{"gene":"NCAN","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1998,"finding":"Human neurocan (NCAN/CSPG3) encodes a 1321 amino acid brain-specific chondroitin sulfate proteoglycan; Northern analysis confirmed a brain-specific transcript of ~7.5 kb; the gene spans ~41 kb on chromosome 19 and is involved in modulation of cell adhesion and migration.","method":"cDNA cloning, Northern analysis, chromosomal mapping, genomic sequencing","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular characterization of the human gene with multiple methods in a single study","pmids":["9795216"],"is_preprint":false},{"year":2010,"finding":"NCAN (CSPG3/neurocan) is upregulated in periventricular white matter and cortex following inflammatory injury in EAE, coinciding with neuronal progenitor cell proliferation and migration from the subventricular zone, suggesting a role in lesion remodeling of the brain extracellular matrix.","method":"EAE mouse model, immunofluorescence, GFAP immunoreactivity, BrdU labeling of NPCs","journal":"Journal of molecular neuroscience : MN","confidence":"Medium","confidence_rationale":"Tier 3 — single study with multiple immunohistochemical readouts but no direct functional manipulation of NCAN","pmids":["21107918"],"is_preprint":false},{"year":2014,"finding":"The NCAN rs2228603 risk polymorphism is associated with hepatocellular carcinoma in alcoholic liver disease; NCAN protein expression was identified in human liver tissue (not only neuronal tissue) by RT-PCR and immunofluorescence microscopy.","method":"RT-PCR, immunofluorescence microscopy, genotyping in patient cohorts","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization of NCAN in liver confirmed by two orthogonal methods in a single study","pmids":["24946282"],"is_preprint":false},{"year":2025,"finding":"The hyaluronan (HA)-binding domain of neurocan (NCAN) was sufficient to bind HA when fused to GFP and secreted extracellularly via an AAV vector, enabling labeling of perineuronal nets and interstitial matrix in the mouse brain; binding was validated by colocalization with HABP and sensitivity to hyaluronidase.","method":"AAV-mediated expression of NCAN HA-binding domain fused to GFP, colocalization with HABP, hyaluronidase sensitivity assay, live and in vivo imaging","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — functional domain characterization with multiple validation methods (colocalization, enzymatic disruption, shadow imaging), but preprint","pmids":[],"is_preprint":true}],"current_model":"NCAN encodes a brain-enriched (and also liver-expressed) chondroitin sulfate proteoglycan whose hyaluronan-binding domain directly engages the extracellular matrix to modulate cell adhesion and migration; it is upregulated after CNS inflammatory injury coincident with neuronal progenitor proliferation, and common risk variants in the gene influence cortical structure and cognitive performance in humans."},"narrative":{"teleology":[{"year":1998,"claim":"Cloning of the human NCAN gene established that neurocan is a brain-specific chondroitin sulfate proteoglycan of 1321 amino acids involved in modulation of cell adhesion and migration, resolving its molecular identity and genomic organization.","evidence":"cDNA cloning, Northern analysis, chromosomal mapping, and genomic sequencing of the human gene","pmids":["9795216"],"confidence":"Medium","gaps":["No functional perturbation experiment to directly test adhesion/migration roles","Brain-specific expression claim based on Northern blot alone; expression in other tissues not systematically surveyed","No identification of specific binding partners or receptors"]},{"year":2010,"claim":"Demonstration that NCAN is upregulated in white matter and cortex during inflammatory demyelination linked neurocan to injury-associated extracellular matrix remodeling coincident with neural progenitor cell activity.","evidence":"EAE mouse model with immunofluorescence, GFAP staining, and BrdU labeling of neural progenitor cells","pmids":["21107918"],"confidence":"Medium","gaps":["Correlative — no loss-of-function or gain-of-function manipulation of NCAN in the injury model","Causal relationship between NCAN upregulation and progenitor migration not tested","Mechanism by which NCAN influences progenitor behavior unknown"]},{"year":2014,"claim":"Detection of NCAN protein in human liver tissue by RT-PCR and immunofluorescence expanded the expression map beyond the nervous system and connected the rs2228603 polymorphism to hepatocellular carcinoma risk in alcoholic liver disease.","evidence":"RT-PCR, immunofluorescence microscopy, and genotyping in patient cohorts","pmids":["24946282"],"confidence":"Medium","gaps":["Functional role of neurocan in liver tissue is unknown","Mechanism linking rs2228603 to hepatocellular carcinoma not characterized","Single cohort association; no mechanistic follow-up"]},{"year":2025,"claim":"Isolation of the hyaluronan-binding domain showed it is sufficient for engagement with brain extracellular matrix including perineuronal nets, establishing the minimal structural element responsible for NCAN–hyaluronan interaction.","evidence":"AAV-mediated secretion of NCAN HA-binding domain–GFP fusion, colocalization with HABP, hyaluronidase sensitivity assay in mouse brain (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Contribution of the chondroitin sulfate chains versus the HA-binding domain to in vivo function not dissected","Downstream signaling consequences of HA binding not addressed"]},{"year":null,"claim":"The precise cellular mechanisms by which neurocan modulates cell adhesion, migration, and neural progenitor behavior remain unresolved, as no loss-of-function studies in mammalian systems have dissected its non-redundant roles in brain or liver.