve, immunolabeling","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived iPSC functional assay, TEM structural confirmation, consistent with multiple prior animal studies","pmids":["28318499"],"is_preprint":false},{"year":2021,"finding":"AMC-associated LGI4 missense mutations largely impair progression of the mutant protein through the endomembrane system, resulting in severely reduced protein expression/secretion. Binding to ADAM22 and myelination-promoting activity are largely unaffected in these mutants, suggesting the pathogenic mechanism is a secretion defect rather than loss of receptor binding.","method":"In vitro expression assays, ADAM22 binding assays, myelination assay in cocultures, protein trafficking analysis","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding and functional myelination assays in single lab, multiple orthogonal methods","pmids":["34288120"],"is_preprint":false},{"year":2023,"finding":"IgG4 autoantibodies against LGI4 are found in patients with CIDP. Patient IgG binds cells co-transfected with LGI4 and ADAM22. Application of anti-LGI4 patient serum to Schwann cells expressing ADAM22 significantly reduced Krox20 mRNA expression (a key myelination transcription factor), demonstrating that anti-LGI4 antibodies functionally impair the LGI4-ADAM22 myelination signaling axis.","method":"Indirect immunofluorescence, Western blotting, cell-based assay with LGI4/ADAM22 co-transfection, LGI4 siRNA knockdown, Schwann cell culture with patient serum, quantitative RT-PCR for Krox20","journal":"Neurology(R) neuroimmunology & neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assay and Schwann cell myelination readout, single lab, multiple orthogonal methods","pmids":["36631269"],"is_preprint":false},{"year":2025,"finding":"Anti-LGI4 IgG (from patients with autoimmune nodopathy) promotes Schwann cell proliferation and reduces Krox20 mRNA in chronic-onset cases. Intraneural injection of LGI4-IgG4 and LGI4-IgG2 into mouse sciatic nerves deposits antibody mainly at nodes extending toward paranodes and causes nodal/paranodal alterations, establishing a pathogenic antibody mechanism at the node.","method":"Live cell-based assay, BrdU cell proliferation assay, RT-PCR, intraneural injection in mouse sciatic nerve, immunohistochemistry, electron microscopy","journal":"Neurology(R) neuroimmunology & neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo injection model with morphometric analysis, cell-based proliferation assay, single lab with multiple orthogonal readouts","pmids":["41092257"],"is_preprint":false},{"year":2025,"finding":"IGF2BP2 stabilizes LGI4 mRNA in an m6A-dependent manner in intestinal epithelial cells. LGI4 inhibits the MEK1/2-ERK1/2 signaling pathway, suppressing pro-inflammatory cytokine expression. AAV9-mediated LGI4 overexpression partially rescues the inflammatory phenotype caused by IGF2BP2 knockout in DSS-induced colitis mice.","method":"meRIP-qPCR, RNA pulldown, RIP, mRNA stability assay, lentiviral knockdown/overexpression, transcriptomic sequencing, IGF2BP2 knockout mice, AAV9-mediated rescue, DSS colitis model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple RNA-protein interaction assays plus in vivo rescue, single lab","pmids":["40663812"],"is_preprint":false},{"year":2024,"finding":"LGI4 interacts with KV1.5 channels in human atrial tissue and heterologous cells. LGI4 (and LGI3) impairs KV1.5/KVβ association, partially reverses KVβ-induced N-type inactivation, and reduces IKur amplitude. Cardiac-specific Lgi4 overexpression in mice reduces KV1.5 membrane expression and IKur density, prolongs early action potential repolarization, and prolongs QRS interval.","method":"Co-immunoprecipitation, patch clamping, AAV-mediated cardiac-specific gene transfer in mice, surface ECG, immunolocalization, intracardiac stimulation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, electrophysiology, and in vivo cardiac model; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.10.03.616587"],"is_preprint":true},{"year":2025,"finding":"In glioma cells, LGI4 promotes tumor growth by binding to p53 and blocking its nuclear import, thereby inhibiting TP53 self-transcription. LGI4 is transcriptionally activated by NF-κB signaling, and LGI4 in turn feedback-activates NF-κB by inhibiting the interaction of IKIP with the IKKα/IKKβ/NEMO complex.","method":"Co-immunoprecipitation (LGI4-p53 binding), nuclear fractionation, reporter assays, knockdown/overexpression, NF-κB signaling pathway analysis","journal":"Translational oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic claims (p53 binding, nuclear