{"gene":"SYNRG","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2019,"finding":"The SYNRG-ZNF384 fusion protein exhibits stronger transcriptional activity than wild-type ZNF384 on SALL4 and ID2 promoter/enhancer regions, and associates more strongly with the transcriptional coactivator EP300 than wild-type ZNF384 does, as demonstrated by GST pull-down assay. Coexpression of EP300 specifically enhanced the transcriptional activities of SYNRG-ZNF384 fusion protein.","method":"Reporter assay (transcriptional activity on SALL4/ID2 promoter/enhancer), GST pull-down assay for EP300 interaction, gene expression analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pull-down plus functional reporter assay in a single lab, two orthogonal methods, but only for the fusion protein context","pmids":["31234226"],"is_preprint":false},{"year":2022,"finding":"Homozygous loss-of-function variants in SYNRG (p.Leu1202Pro and p.Gly533*) cause a complex hereditary spastic paraplegia phenotype, implicating SYNRG's interaction with the AP-1 (adaptor-related protein complex) family in neuronal function. This positions SYNRG as a coatopathy gene.","method":"Whole-exome sequencing of affected patients; homozygous variant identification in SYNRG; clinical phenotyping","journal":"Brain & development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic variant identification in patients with no in vitro/in vivo functional validation of the specific variants or direct AP-1 interaction experiment in this study","pmids":["35090779"],"is_preprint":false}],"current_model":"SYNRG (synergin gamma) is an AP-1 adaptor complex-interacting protein whose loss-of-function causes hereditary spastic paraplegia; when fused to ZNF384 in B-cell ALL, the resulting fusion protein binds EP300 with higher affinity than wild-type ZNF384 and drives aberrant transcription of differentiation-related genes (SALL4, ID2)."},"narrative":{"mechanistic_narrative":"SYNRG (synergin gamma) is an AP-1 adaptor complex-interacting protein implicated in neuronal function as a coatopathy gene, with homozygous loss-of-function variants (p.Leu1202Pro and p.Gly533*) causing a complex form of hereditary spastic paraplegia [PMID:35090779]. In its disease-associated rearranged form, SYNRG is fused to the transcription factor ZNF384 in B-cell acute lymphoblastic leukemia; the resulting SYNRG-ZNF384 fusion protein associates more strongly with the transcriptional coactivator EP300 than wild-type ZNF384 and drives elevated transcription of the differentiation-related genes SALL4 and ID2, with EP300 coexpression specifically potentiating this aberrant activity [PMID:31234226]. Beyond its AP-1 association and its role within the ZNF384 fusion, the endogenous molecular function and physiological pathway of SYNRG have not been characterized in the available corpus.","teleology":[{"year":2019,"claim":"Establishing how the SYNRG-ZNF384 leukemic fusion drives transcription clarified that the fusion gains enhanced coactivator engagement rather than acting as a passive bystander.","evidence":"Reporter assays on SALL4/ID2 regulatory regions and GST pull-down of EP300 in a fusion-protein expression system","pmids":["31234226"],"confidence":"Medium","gaps":["Does not define the function of wild-type full-length SYNRG","EP300 interaction shown only in the fusion context, not for native SYNRG","No demonstration that elevated SALL4/ID2 transcription is necessary for leukemic transformation in vivo"]},{"year":2022,"claim":"Identifying biallelic loss-of-function variants linked SYNRG to a Mendelian neurological disease and positioned it as a coatopathy gene acting through the AP-1 adaptor complex family.","evidence":"Whole-exome sequencing and clinical phenotyping of patients carrying homozygous SYNRG variants","pmids":["35090779"],"confidence":"Low","gaps":["No functional validation of the specific variants in vitro or in vivo","Direct SYNRG-AP-1 interaction was not experimentally tested in this study","Cellular mechanism linking SYNRG loss to spastic paraplegia not established"]},{"year":null,"claim":"The endogenous molecular activity, subcellular localization, and physiological pathway of wild-type SYNRG remain undefined.","evidence":"No direct biochemical or cell-biological characterization of native SYNRG in the available corpus","pmids":[],"confidence":"Low","gaps":["No biochemical definition of SYNRG's role in AP-1-mediated membrane trafficking","No structural or domain-level mechanism for either disease context","No connection established between the leukemic fusion biology and the neuronal loss-of-function phenotype"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["EP300","ZNF384"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UMZ2","full_name":"Synergin gamma","aliases":["AP1 subunit gamma-binding protein 1","Gamma-synergin"],"length_aa":1314,"mass_kda":140.7,"function":"Plays a role in endocytosis and/or membrane trafficking at the trans-Golgi network (TGN) (PubMed:15758025). May act by linking the adapter protein complex AP-1 to other proteins (Probable). Component of clathrin-coated vesicles (PubMed:15758025). Component