{"gene":"CNTN5","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2003,"finding":"NB-2-deficient mice exhibit aberrant responses to acoustic stimuli, with attenuated neural excitability in the dorsal and external cortices of the inferior colliculus and diffuse/low-level c-Fos expression in the central nucleus of the inferior colliculus in response to pure-tone stimulation, indicating NB-2 is required for normal neuronal activity patterning in the auditory system.","method":"Knockout mouse model (tau-LacZ replacement), audiogenic seizure testing, c-Fos immunohistochemistry","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, multiple orthogonal readouts (audiogenic seizure, c-Fos mapping), replicated across stimulation paradigms in a single rigorous study","pmids":["12653969"],"is_preprint":false},{"year":2001,"finding":"NB-2 (rat contactin-5 ortholog) promotes neurite outgrowth of cerebral cortical neurons but not hippocampal neurons, demonstrating cell-type specificity in its neurite outgrowth-promoting activity. NB-2 is expressed in restricted brain regions including cochlear nuclei, superior olive, inferior colliculi, medial geniculate nuclei, auditory cortex, accessory olfactory bulb, thalamic nuclei, facial nucleus, and inferior olive.","method":"Neurite outgrowth assay (in vitro), in situ hybridization, immunohistochemistry, western blot developmental profile","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assay plus expression mapping, single lab, two orthogonal methods","pmids":["11438979"],"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: a long isoform (1100 amino acids, 91% homologous to rat NB-2) and a short isoform lacking 74 amino acid residues (residues 19–93). High-level expression was detected in the amygdala and occipital lobe in the adult human brain.","method":"FISH chromosomal mapping, cDNA cloning and sequencing, northern blot/expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal localization by FISH, cDNA characterization, single lab with two orthogonal methods","pmids":["11013081"],"is_preprint":false},{"year":2009,"finding":"NB-2 is preferentially expressed in glutamatergic neurons in the auditory brainstem, colocalizing with glutamatergic elements in the neuropil and calyces of Held but not with glycinergic or GABAergic elements. NB-2 is expressed at glutamatergic synapses (colocalized with VGLUT1 and VGLUT2 markers), and its expression peaks at postnatal day 7 in the superior olivary complex, suggesting a role in maturation of glutamatergic synapses during final stages of auditory development.","method":"In situ hybridization combined with immunohistochemistry, VGLUT1/VGLUT2 immunolabeling, developmental expression analysis","journal":"The Journal of comparative neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal immunohistochemical methods, systematic developmental profiling, functional context established by NB-2 KO phenotype from prior work","pmids":["19177518"],"is_preprint":false},{"year":2012,"finding":"NB-2/contactin-5 forms a cis-complex with amyloid precursor-like protein 1 (APLP1) on the presynaptic membrane. Both NB-2 and APLP1 colocalize with synapsin (presynaptic marker) in cultured hippocampal neurons, and both are enriched in the presynaptic fraction by biochemical fractionation.","method":"Pull-down assay, cell surface binding assay, immunofluorescence colocalization with synapsin, subcellular fractionation (presynaptic fraction enrichment), western blot","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown and cell surface binding plus biochemical fractionation, single lab, multiple orthogonal methods","pmids":["22285261"],"is_preprint":false},{"year":2019,"finding":"CNTN5-deficient human iPSC-derived glutamatergic neurons exhibit consistent spontaneous network hyperactivity, as measured by multi-electrode array and patch-clamp recordings, identifying a specific electrophysiological phenotype associated with CNTN5 loss of function relevant to autism spectrum disorder.","method":"iPSC-derived neuron differentiation from ASD patients with heterozygous CNTN5 variants, multi-electrode array (MEA) recordings, patch-clamp electrophysiology","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic iPSC-derived neurons with defined loss-of-function, two electrophysiological methods (MEA + patch clamp), single lab","pmids":["30747104"],"is_preprint":false}],"current_model":"CNTN5 (NB-2/contactin-5) is a GPI-anchored neural cell recognition molecule of the contactin/immunoglobulin superfamily that is preferentially expressed in glutamatergic neurons of the central auditory pathway; it promotes neurite outgrowth of cortical neurons in vitro, forms a cis-complex with APLP1 on the presynaptic membrane, and is required for proper tonotopic organization and neuronal excitability in the auditory brainstem, with loss of function causing network hyperactivity in human neurons and aberrant acoustic responses in mice."