import blockade) described from abstracts without detailed method disclosure; findings not replicated","pmids":["41130018"],"is_preprint":false}],"current_model":"LGI4 is a secreted, glycosylated leucine-rich repeat protein primarily expressed by Schwann cells that acts as a paracrine ligand: it binds axonal ADAM22 (and also ADAM23/ADAM11) to drive peripheral nerve myelination and glial progenitor proliferation/differentiation throughout the PNS; pathogenic mutations disrupt LGI4 secretion (rather than ADAM22 binding), autoantibodies against LGI4 impair the LGI4-ADAM22 myelination axis and cause nodal/paranodal damage, and LGI4 additionally modulates KV1.5 channel function in the heart and MEK/ERK signaling in intestinal epithelial cells."},"narrative":{"mechanistic_narrative":"LGI4 is a secreted, glycosylated leucine-rich repeat protein produced by Schwann cells that functions as a paracrine ligand controlling peripheral nerve myelination and glial development [PMID:16341215, PMID:20220021]. Schwann cell-secreted LGI4 binds directly to axonal ADAM22 — and also to ADAM23 and ADAM11 — without requiring additional membrane cofactors, defining a glia-to-axon signaling axis that drives Schwann cell differentiation and myelination [PMID:18974846, PMID:20220021]; cell type-specific knockouts place LGI4 on the Schwann cell side and ADAM22 on the axon [PMID:20220021]. Beyond myelinating Schwann cells, LGI4 promotes proliferation and differentiation of glial-restricted progenitors across sensory, sympathetic, and enteric ganglia, an activity that is genetically epistatic to ADAM22 [PMID:21068328]. The myelination function is genetically validated in disease: biallelic loss-of-function mutations in humans abolish peripheral nerve myelin [PMID:28318499], and arthrogryposis-associated missense mutations act predominantly by impairing trafficking and secretion of LGI4 through the endomembrane system rather than by disrupting ADAM22 binding or intrinsic myelinating activity [PMID:34288120]. The same LGI4-ADAM22 axis is targeted by autoimmunity, as IgG4 autoantibodies against LGI4 in patients reduce expression of the myelination transcription factor Krox20 and produce nodal/paranodal damage in vivo [PMID:36631269, PMID:41092257]. LGI4 has additionally been linked to a paracrine role in tumor proliferation and invasion [PMID:24662834], to suppression of MEK1/2-ERK1/2 inflammatory signaling in intestinal epithelium downstream of IGF2BP2-mediated mRNA stabilization [PMID:40663812], and to modulation of cardiac KV1.5 channel function [PMID:bio_10.1101_2024.10.03.616587].","teleology":[{"year":2005,"claim":"Established that LGI4 is a Schwann cell-derived secreted LRR protein functionally required for peripheral myelination, answering whether the claw paw phenotype reflected an autonomous glial signaling defect.","evidence":"Positional cloning of the claw paw mutation plus siRNA knockdown and exogenous protein rescue in neuron-Schwann cell cocultures","pmids":["16341215"],"confidence":"High","gaps":["Did not identify the receptor or binding partner","Mechanism of how secreted LGI4 acts on Schwann cells was undefined"]},{"year":2008,"claim":"Identified the receptor specificity of LGI4 by showing direct binding to ADAM22, ADAM23, and ADAM11, establishing that ADAM22 is not the sole receptor.","evidence":"Immunoprecipitation, mass spectrometry, and quantitative cell-ELISA binding assays","pmids":["18974846"],"confidence":"Medium","gaps":["Functional relevance of ADAM11/ADAM23 binding to myelination not resolved","Single lab"]},{"year":2010,"claim":"Defined the paracrine architecture of the signaling axis — LGI4 secreted by Schwann cells acts on axonal ADAM22 — resolving which cell contributes ligand and which contributes receptor.","evidence":"Direct cell-based binding assay and cell type-specific conditional knockout mice (Schwann cell Lgi4 ablation, axonal Adam22 ablation)","pmids":["20220021"],"confidence":"High","gaps":["Downstream Schwann cell signaling events not mapped","Structural basis of LGI4-ADAM22 binding not determined"]},{"year":2010,"claim":"Extended LGI4 function beyond myelinating Schwann cells to glial progenitor proliferation/differentiation across PNS ganglia, acting through ADAM22.","evidence":"Gene-targeted knockout mice, expression profiling, and compound-mutant epistasis with Adam22","pmids":["21068328"],"confidence":"High","gaps":["Signaling effectors downstream of ADAM22 in progenitors not identified"]},{"year":2014,"claim":"Showed LGI4 can mediate paracrine signaling in a non-neural context, with ADAM23-negative tumor cells secreting LGI4 to promote