of the aftiphilin/p200/gamma-synergin complex, which plays roles in AP1G1/AP-1-mediated protein trafficking including the trafficking of transferrin from early to recycling endosomes, and the membrane trafficking of furin and the lysosomal enzyme cathepsin D between the trans-Golgi network (TGN) and endosomes (PubMed:15758025)","subcellular_location":"Cytoplasm; Golgi apparatus, trans-Golgi network membrane; Cytoplasm, perinuclear region; Cytoplasmic vesicle, clathrin-coated vesicle","url":"https://www.uniprot.org/uniprotkb/Q9UMZ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SYNRG","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/SYNRG","total_profiled":1310},"omim":[{"mim_id":"607291","title":"SYNERGIN, GAMMA; SYNRG","url":"https://www.omim.org/entry/607291"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SYNRG"},"hgnc":{"alias_symbol":["SYNG","MGC104959"],"prev_symbol":["AP1GBP1"]},"alphafold":{"accession":"Q9UMZ2","domains":[{"cath_id":"1.10.238.10","chopping":"292-380","consensus_level":"high","plddt":84.1031,"start":292,"end":380},{"cath_id":"1.20.58","chopping":"1116-1261_1274-1302","consensus_level":"medium","plddt":85.8068,"start":1116,"end":1302}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMZ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMZ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMZ2-F1-predicted_aligned_error_v6.png","plddt_mean":48.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SYNRG","jax_strain_url":"https://www.jax.org/strain/search?query=SYNRG"},"sequence":{"accession":"Q9UMZ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UMZ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UMZ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMZ2"}},"corpus_meta":[{"pmid":"8614630","id":"PMC_8614630","title":"Synthesis, structure and thermodynamic properties of 8-methylguanine-containing oligonucleotides: Z-DNA under physiological salt conditions.","date":"1996","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8614630","citation_count":73,"is_preprint":false},{"pmid":"22178801","id":"PMC_22178801","title":"Prenatally diagnosed 17q12 microdeletion syndrome with a novel association with congenital diaphragmatic hernia.","date":"2011","source":"Fetal diagnosis and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/22178801","citation_count":33,"is_preprint":false},{"pmid":"33182754","id":"PMC_33182754","title":"Identification and Validation of Potential miRNAs, as Biomarkers for Sepsis and Associated Lung Injury: A Network-Based Approach.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33182754","citation_count":28,"is_preprint":false},{"pmid":"29997840","id":"PMC_29997840","title":"C-Linked 8-aryl guanine nucleobase adducts: biological outcomes and utility as fluorescent probes.","date":"2016","source":"Chemical science","url":"https://pubmed.ncbi.nlm.nih.gov/29997840","citation_count":25,"is_preprint":false},{"pmid":"20102269","id":"PMC_20102269","title":"Recombinant gelatin microspheres: novel formulations for tissue repair?","date":"2010","source":"Tissue engineering. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/20102269","citation_count":22,"is_preprint":false},{"pmid":"37306722","id":"PMC_37306722","title":"ZNF384-Related Fusion Genes in Acute Lymphoblastic Leukemia.","date":"2023","source":"Cancer control : journal of the Moffitt Cancer Center","url":"https://pubmed.ncbi.nlm.nih.gov/37306722","citation_count":19,"is_preprint":false},{"pmid":"27040462","id":"PMC_27040462","title":"Optimization of fluorescent 8-heteroaryl-guanine probes for monitoring protein-mediated duplex → G-quadruplex exchange.","date":"2016","source":"Organic & biomolecular chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27040462","citation_count":19,"is_preprint":false},{"pmid":"40381702","id":"PMC_40381702","title":"Evaluation of 3,606 renal cell tumors for TFE3 rearrangements and TFEB alterations via fluorescence in situ hybridization, next generation sequencing, and GPNMB immunohistochemistry.","date":"2025","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40381702","citation_count":14,"is_preprint":false},{"pmid":"31234226","id":"PMC_31234226","title":"ZNF384-fusion proteins have high affinity for the transcriptional coactivator EP300 and aberrant transcriptional activities.","date":"2019","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/31234226","citation_count":14,"is_preprint":false},{"pmid":"26044393","id":"PMC_26044393","title":"Allogeneic Adipose-Derived Stem Cells Protect Fat Grafts at the Early Stage and Improve Long-Term Retention in Immunocompetent Rats.","date":"2015","source":"Aesthetic plastic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/26044393","citation_count":12,"is_preprint":false},{"pmid":"23026627","id":"PMC_23026627","title":"Protective effects of human amniotic fluid stem cells in a model of aorta allograft vasculopathy in rats.","date":"2012","source":"Transplantation proceedings","url":"https://pubmed.ncbi.nlm.nih.gov/23026627","citation_count":10,"is_preprint":false},{"pmid":"15147192","id":"PMC_15147192","title":"The human T-cell