{"gene":"CNTN5","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2003,"finding":"NB-2/CNTN5-deficient mice exhibit aberrant responses to acoustic stimuli, with attenuated neural excitability in the inferior colliculus and disrupted tonotopic c-Fos expression patterns, establishing NB-2's role in auditory pathway neural circuit function.","method":"Knockout mouse model (tau-LacZ knockin), audiogenic seizure test, c-Fos immunohistochemistry","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, replicated across multiple assays in one study","pmids":["12653969"],"is_preprint":false},{"year":2001,"finding":"NB-2/CNTN5 promotes neurite outgrowth specifically from cerebral cortical neurons but not hippocampal neurons, and is preferentially expressed in central auditory pathway structures including cochlear nuclei, superior olive, inferior colliculi, medial geniculate nuclei, and auditory cortex.","method":"Neurite outgrowth assay (in vitro), in situ hybridization, immunohistochemistry","journal":"Journal of neuroscience research","confidence":"High","confidence_rationale":"Tier 2 — direct functional assay with defined cellular specificity, localization by multiple methods","pmids":["11438979"],"is_preprint":false},{"year":2009,"finding":"NB-2/CNTN5 is expressed exclusively in glutamatergic neurons in the auditory brainstem, co-localizes with VGLUT1/VGLUT2-positive glutamatergic synapses including calyces of Held, and is enriched in high-frequency response regions, suggesting a role in maturation of glutamatergic synapses.","method":"In situ hybridization combined with immunohistochemistry, co-localization with synaptic markers (VGLUT1, VGLUT2, synapsin), developmental expression analysis","journal":"The Journal of comparative neurology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal localization methods with functional context linking to glutamatergic synapse maturation","pmids":["19177518"],"is_preprint":false},{"year":2012,"finding":"NB-2/CNTN5 forms a cis-complex with amyloid precursor-like protein 1 (APLP1) on the presynaptic membrane in developing auditory neurons.","method":"Pull-down assay, cell surface binding assay, immunofluorescence co-localization with synapsin, biochemical fractionation (presynaptic fraction enrichment), western blot","journal":"Neuroscience letters","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays plus subcellular fractionation with functional localization context","pmids":["22285261"],"is_preprint":false},{"year":2000,"finding":"Human NB-2/CNTN5 gene was mapped to chromosome 11q21-q22.2 by fluorescence in situ hybridization; two splicing isoforms were identified (long: 1100 aa; short: lacking 74 aa at N-terminus), with highest expression in amygdala and occipital lobe of adult human brain.","method":"cDNA cloning, FISH chromosomal mapping, RT-PCR expression analysis across brain regions","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic/molecular characterization, single lab but multiple methods","pmids":["11013081"],"is_preprint":false},{"year":2019,"finding":"iPSC-derived glutamatergic neurons from individuals with heterozygous de novo CNTN5 variants show consistent spontaneous network hyperactivity as measured by multi-electrode array and patch-clamp recordings, establishing a loss-of-function neuronal phenotype for CNTN5 deficiency in ASD.","method":"iPSC-derived neuron differentiation (isogenic lines), multi-electrode array (MEA) recordings, patch-clamp electrophysiology","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with defined electrophysiological phenotype, multiple lines and orthogonal recording methods","pmids":["30747104"],"is_preprint":false}],"current_model":"CNTN5/NB-2 is a GPI-anchored neural cell recognition molecule of the contactin/immunoglobulin superfamily that promotes neurite outgrowth from cortical neurons, is preferentially expressed in glutamatergic neurons of the central auditory pathway where it localizes to presynaptic membranes via a cis-complex with APLP1, and is required for normal auditory circuit maturation and synaptic activity — with loss of function causing disrupted tonotopic organization in vivo and neuronal network hyperactivity in human iPSC-derived neurons."