proliferation/invasion of neighboring ADAM23-positive cells.","evidence":"siRNA ablation with proliferation and invasion assays in heterotypic tumor cell co-cultures","pmids":["24662834"],"confidence":"Medium","gaps":["In vivo tumor relevance not established here","Receptor engaged on responding cells not directly confirmed"]},{"year":2017,"claim":"Confirmed in humans that biallelic LGI4 loss-of-function causes absence of peripheral myelin, linking the secretion-dependent paracrine mechanism to disease.","evidence":"Whole-exome sequencing, iPSC-based secretion assay, and transmission electron microscopy of patient sciatic nerve","pmids":["28318499"],"confidence":"High","gaps":["Genotype-phenotype range across mutation classes not fully defined"]},{"year":2021,"claim":"Resolved the pathogenic mechanism of disease-associated missense alleles as a trafficking/secretion defect rather than loss of ADAM22 binding or intrinsic activity.","evidence":"In vitro expression, protein trafficking analysis, ADAM22 binding assays, and coculture myelination assays","pmids":["34288120"],"confidence":"Medium","gaps":["Specific ER/secretory checkpoint that retains mutant protein not identified","Single lab"]},{"year":2023,"claim":"Demonstrated that anti-LGI4 IgG4 autoantibodies functionally impair the LGI4-ADAM22 myelination axis, implicating it in CIDP.","evidence":"Cell-based binding assay with LGI4/ADAM22 co-transfection and Krox20 RT-PCR in Schwann cell cultures exposed to patient serum","pmids":["36631269"],"confidence":"Medium","gaps":["Causal in vivo demonstration not yet provided in this study","Single lab"]},{"year":2025,"claim":"Provided in vivo evidence that anti-LGI4 IgG causes nodal/paranodal pathology, localizing the autoimmune lesion to the node.","evidence":"Intraneural injection of LGI4-IgG4/IgG2 into mouse sciatic nerve with immunohistochemistry and electron microscopy, plus BrdU proliferation and Krox20 RT-PCR","pmids":["41092257"],"confidence":"Medium","gaps":["Molecular events linking antibody binding to nodal disruption not detailed","Single lab"]},{"year":2025,"claim":"Identified a non-neural intestinal role in which IGF2BP2 stabilizes LGI4 mRNA via m6A and LGI4 suppresses MEK-ERK driven inflammation.","evidence":"meRIP-qPCR, RNA pulldown/RIP, mRNA stability assays, IGF2BP2 knockout mice, and AAV9 LGI4 rescue in DSS colitis","pmids":["40663812"],"confidence":"Medium","gaps":["Receptor mediating LGI4 effect on epithelial MEK-ERK signaling not identified","Single lab"]},{"year":2024,"claim":"Linked LGI4 to cardiac electrophysiology through modulation of KV1.5 channel association, surface expression, and IKur.","evidence":"Co-immunoprecipitation, patch clamping, and AAV cardiac-specific overexpression in mice with ECG (preprint)","pmids":["bio_10.1101_2024.10.03.616587"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Endogenous cardiac role versus overexpression effect not separated"]},{"year":2025,"claim":"Reported an intracellular tumor-promoting role in glioma via p53 binding and NF-kB feedback, distinct from the canonical secreted paracrine model.","evidence":"Co-immunoprecipitation, nuclear fractionation, reporter assays, and knockdown/overexpression","pmids":["41130018"],"confidence":"Low","gaps":["Single lab, mechanistic claims not independently replicated","Reconciliation of an intracellular p53-binding role with the secreted ligand model unresolved"]},{"year":null,"claim":"How LGI4-ADAM22 engagement is transduced into intracellular Schwann cell differentiation signaling, and how the diverse non-neural activities (epithelial, cardiac, tumor) mechanistically relate to the canonical secreted paracrine axis, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the LGI4-ADAM complex","Downstream effector pathway in Schwann cells unmapped","Unclear whether intracellular roles reflect a separate function or contamination of context"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,9]}],"complexes":[],"partners":["ADAM22","ADAM23","ADAM11","KCNA5","IGF2BP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N135","full_name":"Leucine-rich repeat LGI family member 4","aliases":["LGI1-like protein 3","Leucine-rich glioma-inactivated protein 4"],"length_aa":537,"mass_kda":59.1,"function":"Component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8N135/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LGI4","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LGI4","total_profiled":1310},"omim":[{"mim_id":"617468","title":"ARTHROGRYPOSIS MULTIPLEX CONGENITA 1, NEUROGENIC, WITH MYELIN DEFECT; AMC1","url":"https://www.omim.org/entry/617468"},{"mim_id":"610671","title":"ZINC FINGER PROTEIN 628; ZNF628","url":"https://www.omim.org/entry/610671"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LGI4"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8N135","domains":[{"cath_id":"3.80.10.10","chopping":"32-205","consensus_level":"high","plddt":94.8595,"start":32,"end":205},{"cath_id":"2.120.10.30","chopping":"207-221_404-537","consensus_level":"medium","plddt":94.4958,"start":207,"end":537}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N135","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N135-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N135-F1-predicted_aligned_error_v6.png","plddt_mean":92.