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genetic knockout or conditional deletion phenotype reported in the timeline","Specific cell-surface receptors or signaling pathways engaged by neurocan are unidentified","Functional significance of hepatic neurocan is entirely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"NCAN encodes neurocan, a chondroitin sulfate proteoglycan predominantly expressed in the brain but also detected in liver, that modulates cell adhesion and migration through its extracellular matrix interactions [PMID:9795216, PMID:24946282]. The hyaluronan-binding domain of neurocan is sufficient to engage hyaluronan in the brain extracellular matrix, including perineuronal nets and interstitial matrix, as demonstrated by colocalization with hyaluronan-binding protein and sensitivity to hyaluronidase digestion. NCAN is upregulated in periventricular white matter and cortex following inflammatory CNS injury, coinciding with neuronal progenitor cell proliferation and migration, implicating it in lesion-associated extracellular matrix remodeling [PMID:21107918]."},"prefetch_data":{"uniprot":{"accession":"O14594","full_name":"Neurocan core protein","aliases":["Chondroitin sulfate proteoglycan 3"],"length_aa":1321,"mass_kda":143.1,"function":"May modulate neuronal adhesion and neurite growth during development by binding to neural cell adhesion molecules (NG-CAM and N-CAM). Chondroitin sulfate proteoglycan; binds to hyaluronic acid","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O14594/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NCAN","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/NCAN","total_profiled":1310},"omim":[{"mim_id":"600826","title":"CHONDROITIN SULFATE PROTEOGLYCAN 3; CSPG3","url":"https://www.omim.org/entry/600826"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":98.5}],"url":"https://www.proteinatlas.org/search/NCAN"},"hgnc":{"alias_symbol":[],"prev_symbol":["CSPG3"]},"alphafold":{"accession":"O14594","domains":[{"cath_id":"2.60.40.10","chopping":"38-157","consensus_level":"high","plddt":84.0319,"start":38,"end":157},{"cath_id":"3.10.100.10","chopping":"160-359","consensus_level":"medium","plddt":90.7442,"start":160,"end":359},{"cath_id":"3.10.100.10","chopping":"1061-1213","consensus_level":"high","plddt":89.6646,"start":1061,"end":1213},{"cath_id":"2.10.70.10","chopping":"1225-1273","consensus_level":"high","plddt":85.7527,"start":1225,"end":1273}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14594","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14594-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14594-F1-predicted_aligned_error_v6.png","plddt_mean":57.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NCAN","jax_strain_url":"https://www.jax.org/strain/search?query=NCAN"},"sequence":{"accession":"O14594","fasta_url":"https://rest.uniprot.org/uniprotkb/O14594.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14594/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14594"}},"corpus_meta":[{"pmid":"22497794","id":"PMC_22497794","title":"Association between schizophrenia and common variation in neurocan (NCAN), a genetic risk factor for bipolar disorder.","date":"2012","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/22497794","citation_count":64,"is_preprint":false},{"pmid":"23795679","id":"PMC_23795679","title":"Common variation in NCAN, a risk factor for bipolar disorder and schizophrenia, influences local cortical folding in schizophrenia.","date":"2014","source":"Psychological medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23795679","citation_count":49,"is_preprint":false},{"pmid":"24946282","id":"PMC_24946282","title":"A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease.","date":"2014","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/24946282","citation_count":39,"is_preprint":false},{"pmid":"27853371","id":"PMC_27853371","title":"The NCAN gene: schizophrenia susceptibility and cognitive dysfunction.","date":"2016","source":"Neuropsychiatric disease and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/27853371","citation_count":27,"is_preprint":false},{"pmid":"25220293","id":"PMC_25220293","title":"A genome-wide supported psychiatric risk variant in NCAN influences brain function and cognitive performance in healthy subjects.","date":"2014","source":"Human brain mapping","url":"https://pubmed.ncbi.nlm.nih.gov/25220293","citation_count":26,"is_preprint":false},{"pmid":"28839234","id":"PMC_28839234","title":"Identification of NCAN as a candidate gene for developmental dyslexia.