{"gene":"SYN2","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":2013,"finding":"Loss-of-function mutations in SYN2 (nonsense A94fs199X and missense Y236S, G464R) impair synaptic vesicle cycling and axon outgrowth; wild-type human Syn II rescues the SYN2 knockout phenotype in neurons, while the nonsense mutant is not expressed and missense mutants fail to rescue, establishing SYN2 as a regulator of synaptic vesicle cycling and synaptogenesis.","method":"Functional rescue assay in SYN2 knockout neurons (expression of wild-type and mutant human SYN2), synaptic vesicle cycling assays, axon outgrowth measurements","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO rescue experiment with defined cellular phenotypes; single lab","pmids":["23956174"],"is_preprint":false},{"year":1995,"finding":"The human SYN2 gene was mapped to chromosome 3p and the mouse Syn2 gene to chromosome 6 band F, establishing SYN2 as a neuron-specific phosphoprotein gene on autosomes distinct from the X-linked SYN1.","method":"PCR amplification from somatic hybrid cell lines, single-strand conformation analysis, FISH, and backcross genotyping","journal":"Cytogenetics and cell genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal mapping methods (somatic hybrids, FISH, genetic backcross)","pmids":["7587399"],"is_preprint":false}],"current_model":"SYN2 encodes a neuron-specific phosphoprotein localized to synaptic vesicles that regulates neurotransmitter release and synaptogenesis; loss-of-function mutations impair synaptic vesicle cycling and axon outgrowth, with the protein's function demonstrated by rescue of the SYN2 knockout phenotype in neurons by wild-type but not mutant Syn II."},"narrative":{"teleology":[{"year":1995,"claim":"Chromosomal mapping resolved SYN2 as an autosomal locus on human chromosome 3p (and mouse chromosome 6F), establishing it as a distinct synapsin family member separate from X-linked SYN1.","evidence":"PCR from somatic hybrid cell lines, FISH, and backcross genotyping in human and mouse","pmids":["7587399"],"confidence":"High","gaps":["No functional data provided at this stage","Tissue-specific expression pattern not characterized beyond neuron-specific designation"]},{"year":2013,"claim":"Functional rescue experiments established that SYN2 directly regulates synaptic vesicle cycling and axon outgrowth, as wild-type human Synapsin II restored these functions in SYN2 knockout neurons while disease-associated missense mutants (Y236S, G464R) failed to rescue.","evidence":"Expression of wild-type and mutant human SYN2 in SYN2 knockout mouse neurons, with synaptic vesicle cycling assays and axon outgrowth measurements","pmids":["23956174"],"confidence":"Medium","gaps":["Single-lab study; independent replication in additional systems not reported","Biochemical mechanism by which missense mutations disrupt vesicle cycling is not determined","Phosphorylation-dependent regulation of Synapsin II function not dissected"]},{"year":null,"claim":"The precise molecular mechanism by which Synapsin II tethers or regulates synaptic vesicles, the identity of its critical binding partners at the vesicle surface, and the functional consequences of its phosphorylation remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of Synapsin II–vesicle interactions","No systematic identification of direct protein interaction partners","Role of individual phosphorylation sites in vesicle cycling not defined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"SYN2 encodes a neuron-specific phosphoprotein associated with synaptic vesicles that regulates synaptic vesicle cycling and axon outgrowth [PMID:23956174]. The human SYN2 gene maps to chromosome 3p, distinct from the X-linked SYN1 paralog [PMID:7587399]. Loss-of-function mutations (nonsense and missense) in SYN2 abolish rescue of the SYN2 knockout neuronal phenotype, demonstrating that intact Synapsin II is required for normal synaptogenesis and neurotransmitter release [PMID:23956174]."},"prefetch_data":{"uniprot":{"accession":"Q92777","full_name":"Synapsin-2","aliases":["Synapsin II"],"length_aa":582,"mass_kda":63.0,"function":"Neuronal phosphoprotein that coats synaptic vesicles, binds to the cytoskeleton, and is believed to function in the regulation of neurotransmitter release. 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CB09001.","date":"2019","source":"Natural product research","url":"https://pubmed.ncbi.nlm.nih.gov/31135217","citation_count":12,"is_preprint":false},{"pmid":"21465568","id":"PMC_21465568","title":"Lack of association between synapsin II (SYN2) gene polymorphism and susceptibility epilepsy: a case-control study and meta-analysis.","date":"2011","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21465568","citation_count":9,"is_preprint":false},{"pmid":"30666415","id":"PMC_30666415","title":"A case of nasal low-grade non-intestinal-type adenocarcinoma with aberrant CDX2 expression and a novel SYN2-PPARG gene fusion in a 13-year-old girl.","date":"2019","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30666415","citation_count":9,"is_preprint":false},{"pmid":"7587399","id":"PMC_7587399","title":"Mapping of synapsin II (SYN2) genes to human chromosome 3p and mouse chromosome 6 band F.","date":"1995","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7587399","citation_count":8,"is_preprint":false},{"pmid":"38238071","id":"PMC_38238071","title":"Small cell lung cancer with SYN2::PPARG