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LGI4","jax_strain_url":"https://www.jax.org/strain/search?query=LGI4"},"sequence":{"accession":"Q8N135","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N135.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N135/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N135"}},"corpus_meta":[{"pmid":"18974846","id":"PMC_18974846","title":"LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11.","date":"2008","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18974846","citation_count":95,"is_preprint":false},{"pmid":"16341215","id":"PMC_16341215","title":"The claw paw mutation reveals a role for Lgi4 in peripheral nerve development.","date":"2005","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16341215","citation_count":83,"is_preprint":false},{"pmid":"20220021","id":"PMC_20220021","title":"Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20220021","citation_count":81,"is_preprint":false},{"pmid":"21068328","id":"PMC_21068328","title":"Lgi4 promotes the proliferation and differentiation of glial lineage cells throughout the developing peripheral nervous system.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21068328","citation_count":45,"is_preprint":false},{"pmid":"28318499","id":"PMC_28318499","title":"Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita.","date":"2017","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28318499","citation_count":25,"is_preprint":false},{"pmid":"14505228","id":"PMC_14505228","title":"Genotypic association of exonic LGI4 polymorphisms and childhood absence epilepsy.","date":"2003","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/14505228","citation_count":20,"is_preprint":false},{"pmid":"24662834","id":"PMC_24662834","title":"Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24662834","citation_count":19,"is_preprint":false},{"pmid":"36631269","id":"PMC_36631269","title":"Anti-LGI4 Antibody Is a Novel Juxtaparanodal Autoantibody for Chronic Inflammatory Demyelinating Polyneuropathy.","date":"2023","source":"Neurology(R) neuroimmunology & neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/36631269","citation_count":16,"is_preprint":false},{"pmid":"14694902","id":"PMC_14694902","title":"Fxyd3 and Lgi4 expression in the adult mouse: a case of endogenous antisense expression.","date":"2003","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/14694902","citation_count":10,"is_preprint":false},{"pmid":"31513940","id":"PMC_31513940","title":"A mild phenotype of LGI4-Related arthrogryposis multiplex congenita with intrafamilial variability.","date":"2019","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31513940","citation_count":7,"is_preprint":false},{"pmid":"19815358","id":"PMC_19815358","title":"Positive association between benign familial infantile convulsions and LGI4.","date":"2009","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/19815358","citation_count":7,"is_preprint":false},{"pmid":"41092257","id":"PMC_41092257","title":"Clinical Spectrum, Pathology, and Mechanisms of Anti-LGI4 Antibody-Positive Autoimmune Nodopathy.","date":"2025","source":"Neurology(R) neuroimmunology & neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/41092257","citation_count":1,"is_preprint":false},{"pmid":"40663812","id":"PMC_40663812","title":"IGF2BP2 alleviates ulcerative colitis by inhibiting MEK1/2 and ERK1/2 signaling pathways in intestinal epithelial cells via m6A-dependent stabilization of LGI4 mRNA.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40663812","citation_count":1,"is_preprint":false},{"pmid":"34288120","id":"PMC_34288120","title":"Characterizing the molecular etiology of arthrogryposis multiplex congenita in patients with LGI4 mutations.","date":"2021","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/34288120","citation_count":1,"is_preprint":false},{"pmid":"41130018","id":"PMC_41130018","title":"Propofol inhibits glioma growth by blocking the formation of the NF-κB/LGI4 feedback loop to activate TP53 self-transcription.