{"gene":"TRAPPC2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2002,"finding":"Crystal structure of SEDL (TRAPPC2) at 2.4 Å resolution reveals unexpected structural similarity to the N-terminal regulatory domains of SNAREs Ykt6p and Sec22b, despite no sequence homology, suggesting regulatory/adaptor functions through multiple protein-protein interactions. Three disease-causing missense mutations (S73L, F83S, V130D) map to the protein interior where they would disrupt structure, while D47Y maps to a surface where it may abrogate functional interactions with a partner protein.","method":"X-ray crystallography (2.4 Å resolution) combined with mapping of known disease-causing mutations onto the structure","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structure with functional interpretation of disease mutations; single lab but rigorous structural method","pmids":["12361953"],"is_preprint":false},{"year":2000,"finding":"SEDL (TRAPPC2) protein localizes to perinuclear structures that partly overlap with the intermediate ER-Golgi compartment (ERGIC/VTC). Disease-causing mutations (157-158delAT and C271T stop) cause misplacement of the protein primarily to the cell nucleus and partially to the cytoplasm, suggesting the C-terminal region is required for proper ER-Golgi targeting.","method":"Transient transfection of tagged (FLAG and GFP) recombinant SEDL constructs in COS-7 cells with subcellular localization analysis by fluorescence microscopy","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization experiment with functional consequence (mislocalization by disease mutations), single lab, two construct types used","pmids":["11031107"],"is_preprint":false},{"year":2003,"finding":"Human SEDL (TRAPPC2) protein functionally complements the essential yeast TRS20 (Trs20p) knockout, establishing functional conservation. Truncation mutations (157delAT, C271T) and one missense mutation (G139T/V47G) failed to rescue the trs20Δ lethal phenotype, while two missense mutations (C218T/S73L and T389A/V130D) did complement, indicating these residues are dispensable for core TRAPP function in yeast.","method":"Yeast complementation assay — human SEDL expressed in S. cerevisiae trs20Δ strain; viability tested for multiple disease-causing mutations","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation in yeast with multiple alleles tested; single lab","pmids":["14597397"],"is_preprint":false},{"year":2011,"finding":"TRAPPC2 acts as an adaptor for the formation of mammalian TRAPPII and TRAPPIII complexes. TRAPPC2 directly binds TRAPPII-specific subunit TRAPPC9 (which in turn binds TRAPPC10) and also binds putative TRAPPIII-specific subunit TRAPPC8. Endogenous TRAPPC9-positive TRAPPII does not contain TRAPPC8, indicating TRAPPC2 binds either TRAPPC9 or TRAPPC8 mutually exclusively during complex assembly. The disease-causing D47Y mutation in TRAPPC2 abolishes interaction with both TRAPPC9 and TRAPPC8, identifying Asp47 as critical for TRAPPII/III assembly.","method":"Co-immunoprecipitation of endogenous and overexpressed TRAPP subunits in mammalian cells; interaction mapping with disease-causing mutants","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with endogenous proteins, multiple subunit combinations tested, disease mutation used to define interaction surface, replicated across TRAPPII and TRAPPIII context","pmids":["21858081"],"is_preprint":false},{"year":2013,"finding":"In yeast, Trs20 (TRAPPC2 ortholog) is required for TRAPPII assembly: Trs20 interacts with TRAPPII-specific subunit Trs120, and this interaction is required for TRAPPII assembly and its Ypt32-GEF (guanine nucleotide exchange) activity. The SEDT-equivalent mutation Trs20-D46Y retains interaction with TRAPPI but cannot interact with Trs120, preventing TRAPPII assembly.","method":"Co-immunoprecipitation in yeast, in vitro GEF activity assay for Ypt32, analysis of D46Y mutant","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro GEF assay combined with Co-IP and defined disease-equivalent mutation; mechanistic link between Trs20/TRAPPC2 adaptor role and complex GEF activity established","pmids":["23465091"],"is_preprint":false},{"year":2013,"finding":"The SEDT-causing D47Y mutation in TRAPPC2 (C2) weakens its binding to the SNARE protein Syntaxin 5. The equivalent yeast mutation (Trs20-D46Y) does not block anterograde traffic but disrupts interaction with TRAPPIII-specific subunit Trs85p and TRAPPII-specific subunits Trs120p and Trs130p, destabilizing TRAPPIII and blocking both selective (cvt) and non-selective autophagy.","method":"Co-immunoprecipitation (mammalian TRAPPC2–Syntaxin 5 interaction with D47Y mutant); yeast size exclusion chromatography; yeast autophagy assays with trs20D46Y mutant","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, gel filtration, autophagy assays), two organisms, disease mutation used