},"narrative":{"mechanistic_narrative":"CNTN5 (NB-2/contactin-5) is a neural cell recognition molecule of the contactin/immunoglobulin superfamily that organizes connectivity in the central auditory pathway and broader brain circuits [PMID:12653969, PMID:11438979]. It is expressed in restricted regions including the cochlear nuclei, superior olive, inferior colliculi, medial geniculate nuclei, and auditory cortex, and within the auditory brainstem it is preferentially associated with glutamatergic neurons and glutamatergic synapses, with expression peaking during the final stages of synaptic maturation [PMID:11438979, PMID:19177518]. Functionally, CNTN5 promotes neurite outgrowth in a cell-type-specific manner, supporting cortical but not hippocampal neurons [PMID:11438979], and it engages amyloid precursor-like protein 1 (APLP1) in a cis-complex on the presynaptic membrane [PMID:22285261]. Loss of CNTN5 produces circuit-level dysfunction: knockout mice show aberrant acoustic responses and attenuated, mispatterned neuronal excitability in the inferior colliculus [PMID:12653969], and CNTN5-deficient human iPSC-derived glutamatergic neurons exhibit spontaneous network hyperactivity, linking loss of function to autism spectrum disorder phenotypes [PMID:30747104]. The human gene maps to chromosome 11q21-q22.2 and produces long and short splice isoforms [PMID:11013081]. Beyond these findings, the biochemical signaling downstream of CNTN5 and the structural basis of its interactions have not been characterized in the available corpus.","teleology":[{"year":2000,"claim":"Establishing the human gene's genomic location and isoform structure was the necessary first step toward connecting CNTN5 to brain function and disease.","evidence":"FISH chromosomal mapping and cDNA cloning of human NB-2/CNTN5, with brain expression analysis","pmids":["11013081"],"confidence":"Medium","gaps":["No functional role assigned to the two isoforms","Tissue mapping limited to adult bulk regions, not cellular resolution"]},{"year":2001,"claim":"Defining CNTN5 as a neurite-outgrowth-promoting molecule with cell-type specificity and a restricted auditory expression pattern gave the first mechanistic and anatomical clue to its role.","evidence":"In vitro neurite outgrowth assays on cortical vs hippocampal neurons plus in situ hybridization expression mapping in rat","pmids":["11438979"],"confidence":"Medium","gaps":["Receptor or ligand mediating outgrowth not identified","Molecular basis of cortical vs hippocampal selectivity unknown"]},{"year":2003,"claim":"Showing that CNTN5 loss disrupts auditory-evoked neuronal activity patterns established its requirement in vivo for normal auditory circuit function.","evidence":"NB-2 knockout mice with audiogenic seizure testing and c-Fos mapping in the inferior colliculus","pmids":["12653969"],"confidence":"High","gaps":["Cellular mechanism linking CNTN5 loss to altered excitability not resolved","Whether the defect is synaptic, axonal, or developmental not distinguished"]},{"year":2009,"claim":"Localizing CNTN5 specifically to glutamatergic neurons and synapses with a developmental expression peak refined its role to maturation of excitatory connectivity.","evidence":"Combined in situ hybridization/immunohistochemistry with VGLUT1/VGLUT2 colocalization and developmental profiling in auditory brainstem","pmids":["19177518"],"confidence":"High","gaps":["Functional consequence of synaptic localization not tested directly","No molecular synaptic partner identified in this work"]},{"year":2012,"claim":"Identifying the cis-complex with APLP1 on the presynaptic membrane provided the first direct molecular binding partner for CNTN5.","evidence":"Pull-down, cell surface binding, synapsin colocalization, and presynaptic fractionation in cultured neurons","pmids":["22285261"],"confidence":"Medium","gaps":["Functional output of the CNTN5-APLP1 complex not established","Single lab; no in vivo confirmation of the interaction's role"]},{"year":2019,"claim":"Demonstrating network hyperactivity in CNTN5-deficient human neurons connected loss of function to a defined electrophysiological phenotype relevant to autism spectrum disorder.","evidence":"iPSC-derived glutamatergic neurons from ASD patients with heterozygous CNTN5 variants, MEA and patch-clamp recordings","pmids":["30747104"],"confidence":"Medium","gaps":["Molecular pathway linking CNTN5 loss to hyperactivity unknown","Heterozygous patient lines complicate isolation of CNTN5-specific effect"]},{"year":null,"claim":"The downstream signaling mechanism and structural basis by which CNTN5 controls neuronal excitability and synaptic maturation remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No intracellular signaling pathway identified for a GPI-anchored CNTN5","Functional role of the APLP1 cis-complex not mechanistically tested","No structural model of CNTN5 or its interactions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["APLP1"],"other_free_text":[]}},"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":113,"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":108,"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":87,"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":73,"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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pure-tone stimulation, indicating NB-2 is required for normal neuronal activity patterning in the auditory system.