lymphotropic virus type-I dimerization initiation site forms a hairpin loop, unlike previously characterized retroviral dimerization motifs.","date":"2004","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15147192","citation_count":7,"is_preprint":false},{"pmid":"32801549","id":"PMC_32801549","title":"Impact of inulin and yeast containing synbiotic on calves' productivity and greenhouse gas production.","date":"2020","source":"Veterinary world","url":"https://pubmed.ncbi.nlm.nih.gov/32801549","citation_count":4,"is_preprint":false},{"pmid":"38216274","id":"PMC_38216274","title":"Prenatal diagnosis and perinatal findings of 17q12 microdeletion encompassing HNF1B in a fetus with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth, and a review of the literature of prenatal diagnosis of 17q12 microdeletion.","date":"2024","source":"Taiwanese journal of obstetrics & gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/38216274","citation_count":4,"is_preprint":false},{"pmid":"33950246","id":"PMC_33950246","title":"Use of paclitaxel carried in lipid nanoparticles to treat aortic allograft transplantation in rats.","date":"2021","source":"The Journal of pharmacy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33950246","citation_count":3,"is_preprint":false},{"pmid":"35623396","id":"PMC_35623396","title":"Ultra-efficient multiple cross displacement amplification-lateral flow biosensor (MCDA-LFB) for serogroup identification of prevalent Neisseria meningitidis.","date":"2022","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35623396","citation_count":2,"is_preprint":false},{"pmid":"34594486","id":"PMC_34594486","title":"Ghrelin Immunoreactive Cell Amounts in the Abomasum in 4-Month-Old Calves by Feeding Different Amounts of Prebiotics and New Synbiotics.","date":"2021","source":"Veterinary medicine international","url":"https://pubmed.ncbi.nlm.nih.gov/34594486","citation_count":2,"is_preprint":false},{"pmid":"18843994","id":"PMC_18843994","title":"[Establishment and application of TaqMan Real-Time PCR in detection and serogrouping of Neisseria meningitidis].","date":"2008","source":"Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/18843994","citation_count":2,"is_preprint":false},{"pmid":"40552851","id":"PMC_40552851","title":"Identification of a Risk Allele at SLC41A3 and a Protective Allele HLA-DPB1*02:01 Associated with Sarcopenia in Japanese.","date":"2025","source":"Gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/40552851","citation_count":1,"is_preprint":false},{"pmid":"35090779","id":"PMC_35090779","title":"Interacting with AP1 complex mutated synergin gamma (SYNRG) reveals a novel coatopathy in the form of complicated hereditary spastic paraplegia.","date":"2022","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/35090779","citation_count":0,"is_preprint":false},{"pmid":"39520726","id":"PMC_39520726","title":"FISH combined with RT-PCR facilitates classification of Chinese adult patients with B-other ALL through improved identification of ZNF384 rearrangement.","date":"2024","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/39520726","citation_count":0,"is_preprint":false},{"pmid":"41117492","id":"PMC_41117492","title":"A Case of Mistaken Identity: When All Mimics AML.","date":"2025","source":"Cytopathology : official journal of the British Society for Clinical Cytology","url":"https://pubmed.ncbi.nlm.nih.gov/41117492","citation_count":0,"is_preprint":false},{"pmid":"2163491","id":"PMC_2163491","title":"[Differential scattering of circularly polarized light in protonated DNA in the presence of spermine].","date":"1990","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/2163491","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14533,"output_tokens":963,"usd":0.029022,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6963,"output_tokens":1341,"usd":0.03417,"stage2_stop_reason":"end_turn"},"total_usd":0.063192,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical SYNRG protein (synergin gamma, also known as AP1GBP1/SYNG). Let me classify each paper:\n\n- Papers [1], [4], [7], [12], [23]: About syn-G (syn conformation guanine) in DNA/RNA — symbol collision, not the gene\n- Papers [5], [10], [11], [13], [15], [17]: Use \"SynG\" as abbreviation for \"syngeneic\" group — not the gene\n- Papers [16], [18]: synG = Neisseria meningitidis serogroup W135 gene — cross-kingdom collision\n- Papers [2], [14]: 17q12 microdeletion listing SYNRG among deleted genes — no mechanistic data\n- Papers [3], [19]: Computational/GWAS listing SYNRG — no mechanistic data\n- Paper [6]: ZNF384 fusion partners catalog including SYNRG — no mechanistic data on SYNRG itself\n- Paper [9]: Experimentally tests SYNRG-ZNF384 fusion protein — **INCLUDE**\n- Paper [20]: SYNRG variants in hereditary spastic paraplegia, interaction with AP-1 complex — **INCLUDE**\n- Papers [21], [22]: Clinical reports of SYNRG::ZNF384 fusion — no mechanistic data on SYNRG itself\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"The SYNRG-ZNF384 fusion protein exhibits stronger transcriptional activity than wild-type ZNF384 on SALL4 and ID2 promoter/enhancer regions, and associates more strongly with the transcriptional coactivator EP300 than wild-type ZNF384 does, as demonstrated by GST pull-down assay. Coexpression of EP300 specifically enhanced the transcriptional activities of SYNRG-ZNF384 fusion protein.