functionally","pmids":["23898804"],"is_preprint":false},{"year":2014,"finding":"In yeast, Trs20 (TRAPPC2 ortholog) is required for TRAPPIII assembly at the pre-autophagosomal structure (PAS). Recombinant Trs85 (TRAPPIII-specific subunit) associates with TRAPP only in the presence of Trs20 but not the D46Y mutant. Live-cell colocalization shows Trs85 recruits core TRAPP to the PAS via Trs20. Loss of Trs20 function blocks both selective and non-selective autophagy.","method":"In vitro reconstitution with recombinant proteins; co-precipitation from cell lysates; live-cell fluorescence colocalization; autophagy assays in trs20ts mutant yeast","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution plus live-cell imaging plus genetic phenotype, multiple orthogonal methods, disease-equivalent mutation used","pmids":["24329977"],"is_preprint":false},{"year":2023,"finding":"TRAPPC2 knockdown in SW1353 chondrosarcoma cells and primary human chondrocytes decreases COL2A1 (type II collagen) expression and collagen II secretion. A nonsense variant (c.91A>T) reduces TRAPPC2 mRNA and protein levels and alters the membrane distribution of the mutant protein.","method":"siRNA knockdown of TRAPPC2 in chondrocyte cell lines and primary cells with Western blot and ELISA for COL2A1/collagen II; cell fluorescence and Western blot for mutant protein subcellular distribution","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with specific cellular phenotype (collagen secretion), multiple cell types, single lab","pmids":["37693308"],"is_preprint":false},{"year":2001,"finding":"Articular cartilage from an SEDT patient carrying an exon-skipping SEDL mutation showed chondrocytes with abundant Golgi complexes and dilated rough ER, consistent with disruption of ER-to-Golgi vesicular transport.","method":"Histological/ultrastructural analysis of articular cartilage from a SEDT patient with confirmed SEDL splice mutation","journal":"American journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient pathological observation, no direct biochemical assay of transport function","pmids":["11326333"],"is_preprint":false},{"year":1999,"finding":"SEDL (TRAPPC2) was identified as the gene mutated in X-linked spondyloepiphyseal dysplasia tarda; three dinucleotide deletions causing frameshifts and premature stop codons were found in three families, establishing loss of SEDL function as causative for SEDT. The encoded 140 amino acid protein was inferred to have a role in ER-to-Golgi vesicular transport.","method":"Positional cloning, mutation analysis (sequencing of candidate gene in affected families), expression analysis in fetal cartilage","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — gene identification by positional cloning with mutations in multiple independent families; replicated across labs subsequently","pmids":["10431248"],"is_preprint":false},{"year":2024,"finding":"TRAPPC2 (human ortholog) successfully replaces its yeast counterpart Trs20 in a humanized yeast model, confirming functional conservation of TRAPPC2 across species. This system supports mechanistic study of TRAPPC2 variants.","method":"CRISPR/Cas9-mediated humanization of yeast — replacement of yeast TRS20 with human TRAPPC2 coding sequence; viability assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic complementation in humanized yeast, single study, preprint","pmids":["bio_10.1101_2024.08.04.605925"],"is_preprint":true}],"current_model":"TRAPPC2 (Sedlin/SEDL) is a conserved 140-amino acid subunit of the TRAPP complex that acts as a structural adaptor: it bridges the TRAPP core to TRAPPII-specific subunit TRAPPC9 (and Trs120p in yeast) or TRAPPIII-specific subunit TRAPPC8/Trs85p, enabling assembly and GEF activity of these higher-order complexes toward Rab GTPases Ypt32/Ypt31 and autophagy; it also interacts with the SNARE Syntaxin 5; its disease-causing mutation D47Y (equivalent to yeast D46Y) selectively disrupts these adaptor interactions without affecting TRAPPI, thereby blocking TRAPPII/III-dependent secretion (including procollagen/COL2A1 in chondrocytes) and autophagy, underlying the skeletal dysplasia SEDT."},"narrative":{"mechanistic_narrative":"TRAPPC2 (SEDL/Sedlin) is a small conserved subunit of the TRAPP complex that functions as a structural adaptor governing assembly of higher-order TRAPP complexes that direct membrane traffic and autophagy [PMID:21858081, PMID:23465091]. In mammalian cells it directly binds the TRAPPII-specific subunit TRAPPC9 and, mutually exclusively, the TRAPPIII-specific subunit TRAPPC8, thereby templating formation of either complex [PMID:21858081]; its yeast ortholog Trs20 is correspondingly required for TRAPPII assembly through interaction with Trs120 and for the resulting Ypt32-directed guanine-nucleotide exchange activity [PMID:23465091], and for recruitment of core TRAPP to the pre-autophagosomal structure via the TRAPPIII subunit Trs85 [PMID:24329977]. Consistent