fusion.","date":"2023","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/38238071","citation_count":2,"is_preprint":false},{"pmid":"39417931","id":"PMC_39417931","title":"A Case of Acinic Cell Carcinoma with SYN2::PPARG Fusion.","date":"2024","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39417931","citation_count":0,"is_preprint":false},{"pmid":"42008002","id":"PMC_42008002","title":"High-Grade Acinic Cell Carcinoma of the Parotid with SYN2::PPARG Fusion.","date":"2026","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/42008002","citation_count":0,"is_preprint":false},{"pmid":"41877551","id":"PMC_41877551","title":"Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass C with SYN2::PPARG fusion in an older adult.","date":"2026","source":"CNS oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41877551","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.17.676758","title":"Proteomic and Kinetic Characterization of Prion Seeding in Distinct Human CJD Strains Unveils Early Diagnostic Biomarkers","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.676758","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7231,"output_tokens":571,"usd":0.015129},"stage2":{"model":"claude-opus-4-6","input_tokens":3734,"output_tokens":853,"usd":0.059992},"total_usd":0.075121,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in SYN2 (nonsense A94fs199X and missense Y236S, G464R) impair synaptic vesicle cycling and axon outgrowth; wild-type human Syn II rescues the SYN2 knockout phenotype in neurons, while the nonsense mutant is not expressed and missense mutants fail to rescue, establishing SYN2 as a regulator of synaptic vesicle cycling and synaptogenesis.\",\n      \"method\": \"Functional rescue assay in SYN2 knockout neurons (expression of wild-type and mutant human SYN2), synaptic vesicle cycling assays, axon outgrowth measurements\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO rescue experiment with defined cellular phenotypes; single lab\",\n      \"pmids\": [\"23956174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human SYN2 gene was mapped to chromosome 3p and the mouse Syn2 gene to chromosome 6 band F, establishing SYN2 as a neuron-specific phosphoprotein gene on autosomes distinct from the X-linked SYN1.\",\n      \"method\": \"PCR amplification from somatic hybrid cell lines, single-strand conformation analysis, FISH, and backcross genotyping\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal mapping methods (somatic hybrids, FISH, genetic backcross)\",\n      \"pmids\": [\"7587399\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SYN2 encodes a neuron-specific phosphoprotein localized to synaptic vesicles that regulates neurotransmitter release and synaptogenesis; loss-of-function mutations impair synaptic vesicle cycling and axon outgrowth, with the protein's function demonstrated by rescue of the SYN2 knockout phenotype in neurons by wild-type but not mutant Syn II.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SYN2 encodes a neuron-specific phosphoprotein associated with synaptic vesicles that regulates synaptic vesicle cycling and axon outgrowth [PMID:23956174]. The human SYN2 gene maps to chromosome 3p, distinct from the X-linked SYN1 paralog [PMID:7587399]. Loss-of-function mutations (nonsense and missense) in SYN2 abolish rescue of the SYN2 knockout neuronal phenotype, demonstrating that intact Synapsin II is required for normal synaptogenesis and neurotransmitter release [PMID:23956174].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Chromosomal mapping resolved SYN2 as an autosomal locus on human chromosome 3p (and mouse chromosome 6F), establishing it as a distinct synapsin family member separate from X-linked SYN1.\",\n      \"evidence\": \"PCR from somatic hybrid cell lines, FISH, and backcross genotyping in human and mouse\",\n      \"pmids\": [\"7587399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No functional data provided at this stage\",\n        \"Tissue-specific expression pattern not characterized beyond neuron-specific designation\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Functional rescue experiments established that SYN2 directly regulates synaptic vesicle cycling and axon outgrowth, as wild-type human Synapsin II restored these functions in SYN2 knockout neurons while disease-associated missense mutants (Y236S, G464R) failed to rescue.\",\n      \"evidence\": \"Expression of wild-type and mutant human SYN2 in SYN2 knockout mouse neurons, with synaptic vesicle cycling assays and axon outgrowth measurements\",\n      \"pmids\": [\"23956174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication in additional systems not reported\",\n        \"Biochemical mechanism by which missense mutations disrupt vesicle cycling is not determined\",\n        \"Phosphorylation-dependent regulation of Synapsin II function not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise molecular mechanism by which Synapsin II tethers or regulates synaptic vesicles, the identity of its critical binding partners at the vesicle surface, and the functional consequences of its phosphorylation remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of Synapsin II–vesicle interactions\",\n        \"No systematic identification of direct protein interaction partners\",\n        \"Role of individual phosphorylation sites in vesicle cycling not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0031410\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-112316\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}