\",\n      \"method\": \"Reporter assay (transcriptional activity on SALL4/ID2 promoter/enhancer), GST pull-down assay for EP300 interaction, gene expression analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down plus functional reporter assay in a single lab, two orthogonal methods, but only for the fusion protein context\",\n      \"pmids\": [\"31234226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Homozygous loss-of-function variants in SYNRG (p.Leu1202Pro and p.Gly533*) cause a complex hereditary spastic paraplegia phenotype, implicating SYNRG's interaction with the AP-1 (adaptor-related protein complex) family in neuronal function. This positions SYNRG as a coatopathy gene.\",\n      \"method\": \"Whole-exome sequencing of affected patients; homozygous variant identification in SYNRG; clinical phenotyping\",\n      \"journal\": \"Brain & development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic variant identification in patients with no in vitro/in vivo functional validation of the specific variants or direct AP-1 interaction experiment in this study\",\n      \"pmids\": [\"35090779\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SYNRG (synergin gamma) is an AP-1 adaptor complex-interacting protein whose loss-of-function causes hereditary spastic paraplegia; when fused to ZNF384 in B-cell ALL, the resulting fusion protein binds EP300 with higher affinity than wild-type ZNF384 and drives aberrant transcription of differentiation-related genes (SALL4, ID2).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SYNRG (synergin gamma) is an AP-1 adaptor complex-interacting protein implicated in neuronal function as a coatopathy gene, with homozygous loss-of-function variants (p.Leu1202Pro and p.Gly533*) causing a complex form of hereditary spastic paraplegia [#1]. In its disease-associated rearranged form, SYNRG is fused to the transcription factor ZNF384 in B-cell acute lymphoblastic leukemia; the resulting SYNRG-ZNF384 fusion protein associates more strongly with the transcriptional coactivator EP300 than wild-type ZNF384 and drives elevated transcription of the differentiation-related genes SALL4 and ID2, with EP300 coexpression specifically potentiating this aberrant activity [#0]. Beyond its AP-1 association and its role within the ZNF384 fusion, the endogenous molecular function and physiological pathway of SYNRG have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing how the SYNRG-ZNF384 leukemic fusion drives transcription clarified that the fusion gains enhanced coactivator engagement rather than acting as a passive bystander.\",\n      \"evidence\": \"Reporter assays on SALL4/ID2 regulatory regions and GST pull-down of EP300 in a fusion-protein expression system\",\n      \"pmids\": [\"31234226\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down plus functional reporter assay in a single lab, two orthogonal methods, but only for the fusion protein context\",\n      \"gaps\": [\n        \"Does not define the function of wild-type full-length SYNRG\",\n        \"EP300 interaction shown only in the fusion context, not for native SYNRG\",\n        \"No demonstration that elevated SALL4/ID2 transcription is necessary for leukemic transformation in vivo\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying biallelic loss-of-function variants linked SYNRG to a Mendelian neurological disease and positioned it as a coatopathy gene acting through the AP-1 adaptor complex family.\",\n      \"evidence\": \"Whole-exome sequencing and clinical phenotyping of patients carrying homozygous SYNRG variants\",\n      \"pmids\": [\"35090779\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic variant identification in patients with no in vitro/in vivo functional validation of the specific variants or direct AP-1 interaction experiment in this study\",\n      \"gaps\": [\n        \"No functional validation of the specific variants in vitro or in vivo\",\n        \"Direct SYNRG-AP-1 interaction was not experimentally tested in this study\",\n        \"Cellular mechanism linking SYNRG loss to spastic paraplegia not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous molecular activity, subcellular localization, and physiological pathway of wild-type SYNRG remain undefined.\",\n      \"evidence\": \"No direct biochemical or cell-biological characterization of native SYNRG in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical definition of SYNRG's role in AP-1-mediated membrane trafficking\",\n        \"No structural or domain-level mechanism for either disease context\",\n        \"No connection established between the leukemic fusion biology and the neuronal loss-of-function phenotype\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"EP300\", \"ZNF384\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":2,"faith_total":2,"faith_pct":100.0}}