with an adaptor role, its crystal structure resembles the regulatory domains of SNAREs despite lacking sequence homology [PMID:12361953], and it interacts with the SNARE Syntaxin 5 [PMID:23898804]. The protein localizes to perinuclear membranes overlapping the ER-Golgi intermediate compartment [PMID:11031107], and loss of TRAPPC2 function reduces type II collagen (COL2A1) expression and secretion in chondrocytes [PMID:37693308] and blocks both selective and non-selective autophagy in yeast [PMID:23898804, PMID:24329977]. Loss-of-function mutations in TRAPPC2 cause X-linked spondyloepiphyseal dysplasia tarda (SEDT) [PMID:10431248]; the surface mutation D47Y (yeast D46Y) selectively abolishes the adaptor interactions with TRAPPC9/TRAPPC8 (Trs120/Trs85) and weakens Syntaxin 5 binding while sparing core TRAPP, defining a disease mechanism centered on disrupted TRAPPII/III assembly [PMID:21858081, PMID:23465091, PMID:23898804].","teleology":[{"year":1999,"claim":"Establishing the genetic basis of an X-linked skeletal dysplasia first implicated this gene in vesicular transport, before any molecular function was known.","evidence":"positional cloning and mutation analysis in SEDT families with cartilage expression analysis","pmids":["10431248"],"confidence":"Medium","gaps":["Inferred ER-to-Golgi transport role was not biochemically tested","No protein partners identified","No structural information"]},{"year":2000,"claim":"Subcellular localization placed the protein at the ER-Golgi interface and showed disease mutations mislocalize it, linking trafficking compartment to function.","evidence":"transient transfection of tagged constructs in COS-7 cells with fluorescence microscopy","pmids":["11031107"],"confidence":"Medium","gaps":["Partial ERGIC overlap only; precise residence not resolved","Overexpression of tagged constructs may not reflect endogenous distribution","Mechanism of C-terminal targeting unknown"]},{"year":2001,"claim":"Patient cartilage ultrastructure provided in vivo evidence that loss of function perturbs the secretory pathway in the disease-relevant cell type.","evidence":"histological/ultrastructural analysis of SEDT patient articular cartilage","pmids":["11326333"],"confidence":"Low","gaps":["Single patient pathological observation without biochemical assay","Cannot distinguish direct from secondary effects on ER/Golgi morphology"]},{"year":2002,"claim":"The crystal structure revealed an unexpected SNARE-like fold and rationalized disease mutations as either structure-disrupting or surface interaction-disrupting, predicting an adaptor/protein-interaction function.","evidence":"X-ray crystallography at 2.4 A with disease-mutation mapping","pmids":["12361953"],"confidence":"High","gaps":["Predicted partner protein for the D47Y surface not identified in this work","Functional consequence of the SNARE-like fold untested"]},{"year":2003,"claim":"Cross-species complementation established functional conservation with yeast Trs20 and parsed which disease residues affect core TRAPP function versus other activities.","evidence":"yeast trs20 knockout complementation with multiple human disease alleles","pmids":["14597397"],"confidence":"Medium","gaps":["Does not define the molecular interactions affected by non-complementing alleles","Yeast viability readout does not resolve which trafficking step is impaired"]},{"year":2011,"claim":"Defining direct binding to TRAPPC9 and TRAPPC8 identified TRAPPC2 as the mutually exclusive adaptor for mammalian TRAPPII versus TRAPPIII assembly and pinpointed Asp47 as the critical interaction residue.","evidence":"reciprocal Co-IP of endogenous and overexpressed TRAPP subunits with disease-mutant mapping in mammalian cells","pmids":["21858081"],"confidence":"High","gaps":["Structural basis of mutual exclusivity not resolved","Functional consequence for mammalian Rab-GEF activity not measured here"]},{"year":2013,"claim":"Yeast work connected the adaptor role to enzymatic output, showing Trs20-Trs120 interaction is required for TRAPPII assembly and its Ypt32-GEF activity, which the D46Y mutation selectively abolishes while sparing TRAPPI.","evidence":"Co-IP and in vitro Ypt32-GEF assay with D46Y mutant in yeast","pmids":["23465091"],"confidence":"High","gaps":["Mammalian GEF activity not directly tested","Whether D47Y similarly affects mammalian Rab substrates not shown here"]},{"year":2013,"claim":"TRAPPC2 was linked to autophagy and to SNARE binding, with D47Y weakening Syntaxin 5 interaction and the yeast equivalent destabilizing TRAPPIII to block selective and non-selective autophagy.","evidence":"mammalian Co-IP of TRAPPC2-Syntaxin 5, yeast size-exclusion chromatography and autophagy assays with D46Y","pmids":["23898804"],"confidence":"High","gaps":["Functional role of mammalian Syntaxin 5 binding in autophagy not established","Anterograde traffic was unaffected by D46Y in