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28839234","citation_count":16,"is_preprint":false},{"pmid":"9795216","id":"PMC_9795216","title":"Characterization of the human neurocan gene, CSPG3.","date":"1998","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9795216","citation_count":16,"is_preprint":false},{"pmid":"32568739","id":"PMC_32568739","title":"Association of the NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 SNPs and gene-gene and gene-environment interactions with serum lipid levels.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32568739","citation_count":15,"is_preprint":false},{"pmid":"21107918","id":"PMC_21107918","title":"Upregulation of CSPG3 accompanies neuronal progenitor proliferation and migration in EAE.","date":"2010","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/21107918","citation_count":13,"is_preprint":false},{"pmid":"29998116","id":"PMC_29998116","title":"Further Evidence of an Association between NCAN rs1064395 and Bipolar Disorder.","date":"2018","source":"Molecular neuropsychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/29998116","citation_count":11,"is_preprint":false},{"pmid":"26758378","id":"PMC_26758378","title":"Replication analysis of genetic association of the NCAN-CILP2 region with plasma lipid levels and non-alcoholic fatty liver disease in Asian and Pacific ethnic groups.","date":"2016","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/26758378","citation_count":10,"is_preprint":false},{"pmid":"27887608","id":"PMC_27887608","title":"Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study.","date":"2016","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/27887608","citation_count":5,"is_preprint":false},{"pmid":"40806538","id":"PMC_40806538","title":"Contribution of PNPLA3, GCKR, MBOAT7, NCAN, and TM6SF2 Genetic Variants to Hepatocellular Carcinoma Development in Mexican Patients.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40806538","citation_count":1,"is_preprint":false},{"pmid":"38800981","id":"PMC_38800981","title":"Neuromodulation of Cardiovascular Risks Associated With Cardiotoxic Chemotherapy: A First-in-Human Randomized Pilot Study. Neuromodulation in Cancer Study (NCAN).","date":"2024","source":"American journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38800981","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.13.24315422","title":"Discovery of novel obesity genes through cross-ancestry analysis","date":"2024-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.13.24315422","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.31.635882","title":"Viral-mediated fluorescent labeling of hyaluronan reveals extracellular matrix dynamics in the mouse brain in vivo","date":"2025-02-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.31.635882","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9854,"output_tokens":944,"usd":0.021861},"stage2":{"model":"claude-opus-4-6","input_tokens":4136,"output_tokens":1346,"usd":0.081495},"total_usd":0.103356,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Human neurocan (NCAN/CSPG3) encodes a 1321 amino acid brain-specific chondroitin sulfate proteoglycan; Northern analysis confirmed a brain-specific transcript of ~7.5 kb; the gene spans ~41 kb on chromosome 19 and is involved in modulation of cell adhesion and migration.\",\n      \"method\": \"cDNA cloning, Northern analysis, chromosomal mapping, genomic sequencing\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular characterization of the human gene with multiple methods in a single study\",\n      \"pmids\": [\"9795216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NCAN (CSPG3/neurocan) is upregulated in periventricular white matter and cortex following inflammatory injury in EAE, coinciding with neuronal progenitor cell proliferation and migration from the subventricular zone, suggesting a role in lesion remodeling of the brain extracellular matrix.\",\n      \"method\": \"EAE mouse model, immunofluorescence, GFAP immunoreactivity, BrdU labeling of NPCs\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single study with multiple immunohistochemical readouts but no direct functional manipulation of NCAN\",\n      \"pmids\": [\"21107918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The NCAN rs2228603 risk polymorphism is associated with hepatocellular carcinoma in alcoholic liver disease; NCAN protein expression was identified in human liver tissue (not only neuronal tissue) by RT-PCR and immunofluorescence microscopy.\",\n      \"method\": \"RT-PCR, immunofluorescence microscopy, genotyping in patient cohorts\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization of NCAN in liver confirmed by two orthogonal methods in a single study\",\n      \"pmids\": [\"24946282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The hyaluronan (HA)-binding domain of neurocan (NCAN) was sufficient to bind HA when fused to GFP and secreted extracellularly via an AAV vector, enabling labeling of perineuronal nets and interstitial matrix in the mouse brain; binding was validated by colocalization with HABP and sensitivity to hyaluronidase.