},"narrative":{"teleology":[{"year":2000,"claim":"Cloning and chromosomal mapping of human CNTN5 established its genomic identity and brain expression pattern, revealing two splice isoforms and enrichment in amygdala and occipital lobe.","evidence":"cDNA cloning, FISH mapping to 11q21-q22.2, and RT-PCR across human brain regions","pmids":["11013081"],"confidence":"Medium","gaps":["Single-lab characterization without independent replication","Functional significance of the two splice isoforms unknown","No mechanistic data on protein function"]},{"year":2001,"claim":"Demonstration that CNTN5 promotes neurite outgrowth specifically from cortical neurons and is concentrated in auditory pathway nuclei answered what cell types respond to CNTN5 and where it acts in the brain.","evidence":"In vitro neurite outgrowth assays on cortical vs. hippocampal neurons; in situ hybridization and immunohistochemistry across brain regions","pmids":["11438979"],"confidence":"High","gaps":["Receptor or signaling pathway mediating neurite outgrowth not identified","Basis for cortical vs. hippocampal selectivity unknown"]},{"year":2003,"claim":"Knockout mouse studies revealed that CNTN5 loss disrupts auditory circuit function in vivo, establishing a causal role in tonotopic organization and neural excitability rather than merely correlative expression.","evidence":"NB-2-deficient mice (tau-LacZ knockin) assessed by audiogenic seizure testing and c-Fos immunohistochemistry in the inferior colliculus","pmids":["12653969"],"confidence":"High","gaps":["Synaptic versus axon guidance mechanism not distinguished","Whether auditory phenotype reflects developmental or maintenance defect unclear"]},{"year":2009,"claim":"Restriction of CNTN5 expression to glutamatergic neurons and its co-localization with glutamatergic synaptic markers refined the cellular context, implicating CNTN5 specifically in glutamatergic synapse maturation within auditory brainstem nuclei.","evidence":"Combined in situ hybridization and immunohistochemistry with VGLUT1, VGLUT2, and synapsin markers across developmental stages","pmids":["19177518"],"confidence":"High","gaps":["Direct evidence that CNTN5 is required for glutamatergic synapse formation or function not yet provided","Trans-synaptic binding partners unknown"]},{"year":2012,"claim":"Identification of APLP1 as a cis-interaction partner on presynaptic membranes provided the first molecular complex context for CNTN5, explaining how a GPI-anchored protein can be retained at synaptic sites.","evidence":"Pull-down and cell surface binding assays, immunofluorescence co-localization with synapsin, presynaptic fraction biochemical enrichment","pmids":["22285261"],"confidence":"High","gaps":["Functional consequence of CNTN5-APLP1 interaction on synapse maturation not tested","Trans-synaptic ligands that the complex engages unknown","No structural data on the complex"]},{"year":2019,"claim":"Human iPSC-derived neuron studies demonstrated that heterozygous CNTN5 loss-of-function causes network hyperactivity, directly connecting CNTN5 haploinsufficiency to a neuronal electrophysiological phenotype relevant to ASD.","evidence":"iPSC-derived glutamatergic neurons from individuals with de novo CNTN5 variants, multi-electrode array and patch-clamp recordings across multiple lines","pmids":["30747104"],"confidence":"High","gaps":["Molecular pathway from CNTN5 loss to hyperactivity not delineated","Whether hyperactivity is excitatory/inhibitory imbalance or cell-autonomous not resolved","In vivo validation in human-relevant models pending"]},{"year":null,"claim":"The signaling pathway downstream of CNTN5, the identity of its trans-synaptic binding partners, and the mechanism by which CNTN5-APLP1 complexes regulate glutamatergic synapse maturation remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No trans-synaptic ligand identified","Intracellular signaling cascade unknown for a GPI-anchored molecule","Structural basis of CNTN5-APLP1 interaction uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,3]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["APLP1"],"other_free_text":[]},"mechanistic_narrative":"CNTN5 (NB-2) is a GPI-anchored immunoglobulin superfamily cell recognition molecule that functions in the development and maturation of glutamatergic synapses within central auditory circuits. It is preferentially expressed in glutamatergic neurons of the auditory brainstem, where it localizes to presynaptic membranes through a cis-complex with APLP1 and co-localizes with VGLUT1/VGLUT2-positive synapses including calyces of Held [PMID:19177518, PMID:22285261]. CNTN5 promotes neurite outgrowth selectively from cortical neurons, and its genetic ablation in mice disrupts tonotopic organization and attenuates neural excitability in the inferior colliculus [PMID:11438979, PMID:12653969]. Human iPSC-derived glutamatergic neurons carrying heterozygous de novo CNTN5 loss-of-function variants exhibit spontaneous network hyperactivity, linking CNTN5 haploinsufficiency to neuronal dysfunction in autism spectrum disorder [PMID:30747104]."