yeast, leaving the secretion defect mechanism in disease cells unresolved"]},{"year":2014,"claim":"Reconstitution and live-cell imaging showed Trs20 mediates recruitment of core TRAPP to the pre-autophagosomal structure via Trs85, providing a spatial mechanism for its autophagy function.","evidence":"in vitro reconstitution with recombinant proteins, co-precipitation, live-cell colocalization, and autophagy assays in trs20ts yeast","pmids":["24329977"],"confidence":"High","gaps":["PAS recruitment demonstrated in yeast; mammalian autophagosome recruitment not directly shown","Rab substrate engaged at the PAS not defined here"]},{"year":2023,"claim":"Loss-of-function in chondrocytes tied TRAPPC2 directly to the disease-relevant cargo, reducing COL2A1 expression and collagen II secretion.","evidence":"siRNA knockdown in SW1353 cells and primary human chondrocytes with Western blot/ELISA, plus characterization of a nonsense variant","pmids":["37693308"],"confidence":"Medium","gaps":["Whether reduced secretion reflects TRAPPII or TRAPPIII dysfunction not dissected","Single lab; mechanism linking TRAPP adaptor role to collagen trafficking not resolved"]},{"year":2024,"claim":"A humanized yeast model confirmed cross-species functional replacement, providing a tractable platform for variant analysis.","evidence":"CRISPR/Cas9 humanization replacing yeast TRS20 with human TRAPPC2 and viability assay (preprint)","pmids":["bio_10.1101_2024.08.04.605925"],"confidence":"Medium","gaps":["Preprint, single study","Does not itself define disease variant mechanisms"]},{"year":null,"claim":"How disrupted TRAPPII/III assembly in human chondrocytes mechanistically produces the specific procollagen secretion defect and skeletal phenotype remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct demonstration that mammalian D47Y impairs Rab-GEF activity in chondrocytes","Mammalian Rab substrate(s) downstream of TRAPPC2 not identified in the corpus","Connection between Syntaxin 5 binding and procollagen export untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,4,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5,6]}],"complexes":["TRAPP","TRAPPII","TRAPPIII"],"partners":["TRAPPC9","TRAPPC8","STX5","TRS120","TRS85","TRAPPC10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P0DI81","full_name":"Trafficking protein particle complex subunit 2","aliases":["Sedlin"],"length_aa":140,"mass_kda":16.4,"function":"Prevents transcriptional repression and induction of cell death by ENO1 (By similarity). May play a role in vesicular transport from endoplasmic reticulum to Golgi","subcellular_location":"Cytoplasm, perinuclear region; Endoplasmic reticulum-Golgi intermediate compartment; Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P0DI81/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRAPPC2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":70,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000196459","cell_line_id":"CID000473","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"golgi","grade":2},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"TRAPPC5","stoichiometry":10.0},{"gene":"TRAPPC11","stoichiometry":10.0},{"gene":"TRAPPC6B","stoichiometry":10.0},{"gene":"TRAPPC4","stoichiometry":10.0},{"gene":"TRAPPC8","stoichiometry":10.0},{"gene":"TRAPPC12;CGI-87","stoichiometry":10.0},{"gene":"TRAPPC1","stoichiometry":10.0},{"gene":"TRAPPC2L","stoichiometry":10.0},{"gene":"TRAPPC3","stoichiometry":10.0},{"gene":"TRAPPC13","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000473","total_profiled":1310},"omim":[{"mim_id":"614139","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 12; TRAPPC12","url":"https://www.omim.org/entry/614139"},{"mim_id":"614138","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 11; TRAPPC11","url":"https://www.omim.org/entry/614138"},{"mim_id":"614137","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 3-LIKE; TRAPPC3L","url":"https://www.omim.org/entry/614137"},{"mim_id":"614136","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 8; TRAPPC8","url":"https://www.omim.org/entry/614136"},{"mim_id":"610970","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 2L; TRAPPC2L","url":"https://www.omim.org/entry/610970"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRAPPC2"},"hgnc":{"alias_symbol":["TRS20","SEDT","MIP-2A","ZNF547L","hYP38334"],"prev_symbol":["SEDL"]},"alphafold":{"accession":"P0DI81","domains":[{"cath_id":"3.30.450.70","chopping":"4-137","consensus_level":"high","plddt":93.062,"start":4,"end":137}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DI81","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0DI81-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0DI81-F1-predicted_aligned_error_v6.png","plddt_mean":92.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRAPPC2","jax_strain_url":"https://www.jax.org/strain/search?query=TRAPPC2"},"sequence":{"accession":"P0DI81","fasta_url":"https://rest.uniprot.org/uniprotkb/P0DI81.