\",\n      \"method\": \"AAV-mediated expression of NCAN HA-binding domain fused to GFP, colocalization with HABP, hyaluronidase sensitivity assay, live and in vivo imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional domain characterization with multiple validation methods (colocalization, enzymatic disruption, shadow imaging), but preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NCAN encodes a brain-enriched (and also liver-expressed) chondroitin sulfate proteoglycan whose hyaluronan-binding domain directly engages the extracellular matrix to modulate cell adhesion and migration; it is upregulated after CNS inflammatory injury coincident with neuronal progenitor proliferation, and common risk variants in the gene influence cortical structure and cognitive performance in humans.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NCAN encodes neurocan, a chondroitin sulfate proteoglycan predominantly expressed in the brain but also detected in liver, that modulates cell adhesion and migration through its extracellular matrix interactions [PMID:9795216, PMID:24946282]. The hyaluronan-binding domain of neurocan is sufficient to engage hyaluronan in the brain extracellular matrix, including perineuronal nets and interstitial matrix, as demonstrated by colocalization with hyaluronan-binding protein and sensitivity to hyaluronidase digestion. NCAN is upregulated in periventricular white matter and cortex following inflammatory CNS injury, coinciding with neuronal progenitor cell proliferation and migration, implicating it in lesion-associated extracellular matrix remodeling [PMID:21107918].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Cloning of the human NCAN gene established that neurocan is a brain-specific chondroitin sulfate proteoglycan of 1321 amino acids involved in modulation of cell adhesion and migration, resolving its molecular identity and genomic organization.\",\n      \"evidence\": \"cDNA cloning, Northern analysis, chromosomal mapping, and genomic sequencing of the human gene\",\n      \"pmids\": [\"9795216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional perturbation experiment to directly test adhesion/migration roles\",\n        \"Brain-specific expression claim based on Northern blot alone; expression in other tissues not systematically surveyed\",\n        \"No identification of specific binding partners or receptors\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that NCAN is upregulated in white matter and cortex during inflammatory demyelination linked neurocan to injury-associated extracellular matrix remodeling coincident with neural progenitor cell activity.\",\n      \"evidence\": \"EAE mouse model with immunofluorescence, GFAP staining, and BrdU labeling of neural progenitor cells\",\n      \"pmids\": [\"21107918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Correlative — no loss-of-function or gain-of-function manipulation of NCAN in the injury model\",\n        \"Causal relationship between NCAN upregulation and progenitor migration not tested\",\n        \"Mechanism by which NCAN influences progenitor behavior unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Detection of NCAN protein in human liver tissue by RT-PCR and immunofluorescence expanded the expression map beyond the nervous system and connected the rs2228603 polymorphism to hepatocellular carcinoma risk in alcoholic liver disease.\",\n      \"evidence\": \"RT-PCR, immunofluorescence microscopy, and genotyping in patient cohorts\",\n      \"pmids\": [\"24946282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of neurocan in liver tissue is unknown\",\n        \"Mechanism linking rs2228603 to hepatocellular carcinoma not characterized\",\n        \"Single cohort association; no mechanistic follow-up\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Isolation of the hyaluronan-binding domain showed it is sufficient for engagement with brain extracellular matrix including perineuronal nets, establishing the minimal structural element responsible for NCAN–hyaluronan interaction.\",\n      \"evidence\": \"AAV-mediated secretion of NCAN HA-binding domain–GFP fusion, colocalization with HABP, hyaluronidase sensitivity assay in mouse brain (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"Contribution of the chondroitin sulfate chains versus the HA-binding domain to in vivo function not dissected\",\n        \"Downstream signaling consequences of HA binding not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise cellular mechanisms by which neurocan modulates cell adhesion, migration, and neural progenitor behavior remain unresolved, as no loss-of-function studies in mammalian systems have dissected its non-redundant roles in brain or liver.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genetic knockout or conditional deletion phenotype reported in the timeline\",\n        \"Specific cell-surface receptors or signaling pathways engaged by neurocan are unidentified\",\n        \"Functional significance of hepatic neurocan is entirely uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}