},"prefetch_data":{"uniprot":{"accession":"O94779","full_name":"Contactin-5","aliases":["Neural recognition molecule NB-2","hNB-2"],"length_aa":1100,"mass_kda":120.7,"function":"Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity in the cerebral cortical neurons but not in hippocampal neurons. Probably involved in neuronal activity in the auditory system (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O94779/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNTN5","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CNTN5","total_profiled":1310},"omim":[{"mim_id":"615479","title":"MYOSIN XVI; MYO16","url":"https://www.omim.org/entry/615479"},{"mim_id":"615478","title":"NEURONAL TYROSINE-PHOSPHORYLATED PHOSPHOINOSITIDE 3-KINASE ADAPTOR 2; NYAP2","url":"https://www.omim.org/entry/615478"},{"mim_id":"615477","title":"NEURONAL TYROSINE-PHOSPHORYLATED PHOSPHOINOSITIDE 3-KINASE ADAPTOR 1; NYAP1","url":"https://www.omim.org/entry/615477"},{"mim_id":"607219","title":"CONTACTIN 5; CNTN5","url":"https://www.omim.org/entry/607219"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":1.9},{"tissue":"placenta","ntpm":2.4},{"tissue":"salivary gland","ntpm":1.9},{"tissue":"thyroid gland","ntpm":1.8}],"url":"https://www.proteinatlas.org/search/CNTN5"},"hgnc":{"alias_symbol":["NB-2","hNB-2"],"prev_symbol":[]},"alphafold":{"accession":"O94779","domains":[{"cath_id":"2.60.40.10","chopping":"98-193","consensus_level":"high","plddt":90.4401,"start":98,"end":193},{"cath_id":"2.60.40.10","chopping":"199-296","consensus_level":"medium","plddt":91.677,"start":199,"end":296},{"cath_id":"2.60.40.10","chopping":"298-390","consensus_level":"medium","plddt":94.846,"start":298,"end":390},{"cath_id":"2.60.40.10","chopping":"396-477","consensus_level":"high","plddt":89.201,"start":396,"end":477},{"cath_id":"2.60.40.10","chopping":"500-569","consensus_level":"high","plddt":87.4177,"start":500,"end":569},{"cath_id":"2.60.40.10","chopping":"574-669","consensus_level":"high","plddt":87.0833,"start":574,"end":669},{"cath_id":"2.60.40.10","chopping":"677-769","consensus_level":"high","plddt":93.5929,"start":677,"end":769},{"cath_id":"2.60.40.10","chopping":"779-871","consensus_level":"medium","plddt":90.288,"start":779,"end":871},{"cath_id":"2.60.40.10","chopping":"881-970","consensus_level":"medium","plddt":85.9246,"start":881,"end":970},{"cath_id":"2.60.40.10","chopping":"980-1065","consensus_level":"medium","plddt":86.2794,"start":980,"end":1065}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94779","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94779-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94779-F1-predicted_aligned_error_v6.png","plddt_mean":82.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNTN5","jax_strain_url":"https://www.jax.org/strain/search?query=CNTN5"},"sequence":{"accession":"O94779","fasta_url":"https://rest.uniprot.org/uniprotkb/O94779.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94779/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94779"}},"corpus_meta":[{"pmid":"30214634","id":"PMC_30214634","title":"Therapeutic mesopore construction on 2D Nb2C MXenes for targeted and enhanced chemo-photothermal cancer therapy in NIR-II biowindow.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/30214634","citation_count":112,"is_preprint":false},{"pmid":"34138204","id":"PMC_34138204","title":"Nb2C MXene-Functionalized Scaffolds Enables Osteosarcoma Phototherapy and Angiogenesis/Osteogenesis of Bone Defects.","date":"2021","source":"Nano-micro letters","url":"https://pubmed.ncbi.nlm.nih.gov/34138204","citation_count":105,"is_preprint":false},{"pmid":"32182038","id":"PMC_32182038","title":"Revealing the Rapid Electrocatalytic Behavior of Ultrafine Amorphous Defective Nb2O5- Nanocluster toward Superior Li-S Performance.","date":"2020","source":"ACS nano","url":"https://pubmed.ncbi.nlm.nih.gov/32182038","citation_count":85,"is_preprint":false},{"pmid":"30747104","id":"PMC_30747104","title":"CNTN5-or EHMT2-human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30747104","citation_count":72,"is_preprint":false},{"pmid":"3097147","id":"PMC_3097147","title":"Prolactin-dependent mitogenesis in Nb 2 node lymphoma cells: effects of immunosuppressive cyclopeptides.","date":"1987","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/3097147","citation_count":70,"is_preprint":false},{"pmid":"28441872","id":"PMC_28441872","title":"Unraveling the Nature of Anomalously Fast Energy Storage in T-Nb2O5.","date":"2017","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/28441872","citation_count":62,"is_preprint":false},{"pmid":"29761546","id":"PMC_29761546","title":"Caging Nb2 O5 Nanowires in PECVD-Derived Graphene Capsules toward Bendable Sodium-Ion Hybrid Supercapacitors.","date":"2018","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/29761546","citation_count":51,"is_preprint":false},{"pmid":"3519613","id":"PMC_3519613","title":"Reduction of phosphatidylcholine turnover in a Nb 2 lymphoma cell line after prolactin treatment. 