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0DI81/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DI81"}},"corpus_meta":[{"pmid":"10431248","id":"PMC_10431248","title":"Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10431248","citation_count":149,"is_preprint":false},{"pmid":"12361953","id":"PMC_12361953","title":"Crystal structure of SEDL and its implications for a genetic disease spondyloepiphyseal dysplasia tarda.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12361953","citation_count":68,"is_preprint":false},{"pmid":"21858081","id":"PMC_21858081","title":"The adaptor function of TRAPPC2 in mammalian TRAPPs explains TRAPPC2-associated SEDT and TRAPPC9-associated congenital intellectual disability.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21858081","citation_count":54,"is_preprint":false},{"pmid":"11031107","id":"PMC_11031107","title":"Gene structure and expression study of the SEDL gene for spondyloepiphyseal dysplasia 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genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/14755465","citation_count":8,"is_preprint":false},{"pmid":"17363178","id":"PMC_17363178","title":"Mutant WISP3 triggers the phenotype shift of articular chondrocytes by promoting sensitivity to IGF-1 hypothesis of spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA).","date":"2007","source":"Medical hypotheses","url":"https://pubmed.ncbi.nlm.nih.gov/17363178","citation_count":8,"is_preprint":false},{"pmid":"12650905","id":"PMC_12650905","title":"A single nucleotide deletion of 293delT in SEDL gene causing spondyloepiphyseal dysplasia tarda in a four-generation Chinese family.","date":"2003","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/12650905","citation_count":7,"is_preprint":false},{"pmid":"32471379","id":"PMC_32471379","title":"A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family.","date":"2020","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32471379","citation_count":7,"is_preprint":false},{"pmid":"31053099","id":"PMC_31053099","title":"Novel loss-of-function variants of TRAPPC2 manifesting X-linked spondyloepiphyseal dysplasia tarda: report of two cases.","date":"2019","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31053099","citation_count":6,"is_preprint":false},{"pmid":"18393234","id":"PMC_18393234","title":"[A novel mutation in the SEDL gene leading to X-linked spondyloepiphyseal dysplasia tarda in a large Chinese pedigree].","date":"2008","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18393234","citation_count":6,"is_preprint":false},{"pmid":"11760838","id":"PMC_11760838","title":"Preonset studies of spondyloepiphyseal dysplasia tarda caused by a novel 2-base pair deletion in SEDL encoding sedlin.","date":"2001","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/11760838","citation_count":6,"is_preprint":false},{"pmid":"24841781","id":"PMC_24841781","title":"A novel nonsense mutation in the sedlin gene (SEDL) causes severe spondyloepiphyseal dysplasia tarda in a five-generation Chinese pedigree.","date":"2014","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/24841781","citation_count":5,"is_preprint":false},{"pmid":"25521980","id":"PMC_25521980","title":"Novel TRAPPC2 mutation in a boy with X-linked spondylo-epiphyseal dysplasia tarda.","date":"2014","source":"Pediatrics international : official journal of the Japan Pediatric Society","url":"https://pubmed.ncbi.nlm.nih.gov/25521980","citation_count":4,"is_preprint":false},{"pmid":"23876379","id":"PMC_23876379","title":"A novel splicing mutation in the SEDL gene causes spondyloepiphyseal dysplasia tarda in a large Chinese pedigree.","date":"2013","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23876379","citation_count":4,"is_preprint":false},{"pmid":"12579492","id":"PMC_12579492","title":"[Identification of a novel mutation IVS2-2A-->C of SEDL gene in a Chinese family with X-linked spondyloepiphyseal dysplasia tarda].","date":"2003","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12579492","citation_count":4,"is_preprint":false},{"pmid":"26252088","id":"PMC_26252088","title":"[Mutation analysis of the TRAPPC2 gene in a Chinese family with X-linked spondyloepiphyseal dysplasia tarda].","date":"2015","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26252088","citation_count":2,"is_preprint":false},{"pmid":"15952107","id":"PMC_15952107","title":"Mutation of acceptor splice site of the SEDL gene in X-linked spondyloepiphyseal dysplasia tarda causes the activation of cryptic splice site.","date":"2005","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15952107","citation_count":2,"is_preprint":false},{"pmid":"15300622","id":"PMC_15300622","title":"[Identification of a novel mutation of the SEDL gene in X-linked spondyloepiphyseal dysplasia