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41130018","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.03.616587","title":"Novel insights into  <i>I</i>  <sub>Kur</sub>  modulation by Lgi3-4: Implications in atrial fibrillation","date":"2024-10-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.03.616587","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11230,"output_tokens":3202,"usd":0.04086,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10737,"output_tokens":3734,"usd":0.073517,"stage2_stop_reason":"end_turn"},"total_usd":0.114377,"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\": 2005,\n      \"finding\": \"LGI4 encodes a secreted, glycosylated leucine-rich repeat protein expressed in Schwann cells. Loss of LGI4 function (via a 225-bp insertion causing aberrant splicing and intracellular retention of the mutant protein) causes delayed axonal sorting and hypomyelination in the peripheral nervous system. siRNA-mediated knockdown of Lgi4 in neuron-Schwann cell cocultures inhibits myelination, and exogenous Lgi4 rescues myelination in claw paw (clp/clp) cultures.\",\n      \"method\": \"Positional cloning of claw paw mutation, RT-PCR/splicing analysis, siRNA knockdown in neuron-Schwann cell cocultures, exogenous protein rescue assay\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (genetic identification, coculture knockdown, rescue experiment), replicated in subsequent studies\",\n      \"pmids\": [\"16341215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LGI4 binds directly to ADAM22, ADAM23, and ADAM11. Binding specificity was demonstrated by quantitative cell-ELISA, showing that ADAM22 is not the sole receptor for LGI4, as ADAM11 and ADAM23 also show significant binding to LGI4.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, quantitative cell-ELISA binding assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP and cell-ELISA, single lab, two orthogonal methods\",\n      \"pmids\": [\"18974846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Lgi4 binds directly to Adam22 without requirement for additional membrane-associated factors. Schwann cells are the principal cellular source of Lgi4, while Adam22 is required on axons. This defines a paracrine signaling axis: Schwann cell-secreted Lgi4 binds axonal Adam22 to drive Schwann cell differentiation and peripheral nerve myelination.\",\n      \"method\": \"Direct binding assay (cell-based), heterotypic Schwann cell-sensory neuron cocultures, cell type-specific conditional knockout mice (Schwann cell-specific Lgi4 ablation; axon-specific Adam22 ablation)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay, cell-type-specific conditional knockouts, paracrine mechanism established with multiple orthogonal methods\",\n      \"pmids\": [\"20220021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Lgi4 promotes proliferation and differentiation of glial-restricted progenitors throughout the PNS (sensory, sympathetic, and enteric ganglia). Compound-mutant mouse analysis (genetic epistasis) showed that Lgi4 promotes enteric gliogenesis through binding the ADAM22 receptor.\",\n      \"method\": \"Gene-targeted knockout mice, gene expression profiling, compound-mutant epistasis analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene-targeted KO with defined phenotype, epistasis with Adam22, replicated across multiple ganglia types\",\n      \"pmids\": [\"21068328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In breast tumor cells, ADAM23-negative cells secrete LGI4, which promotes proliferation and invasion of adjacent ADAM23-positive cells. Ablation of LGI4 in ADAM23-negative cells significantly attenuates ADAM23-positive cell proliferation and invasion, placing LGI4 in a paracrine signaling role in tumor intratumoral heterogeneity.\",\n      \"method\": \"siRNA ablation of LGI4, cell proliferation and invasion assays, heterotypic co-culture experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotype, single lab, two orthogonal readouts (proliferation and invasion)\",\n      \"pmids\": [\"24662834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic loss-of-function mutations in LGI4 in humans cause aberrant splicing and impaired secretion of truncated LGI4 protein, resulting in lack of peripheral nerve myelin (confirmed by transmission electron microscopy of sciatic nerve), consistent with the paracrine LGI4-ADAM22 signaling mechanism.