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immunohistochemistry\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, replicated across multiple assays in one study\",\n      \"pmids\": [\"12653969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NB-2/CNTN5 promotes neurite outgrowth specifically from cerebral cortical neurons but not hippocampal neurons, and is preferentially expressed in central auditory pathway structures including cochlear nuclei, superior olive, inferior colliculi, medial geniculate nuclei, and auditory cortex.\",\n      \"method\": \"Neurite outgrowth assay (in vitro), in situ hybridization, immunohistochemistry\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay with defined cellular specificity, localization by multiple methods\",\n      \"pmids\": [\"11438979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NB-2/CNTN5 is expressed exclusively in glutamatergic neurons in the auditory brainstem, co-localizes with VGLUT1/VGLUT2-positive glutamatergic synapses including calyces of Held, and is enriched in high-frequency response regions, suggesting a role in maturation of glutamatergic synapses.\",\n      \"method\": \"In situ hybridization combined with immunohistochemistry, co-localization with synaptic markers (VGLUT1, VGLUT2, synapsin), developmental expression analysis\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal localization methods with functional context linking to glutamatergic synapse maturation\",\n      \"pmids\": [\"19177518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NB-2/CNTN5 forms a cis-complex with amyloid precursor-like protein 1 (APLP1) on the presynaptic membrane in developing auditory neurons.\",\n      \"method\": \"Pull-down assay, cell surface binding assay, immunofluorescence co-localization with synapsin, biochemical fractionation (presynaptic fraction enrichment), western blot\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays plus subcellular fractionation with functional localization context\",\n      \"pmids\": [\"22285261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human NB-2/CNTN5 gene was mapped to chromosome 11q21-q22.2 by fluorescence in situ hybridization; two splicing isoforms were identified (long: 1100 aa; short: lacking 74 aa at N-terminus), with highest expression in amygdala and occipital lobe of adult human brain.\",\n      \"method\": \"cDNA cloning, FISH chromosomal mapping, RT-PCR expression analysis across brain regions\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic/molecular characterization, single lab but multiple methods\",\n      \"pmids\": [\"11013081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"iPSC-derived glutamatergic neurons from individuals with heterozygous de novo CNTN5 variants show consistent spontaneous network hyperactivity as measured by multi-electrode array and patch-clamp recordings, establishing a loss-of-function neuronal phenotype for CNTN5 deficiency in ASD.\",\n      \"method\": \"iPSC-derived neuron differentiation (isogenic lines), multi-electrode array (MEA) recordings, patch-clamp electrophysiology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined electrophysiological phenotype, multiple lines and orthogonal recording methods\",\n      \"pmids\": [\"30747104\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CNTN5/NB-2 is a GPI-anchored neural cell recognition molecule of the contactin/immunoglobulin superfamily that promotes neurite outgrowth from cortical neurons, is preferentially expressed in glutamatergic neurons of the central auditory pathway where it localizes to presynaptic membranes via a cis-complex with APLP1, and is required for normal auditory circuit maturation and synaptic activity — with loss of function causing disrupted tonotopic organization in vivo and neuronal network hyperactivity in human iPSC-derived neurons.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CNTN5 (NB-2) is a GPI-anchored immunoglobulin superfamily cell recognition molecule that functions in the development and maturation of glutamatergic synapses within central auditory circuits. It is preferentially expressed in glutamatergic neurons of the auditory brainstem, where it localizes to presynaptic membranes through a cis-complex with APLP1 and co-localizes with VGLUT1/VGLUT2-positive synapses including calyces of Held [PMID:19177518, PMID:22285261]. CNTN5 promotes neurite outgrowth selectively from cortical neurons, and its genetic ablation in mice disrupts tonotopic organization and attenuates neural excitability in the inferior colliculus [PMID:11438979, PMID:12653969]. Human iPSC-derived glutamatergic neurons carrying heterozygous de novo CNTN5 loss-of-function variants exhibit spontaneous network hyperactivity, linking CNTN5 haploinsufficiency to neuronal dysfunction in autism spectrum disorder [PMID:30747104].