tarda].","date":"2004","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15300622","citation_count":2,"is_preprint":false},{"pmid":"18247296","id":"PMC_18247296","title":"[Identification of a missense mutation in SEDL gene from a Chinese family with X-linked spondyloepiphyseal dysplasia tarda].","date":"2008","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18247296","citation_count":2,"is_preprint":false},{"pmid":"33726005","id":"PMC_33726005","title":"A novel missense variant in TRAPPC2 causes X-linked spondyloepiphyseal dysplasia tarda: A case report.","date":"2021","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33726005","citation_count":2,"is_preprint":false},{"pmid":"16120574","id":"PMC_16120574","title":"[Effect of a novel splicing mutation (IVS2-2A-->C) of SEDL gene on RNA processing].","date":"2005","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/16120574","citation_count":1,"is_preprint":false},{"pmid":"30647738","id":"PMC_30647738","title":"Clinical Diagnosis of X-Linked Spondyloepiphyseal Dysplasia Tarda and a Novel Missense Mutation in the Sedlin Gene (SEDL).","date":"2018","source":"International journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30647738","citation_count":1,"is_preprint":false},{"pmid":"18245897","id":"PMC_18245897","title":"[Construction of WISP3 gene's mutants in SEDT-PA and their expression in COS-7 cells].","date":"2008","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18245897","citation_count":1,"is_preprint":false},{"pmid":"37693308","id":"PMC_37693308","title":"Functional analysis of a novel nonsense variant c.91A>T of the TRAPPC2 gene in a Chinese family with X-linked recessive autosomal spondyloepiphyseal dysplasia tarda.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37693308","citation_count":1,"is_preprint":false},{"pmid":"11856857","id":"PMC_11856857","title":"Crystallization and preliminary X-ray crystallographic analysis of SEDL.","date":"2002","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/11856857","citation_count":1,"is_preprint":false},{"pmid":"25297591","id":"PMC_25297591","title":"[Analysis of SEDL gene mutation in a Chinese pedigree with X-linked spondyloepiphyseal dysplasia tarda].","date":"2014","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25297591","citation_count":1,"is_preprint":false},{"pmid":"41059451","id":"PMC_41059451","title":"A Novel Premature Termination Codon Mutation in TRAPPC2 Is Associated with X-Linked Spondyloepiphyseal Dysplasia Tarda.","date":"2024","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/41059451","citation_count":0,"is_preprint":false},{"pmid":"41732158","id":"PMC_41732158","title":"Identification and functional analysis of a novel TRAPPC2 intronic variant in a four-generation Chinese pedigree with SEDT.","date":"2026","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41732158","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.04.605925","title":"A humanized yeast model for studying TRAPP complex mutations; proof-of-concept using variants from an individual with a  <i>TRAPPC1</i>  -associated neurodevelopmental syndrome","date":"2024-08-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.04.605925","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21919,"output_tokens":3075,"usd":0.055941,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10575,"output_tokens":3681,"usd":0.07245,"stage2_stop_reason":"end_turn"},"total_usd":0.128391,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of SEDL (TRAPPC2) at 2.4 Å resolution reveals unexpected structural similarity to the N-terminal regulatory domains of SNAREs Ykt6p and Sec22b, despite no sequence homology, suggesting regulatory/adaptor functions through multiple protein-protein interactions. Three disease-causing missense mutations (S73L, F83S, V130D) map to the protein interior where they would disrupt structure, while D47Y maps to a surface where it may abrogate functional interactions with a partner protein.\",\n      \"method\": \"X-ray crystallography (2.4 Å resolution) combined with mapping of known disease-causing mutations onto the structure\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structure with functional interpretation of disease mutations; single lab but rigorous structural method\",\n      \"pmids\": [\"12361953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SEDL (TRAPPC2) protein localizes to perinuclear structures that partly overlap with the intermediate ER-Golgi compartment (ERGIC/VTC). Disease-causing mutations (157-158delAT and C271T stop) cause misplacement of the protein primarily to the cell nucleus and partially to the cytoplasm, suggesting the C-terminal region is required for proper ER-Golgi targeting.