\",\n      \"method\": \"Whole-exome sequencing, iPSC-based functional secretion assay, transmission electron microscopy of patient sciatic nerve, immunolabeling\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived iPSC functional assay, TEM structural confirmation, consistent with multiple prior animal studies\",\n      \"pmids\": [\"28318499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AMC-associated LGI4 missense mutations largely impair progression of the mutant protein through the endomembrane system, resulting in severely reduced protein expression/secretion. Binding to ADAM22 and myelination-promoting activity are largely unaffected in these mutants, suggesting the pathogenic mechanism is a secretion defect rather than loss of receptor binding.\",\n      \"method\": \"In vitro expression assays, ADAM22 binding assays, myelination assay in cocultures, protein trafficking analysis\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding and functional myelination assays in single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34288120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IgG4 autoantibodies against LGI4 are found in patients with CIDP. Patient IgG binds cells co-transfected with LGI4 and ADAM22. Application of anti-LGI4 patient serum to Schwann cells expressing ADAM22 significantly reduced Krox20 mRNA expression (a key myelination transcription factor), demonstrating that anti-LGI4 antibodies functionally impair the LGI4-ADAM22 myelination signaling axis.\",\n      \"method\": \"Indirect immunofluorescence, Western blotting, cell-based assay with LGI4/ADAM22 co-transfection, LGI4 siRNA knockdown, Schwann cell culture with patient serum, quantitative RT-PCR for Krox20\",\n      \"journal\": \"Neurology(R) neuroimmunology & neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assay and Schwann cell myelination readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36631269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Anti-LGI4 IgG (from patients with autoimmune nodopathy) promotes Schwann cell proliferation and reduces Krox20 mRNA in chronic-onset cases. Intraneural injection of LGI4-IgG4 and LGI4-IgG2 into mouse sciatic nerves deposits antibody mainly at nodes extending toward paranodes and causes nodal/paranodal alterations, establishing a pathogenic antibody mechanism at the node.\",\n      \"method\": \"Live cell-based assay, BrdU cell proliferation assay, RT-PCR, intraneural injection in mouse sciatic nerve, immunohistochemistry, electron microscopy\",\n      \"journal\": \"Neurology(R) neuroimmunology & neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo injection model with morphometric analysis, cell-based proliferation assay, single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"41092257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP2 stabilizes LGI4 mRNA in an m6A-dependent manner in intestinal epithelial cells. LGI4 inhibits the MEK1/2-ERK1/2 signaling pathway, suppressing pro-inflammatory cytokine expression. AAV9-mediated LGI4 overexpression partially rescues the inflammatory phenotype caused by IGF2BP2 knockout in DSS-induced colitis mice.\",\n      \"method\": \"meRIP-qPCR, RNA pulldown, RIP, mRNA stability assay, lentiviral knockdown/overexpression, transcriptomic sequencing, IGF2BP2 knockout mice, AAV9-mediated rescue, DSS colitis model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple RNA-protein interaction assays plus in vivo rescue, single lab\",\n      \"pmids\": [\"40663812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGI4 interacts with KV1.5 channels in human atrial tissue and heterologous cells. LGI4 (and LGI3) impairs KV1.5/KVβ association, partially reverses KVβ-induced N-type inactivation, and reduces IKur amplitude. Cardiac-specific Lgi4 overexpression in mice reduces KV1.5 membrane expression and IKur density, prolongs early action potential repolarization, and prolongs QRS interval.\",\n      \"method\": \"Co-immunoprecipitation, patch clamping, AAV-mediated cardiac-specific gene transfer in mice, surface ECG, immunolocalization, intracardiac stimulation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, electrophysiology, and in vivo cardiac model; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.10.03.616587\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In glioma cells, LGI4 promotes tumor growth by binding to p53 and blocking its nuclear import, thereby inhibiting TP53 self-transcription. LGI4 is transcriptionally activated by NF-κB signaling, and LGI4 in turn feedback-activates NF-κB by inhibiting the interaction of IKIP with the IKKα/IKKβ/NEMO complex.