\",\n      \"method\": \"Knockout mouse model (tau-LacZ replacement), audiogenic seizure testing, c-Fos immunohistochemistry\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, multiple orthogonal readouts (audiogenic seizure, c-Fos mapping), replicated across stimulation paradigms in a single rigorous study\",\n      \"pmids\": [\"12653969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NB-2 (rat contactin-5 ortholog) promotes neurite outgrowth of cerebral cortical neurons but not hippocampal neurons, demonstrating cell-type specificity in its neurite outgrowth-promoting activity. NB-2 is expressed in restricted brain regions including cochlear nuclei, superior olive, inferior colliculi, medial geniculate nuclei, auditory cortex, accessory olfactory bulb, thalamic nuclei, facial nucleus, and inferior olive.\",\n      \"method\": \"Neurite outgrowth assay (in vitro), in situ hybridization, immunohistochemistry, western blot developmental profile\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assay plus expression mapping, single lab, two orthogonal methods\",\n      \"pmids\": [\"11438979\"],\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: a long isoform (1100 amino acids, 91% homologous to rat NB-2) and a short isoform lacking 74 amino acid residues (residues 19–93). High-level expression was detected in the amygdala and occipital lobe in the adult human brain.\",\n      \"method\": \"FISH chromosomal mapping, cDNA cloning and sequencing, northern blot/expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal localization by FISH, cDNA characterization, single lab with two orthogonal methods\",\n      \"pmids\": [\"11013081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NB-2 is preferentially expressed in glutamatergic neurons in the auditory brainstem, colocalizing with glutamatergic elements in the neuropil and calyces of Held but not with glycinergic or GABAergic elements. NB-2 is expressed at glutamatergic synapses (colocalized with VGLUT1 and VGLUT2 markers), and its expression peaks at postnatal day 7 in the superior olivary complex, suggesting a role in maturation of glutamatergic synapses during final stages of auditory development.\",\n      \"method\": \"In situ hybridization combined with immunohistochemistry, VGLUT1/VGLUT2 immunolabeling, developmental expression analysis\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal immunohistochemical methods, systematic developmental profiling, functional context established by NB-2 KO phenotype from prior work\",\n      \"pmids\": [\"19177518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NB-2/contactin-5 forms a cis-complex with amyloid precursor-like protein 1 (APLP1) on the presynaptic membrane. Both NB-2 and APLP1 colocalize with synapsin (presynaptic marker) in cultured hippocampal neurons, and both are enriched in the presynaptic fraction by biochemical fractionation.\",\n      \"method\": \"Pull-down assay, cell surface binding assay, immunofluorescence colocalization with synapsin, subcellular fractionation (presynaptic fraction enrichment), western blot\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown and cell surface binding plus biochemical fractionation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22285261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CNTN5-deficient human iPSC-derived glutamatergic neurons exhibit consistent spontaneous network hyperactivity, as measured by multi-electrode array and patch-clamp recordings, identifying a specific electrophysiological phenotype associated with CNTN5 loss of function relevant to autism spectrum disorder.\",\n      \"method\": \"iPSC-derived neuron differentiation from ASD patients with heterozygous CNTN5 variants, multi-electrode array (MEA) recordings, patch-clamp electrophysiology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic iPSC-derived neurons with defined loss-of-function, two electrophysiological methods (MEA + patch clamp), single lab\",\n      \"pmids\": [\"30747104\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CNTN5 (NB-2/contactin-5) is a GPI-anchored neural cell recognition molecule of the contactin/immunoglobulin superfamily that is preferentially expressed in glutamatergic neurons of the central auditory pathway; it promotes neurite outgrowth of cortical neurons in vitro, forms a cis-complex with APLP1 on the presynaptic membrane, and is required for proper tonotopic organization and neuronal excitability in the auditory brainstem, with loss of function causing network hyperactivity in human neurons and aberrant acoustic responses in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CNTN5 (NB-2/contactin-5) is a neural cell recognition molecule of the contactin/immunoglobulin superfamily that organizes connectivity