\",\n      \"method\": \"Transient transfection of tagged (FLAG and GFP) recombinant SEDL constructs in COS-7 cells with subcellular localization analysis by fluorescence microscopy\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization experiment with functional consequence (mislocalization by disease mutations), single lab, two construct types used\",\n      \"pmids\": [\"11031107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human SEDL (TRAPPC2) protein functionally complements the essential yeast TRS20 (Trs20p) knockout, establishing functional conservation. Truncation mutations (157delAT, C271T) and one missense mutation (G139T/V47G) failed to rescue the trs20Δ lethal phenotype, while two missense mutations (C218T/S73L and T389A/V130D) did complement, indicating these residues are dispensable for core TRAPP function in yeast.\",\n      \"method\": \"Yeast complementation assay — human SEDL expressed in S. cerevisiae trs20Δ strain; viability tested for multiple disease-causing mutations\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation in yeast with multiple alleles tested; single lab\",\n      \"pmids\": [\"14597397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRAPPC2 acts as an adaptor for the formation of mammalian TRAPPII and TRAPPIII complexes. TRAPPC2 directly binds TRAPPII-specific subunit TRAPPC9 (which in turn binds TRAPPC10) and also binds putative TRAPPIII-specific subunit TRAPPC8. Endogenous TRAPPC9-positive TRAPPII does not contain TRAPPC8, indicating TRAPPC2 binds either TRAPPC9 or TRAPPC8 mutually exclusively during complex assembly. The disease-causing D47Y mutation in TRAPPC2 abolishes interaction with both TRAPPC9 and TRAPPC8, identifying Asp47 as critical for TRAPPII/III assembly.\",\n      \"method\": \"Co-immunoprecipitation of endogenous and overexpressed TRAPP subunits in mammalian cells; interaction mapping with disease-causing mutants\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with endogenous proteins, multiple subunit combinations tested, disease mutation used to define interaction surface, replicated across TRAPPII and TRAPPIII context\",\n      \"pmids\": [\"21858081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast, Trs20 (TRAPPC2 ortholog) is required for TRAPPII assembly: Trs20 interacts with TRAPPII-specific subunit Trs120, and this interaction is required for TRAPPII assembly and its Ypt32-GEF (guanine nucleotide exchange) activity. The SEDT-equivalent mutation Trs20-D46Y retains interaction with TRAPPI but cannot interact with Trs120, preventing TRAPPII assembly.\",\n      \"method\": \"Co-immunoprecipitation in yeast, in vitro GEF activity assay for Ypt32, analysis of D46Y mutant\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro GEF assay combined with Co-IP and defined disease-equivalent mutation; mechanistic link between Trs20/TRAPPC2 adaptor role and complex GEF activity established\",\n      \"pmids\": [\"23465091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The SEDT-causing D47Y mutation in TRAPPC2 (C2) weakens its binding to the SNARE protein Syntaxin 5. The equivalent yeast mutation (Trs20-D46Y) does not block anterograde traffic but disrupts interaction with TRAPPIII-specific subunit Trs85p and TRAPPII-specific subunits Trs120p and Trs130p, destabilizing TRAPPIII and blocking both selective (cvt) and non-selective autophagy.\",\n      \"method\": \"Co-immunoprecipitation (mammalian TRAPPC2–Syntaxin 5 interaction with D47Y mutant); yeast size exclusion chromatography; yeast autophagy assays with trs20D46Y mutant\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, gel filtration, autophagy assays), two organisms, disease mutation used functionally\",\n      \"pmids\": [\"23898804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In yeast, Trs20 (TRAPPC2 ortholog) is required for TRAPPIII assembly at the pre-autophagosomal structure (PAS). Recombinant Trs85 (TRAPPIII-specific subunit) associates with TRAPP only in the presence of Trs20 but not the D46Y mutant. Live-cell colocalization shows Trs85 recruits core TRAPP to the PAS via Trs20. Loss of Trs20 function blocks both selective and non-selective autophagy.\",\n      \"method\": \"In vitro reconstitution with recombinant proteins; co-precipitation from cell lysates; live-cell fluorescence colocalization; autophagy assays in trs20ts mutant yeast\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution plus live-cell imaging plus genetic phenotype, multiple orthogonal methods, disease-equivalent mutation used\",\n      \"pmids\": [\"24329977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRAPPC2 knockdown in SW1353 chondrosarcoma cells and primary human chondrocytes decreases COL2A1 (type II collagen) expression and collagen II secretion. A nonsense variant (c.91A>T) reduces TRAPPC2 mRNA and protein levels and alters the membrane distribution of the mutant protein.