\",\n      \"method\": \"Co-immunoprecipitation (LGI4-p53 binding), nuclear fractionation, reporter assays, knockdown/overexpression, NF-κB signaling pathway analysis\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic claims (p53 binding, nuclear import blockade) described from abstracts without detailed method disclosure; findings not replicated\",\n      \"pmids\": [\"41130018\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGI4 is a secreted, glycosylated leucine-rich repeat protein primarily expressed by Schwann cells that acts as a paracrine ligand: it binds axonal ADAM22 (and also ADAM23/ADAM11) to drive peripheral nerve myelination and glial progenitor proliferation/differentiation throughout the PNS; pathogenic mutations disrupt LGI4 secretion (rather than ADAM22 binding), autoantibodies against LGI4 impair the LGI4-ADAM22 myelination axis and cause nodal/paranodal damage, and LGI4 additionally modulates KV1.5 channel function in the heart and MEK/ERK signaling in intestinal epithelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LGI4 is a secreted, glycosylated leucine-rich repeat protein produced by Schwann cells that functions as a paracrine ligand controlling peripheral nerve myelination and glial development [#0, #2]. Schwann cell-secreted LGI4 binds directly to axonal ADAM22 — and also to ADAM23 and ADAM11 — without requiring additional membrane cofactors, defining a glia-to-axon signaling axis that drives Schwann cell differentiation and myelination [#1, #2]; cell type-specific knockouts place LGI4 on the Schwann cell side and ADAM22 on the axon [#2]. Beyond myelinating Schwann cells, LGI4 promotes proliferation and differentiation of glial-restricted progenitors across sensory, sympathetic, and enteric ganglia, an activity that is genetically epistatic to ADAM22 [#3]. The myelination function is genetically validated in disease: biallelic loss-of-function mutations in humans abolish peripheral nerve myelin [#5], and arthrogryposis-associated missense mutations act predominantly by impairing trafficking and secretion of LGI4 through the endomembrane system rather than by disrupting ADAM22 binding or intrinsic myelinating activity [#6]. The same LGI4-ADAM22 axis is targeted by autoimmunity, as IgG4 autoantibodies against LGI4 in patients reduce expression of the myelination transcription factor Krox20 and produce nodal/paranodal damage in vivo [#7, #8]. LGI4 has additionally been linked to a paracrine role in tumor proliferation and invasion [#4], to suppression of MEK1/2-ERK1/2 inflammatory signaling in intestinal epithelium downstream of IGF2BP2-mediated mRNA stabilization [#9], and to modulation of cardiac KV1.5 channel function [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that LGI4 is a Schwann cell-derived secreted LRR protein functionally required for peripheral myelination, answering whether the claw paw phenotype reflected an autonomous glial signaling defect.\",\n      \"evidence\": \"Positional cloning of the claw paw mutation plus siRNA knockdown and exogenous protein rescue in neuron-Schwann cell cocultures\",\n      \"pmids\": [\"16341215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the receptor or binding partner\", \"Mechanism of how secreted LGI4 acts on Schwann cells was undefined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the receptor specificity of LGI4 by showing direct binding to ADAM22, ADAM23, and ADAM11, establishing that ADAM22 is not the sole receptor.\",\n      \"evidence\": \"Immunoprecipitation, mass spectrometry, and quantitative cell-ELISA binding assays\",\n      \"pmids\": [\"18974846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional relevance of ADAM11/ADAM23 binding to myelination not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the paracrine architecture of the signaling axis — LGI4 secreted by Schwann cells acts on axonal ADAM22 — resolving which cell contributes ligand and which contributes receptor.\",\n      \"evidence\": \"Direct cell-based binding assay and cell type-specific conditional knockout mice (Schwann cell Lgi4 ablation, axonal Adam22 ablation)\",\n      \"pmids\": [\"20220021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream Schwann cell signaling events not mapped\", \"Structural basis of LGI4-ADAM22 binding not determined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended LGI4 function beyond myelinating Schwann cells to glial progenitor proliferation/differentiation across PNS ganglia, acting through ADAM22.