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Cloning and chromosomal mapping of human CNTN5 established its genomic identity and brain expression pattern, revealing two splice isoforms and enrichment in amygdala and occipital lobe.\",\n      \"evidence\": \"cDNA cloning, FISH mapping to 11q21-q22.2, and RT-PCR across human brain regions\",\n      \"pmids\": [\"11013081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab characterization without independent replication\", \"Functional significance of the two splice isoforms unknown\", \"No mechanistic data on protein function\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that CNTN5 promotes neurite outgrowth specifically from cortical neurons and is concentrated in auditory pathway nuclei answered what cell types respond to CNTN5 and where it acts in the brain.\",\n      \"evidence\": \"In vitro neurite outgrowth assays on cortical vs. hippocampal neurons; in situ hybridization and immunohistochemistry across brain regions\",\n      \"pmids\": [\"11438979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor or signaling pathway mediating neurite outgrowth not identified\", \"Basis for cortical vs. hippocampal selectivity unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Knockout mouse studies revealed that CNTN5 loss disrupts auditory circuit function in vivo, establishing a causal role in tonotopic organization and neural excitability rather than merely correlative expression.\",\n      \"evidence\": \"NB-2-deficient mice (tau-LacZ knockin) assessed by audiogenic seizure testing and c-Fos immunohistochemistry in the inferior colliculus\",\n      \"pmids\": [\"12653969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synaptic versus axon guidance mechanism not distinguished\", \"Whether auditory phenotype reflects developmental or maintenance defect unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Restriction of CNTN5 expression to glutamatergic neurons and its co-localization with glutamatergic synaptic markers refined the cellular context, implicating CNTN5 specifically in glutamatergic synapse maturation within auditory brainstem nuclei.\",\n      \"evidence\": \"Combined in situ hybridization and immunohistochemistry with VGLUT1, VGLUT2, and synapsin markers across developmental stages\",\n      \"pmids\": [\"19177518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct evidence that CNTN5 is required for glutamatergic synapse formation or function not yet provided\", \"Trans-synaptic binding partners unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of APLP1 as a cis-interaction partner on presynaptic membranes provided the first molecular complex context for CNTN5, explaining how a GPI-anchored protein can be retained at synaptic sites.\",\n      \"evidence\": \"Pull-down and cell surface binding assays, immunofluorescence co-localization with synapsin, presynaptic fraction biochemical enrichment\",\n      \"pmids\": [\"22285261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CNTN5-APLP1 interaction on synapse maturation not tested\", \"Trans-synaptic ligands that the complex engages unknown\", \"No structural data on the complex\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Human iPSC-derived neuron studies demonstrated that heterozygous CNTN5 loss-of-function causes network hyperactivity, directly connecting CNTN5 haploinsufficiency to a neuronal electrophysiological phenotype relevant to ASD.\",\n      \"evidence\": \"iPSC-derived glutamatergic neurons from individuals with de novo CNTN5 variants, multi-electrode array and patch-clamp recordings across multiple lines\",\n      \"pmids\": [\"30747104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway from CNTN5 loss to hyperactivity not delineated\", \"Whether hyperactivity is excitatory/inhibitory imbalance or cell-autonomous not resolved\", \"In vivo validation in human-relevant models pending\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The signaling pathway downstream of CNTN5, the identity of its trans-synaptic binding partners, and the mechanism by which CNTN5-APLP1 complexes regulate glutamatergic synapse maturation remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No trans-synaptic ligand identified\", \"Intracellular signaling cascade unknown for a GPI-anchored molecule\", \"Structural basis of CNTN5-APLP1 interaction uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"APLP1\"],\n    \"other_free_text\": []\n  }\n}\n```"}