in the central auditory pathway and broader brain circuits [#0, #1]. It is expressed in restricted regions including the cochlear nuclei, superior olive, inferior colliculi, medial geniculate nuclei, and auditory cortex, and within the auditory brainstem it is preferentially associated with glutamatergic neurons and glutamatergic synapses, with expression peaking during the final stages of synaptic maturation [#1, #3]. Functionally, CNTN5 promotes neurite outgrowth in a cell-type-specific manner, supporting cortical but not hippocampal neurons [#1], and it engages amyloid precursor-like protein 1 (APLP1) in a cis-complex on the presynaptic membrane [#4]. Loss of CNTN5 produces circuit-level dysfunction: knockout mice show aberrant acoustic responses and attenuated, mispatterned neuronal excitability in the inferior colliculus [#0], and CNTN5-deficient human iPSC-derived glutamatergic neurons exhibit spontaneous network hyperactivity, linking loss of function to autism spectrum disorder phenotypes [#5]. The human gene maps to chromosome 11q21-q22.2 and produces long and short splice isoforms [#2]. Beyond these findings, the biochemical signaling downstream of CNTN5 and the structural basis of its interactions have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the human gene's genomic location and isoform structure was the necessary first step toward connecting CNTN5 to brain function and disease.\",\n      \"evidence\": \"FISH chromosomal mapping and cDNA cloning of human NB-2/CNTN5, with brain expression analysis\",\n      \"pmids\": [\"11013081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional role assigned to the two isoforms\", \"Tissue mapping limited to adult bulk regions, not cellular resolution\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining CNTN5 as a neurite-outgrowth-promoting molecule with cell-type specificity and a restricted auditory expression pattern gave the first mechanistic and anatomical clue to its role.\",\n      \"evidence\": \"In vitro neurite outgrowth assays on cortical vs hippocampal neurons plus in situ hybridization expression mapping in rat\",\n      \"pmids\": [\"11438979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor or ligand mediating outgrowth not identified\", \"Molecular basis of cortical vs hippocampal selectivity unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that CNTN5 loss disrupts auditory-evoked neuronal activity patterns established its requirement in vivo for normal auditory circuit function.\",\n      \"evidence\": \"NB-2 knockout mice with audiogenic seizure testing and c-Fos mapping in the inferior colliculus\",\n      \"pmids\": [\"12653969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular mechanism linking CNTN5 loss to altered excitability not resolved\", \"Whether the defect is synaptic, axonal, or developmental not distinguished\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Localizing CNTN5 specifically to glutamatergic neurons and synapses with a developmental expression peak refined its role to maturation of excitatory connectivity.\",\n      \"evidence\": \"Combined in situ hybridization/immunohistochemistry with VGLUT1/VGLUT2 colocalization and developmental profiling in auditory brainstem\",\n      \"pmids\": [\"19177518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of synaptic localization not tested directly\", \"No molecular synaptic partner identified in this work\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying the cis-complex with APLP1 on the presynaptic membrane provided the first direct molecular binding partner for CNTN5.\",\n      \"evidence\": \"Pull-down, cell surface binding, synapsin colocalization, and presynaptic fractionation in cultured neurons\",\n      \"pmids\": [\"22285261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of the CNTN5-APLP1 complex not established\", \"Single lab; no in vivo confirmation of the interaction's role\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating network hyperactivity in CNTN5-deficient human neurons connected loss of function to a defined electrophysiological phenotype relevant to autism spectrum disorder.\",\n      \"evidence\": \"iPSC-derived glutamatergic neurons from ASD patients with heterozygous CNTN5 variants, MEA and patch-clamp recordings\",\n      \"pmids\": [\"30747104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking CNTN5 loss to hyperactivity unknown\", \"Heterozygous patient lines complicate isolation of CNTN5-specific effect\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The downstream signaling mechanism and structural basis by which CNTN5 controls neuronal excitability and synaptic maturation remain undefined.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No intracellular signaling pathway identified for a GPI-anchored CNTN5\", \"Functional role of the APLP1 cis-complex not mechanistically tested\", \"No structural model of CNTN5 or its interactions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"APLP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}