\",\n      \"evidence\": \"Gene-targeted knockout mice, expression profiling, and compound-mutant epistasis with Adam22\",\n      \"pmids\": [\"21068328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling effectors downstream of ADAM22 in progenitors not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed LGI4 can mediate paracrine signaling in a non-neural context, with ADAM23-negative tumor cells secreting LGI4 to promote proliferation/invasion of neighboring ADAM23-positive cells.\",\n      \"evidence\": \"siRNA ablation with proliferation and invasion assays in heterotypic tumor cell co-cultures\",\n      \"pmids\": [\"24662834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo tumor relevance not established here\", \"Receptor engaged on responding cells not directly confirmed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed in humans that biallelic LGI4 loss-of-function causes absence of peripheral myelin, linking the secretion-dependent paracrine mechanism to disease.\",\n      \"evidence\": \"Whole-exome sequencing, iPSC-based secretion assay, and transmission electron microscopy of patient sciatic nerve\",\n      \"pmids\": [\"28318499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype range across mutation classes not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the pathogenic mechanism of disease-associated missense alleles as a trafficking/secretion defect rather than loss of ADAM22 binding or intrinsic activity.\",\n      \"evidence\": \"In vitro expression, protein trafficking analysis, ADAM22 binding assays, and coculture myelination assays\",\n      \"pmids\": [\"34288120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ER/secretory checkpoint that retains mutant protein not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that anti-LGI4 IgG4 autoantibodies functionally impair the LGI4-ADAM22 myelination axis, implicating it in CIDP.\",\n      \"evidence\": \"Cell-based binding assay with LGI4/ADAM22 co-transfection and Krox20 RT-PCR in Schwann cell cultures exposed to patient serum\",\n      \"pmids\": [\"36631269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal in vivo demonstration not yet provided in this study\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided in vivo evidence that anti-LGI4 IgG causes nodal/paranodal pathology, localizing the autoimmune lesion to the node.\",\n      \"evidence\": \"Intraneural injection of LGI4-IgG4/IgG2 into mouse sciatic nerve with immunohistochemistry and electron microscopy, plus BrdU proliferation and Krox20 RT-PCR\",\n      \"pmids\": [\"41092257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular events linking antibody binding to nodal disruption not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a non-neural intestinal role in which IGF2BP2 stabilizes LGI4 mRNA via m6A and LGI4 suppresses MEK-ERK driven inflammation.\",\n      \"evidence\": \"meRIP-qPCR, RNA pulldown/RIP, mRNA stability assays, IGF2BP2 knockout mice, and AAV9 LGI4 rescue in DSS colitis\",\n      \"pmids\": [\"40663812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating LGI4 effect on epithelial MEK-ERK signaling not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked LGI4 to cardiac electrophysiology through modulation of KV1.5 channel association, surface expression, and IKur.\",\n      \"evidence\": \"Co-immunoprecipitation, patch clamping, and AAV cardiac-specific overexpression in mice with ECG (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.03.616587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Endogenous cardiac role versus overexpression effect not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported an intracellular tumor-promoting role in glioma via p53 binding and NF-kB feedback, distinct from the canonical secreted paracrine model.\",\n      \"evidence\": \"Co-immunoprecipitation, nuclear fractionation, reporter assays, and knockdown/overexpression\",\n      \"pmids\": [\"41130018\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab, mechanistic claims not independently replicated\", \"Reconciliation of an intracellular p53-binding role with the secreted ligand model unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LGI4-ADAM22 engagement is transduced into intracellular Schwann cell differentiation signaling, and how the diverse non-neural activities (epithelial, cardiac, tumor) mechanistically relate to the canonical secreted paracrine axis, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the LGI4-ADAM complex\", \"Downstream effector pathway in Schwann cells unmapped\", \"Unclear whether intracellular roles reflect a separate function or contamination of context\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ADAM22\", \"ADAM23\", \"ADAM11\", \"KCNA5\", \"IGF2BP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}