\",\n      \"method\": \"siRNA knockdown of TRAPPC2 in chondrocyte cell lines and primary cells with Western blot and ELISA for COL2A1/collagen II; cell fluorescence and Western blot for mutant protein subcellular distribution\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with specific cellular phenotype (collagen secretion), multiple cell types, single lab\",\n      \"pmids\": [\"37693308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Articular cartilage from an SEDT patient carrying an exon-skipping SEDL mutation showed chondrocytes with abundant Golgi complexes and dilated rough ER, consistent with disruption of ER-to-Golgi vesicular transport.\",\n      \"method\": \"Histological/ultrastructural analysis of articular cartilage from a SEDT patient with confirmed SEDL splice mutation\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient pathological observation, no direct biochemical assay of transport function\",\n      \"pmids\": [\"11326333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SEDL (TRAPPC2) was identified as the gene mutated in X-linked spondyloepiphyseal dysplasia tarda; three dinucleotide deletions causing frameshifts and premature stop codons were found in three families, establishing loss of SEDL function as causative for SEDT. The encoded 140 amino acid protein was inferred to have a role in ER-to-Golgi vesicular transport.\",\n      \"method\": \"Positional cloning, mutation analysis (sequencing of candidate gene in affected families), expression analysis in fetal cartilage\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene identification by positional cloning with mutations in multiple independent families; replicated across labs subsequently\",\n      \"pmids\": [\"10431248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRAPPC2 (human ortholog) successfully replaces its yeast counterpart Trs20 in a humanized yeast model, confirming functional conservation of TRAPPC2 across species. This system supports mechanistic study of TRAPPC2 variants.\",\n      \"method\": \"CRISPR/Cas9-mediated humanization of yeast — replacement of yeast TRS20 with human TRAPPC2 coding sequence; viability assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic complementation in humanized yeast, single study, preprint\",\n      \"pmids\": [\"bio_10.1101_2024.08.04.605925\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TRAPPC2 (Sedlin/SEDL) is a conserved 140-amino acid subunit of the TRAPP complex that acts as a structural adaptor: it bridges the TRAPP core to TRAPPII-specific subunit TRAPPC9 (and Trs120p in yeast) or TRAPPIII-specific subunit TRAPPC8/Trs85p, enabling assembly and GEF activity of these higher-order complexes toward Rab GTPases Ypt32/Ypt31 and autophagy; it also interacts with the SNARE Syntaxin 5; its disease-causing mutation D47Y (equivalent to yeast D46Y) selectively disrupts these adaptor interactions without affecting TRAPPI, thereby blocking TRAPPII/III-dependent secretion (including procollagen/COL2A1 in chondrocytes) and autophagy, underlying the skeletal dysplasia SEDT.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRAPPC2 (SEDL/Sedlin) is a small conserved subunit of the TRAPP complex that functions as a structural adaptor governing assembly of higher-order TRAPP complexes that direct membrane traffic and autophagy [#3, #4]. In mammalian cells it directly binds the TRAPPII-specific subunit TRAPPC9 and, mutually exclusively, the TRAPPIII-specific subunit TRAPPC8, thereby templating formation of either complex [#3]; its yeast ortholog Trs20 is correspondingly required for TRAPPII assembly through interaction with Trs120 and for the resulting Ypt32-directed guanine-nucleotide exchange activity [#4], and for recruitment of core TRAPP to the pre-autophagosomal structure via the TRAPPIII subunit Trs85 [#6]. Consistent with an adaptor role, its crystal structure resembles the regulatory domains of SNAREs despite lacking sequence homology [#0], and it interacts with the SNARE Syntaxin 5 [#5]. The protein localizes to perinuclear membranes overlapping the ER-Golgi intermediate compartment [#1], and loss of TRAPPC2 function reduces type II collagen (COL2A1) expression and secretion in chondrocytes [#7] and blocks both selective and non-selective autophagy in yeast [#5, #6]. Loss-of-function mutations in TRAPPC2 cause X-linked spondyloepiphyseal dysplasia tarda (SEDT) [#9]; the surface mutation D47Y (yeast D46Y) selectively abolishes the adaptor interactions with TRAPPC9/TRAPPC8 (Trs120/Trs85) and weakens Syntaxin 5 binding while sparing core TRAPP, defining a disease mechanism centered on disrupted TRAPPII/III assembly [#3, #4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing the genetic basis of an X-linked skeletal dysplasia first implicated this gene in vesicular transport, before any molecular function was known.\",\n      \"evidence\": \"positional cloning and mutation analysis in SEDT families with cartilage expression analysis\",\n      \"pmids\": [\"10431248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inferred ER-to-Golgi transport role was not biochemically tested\", \"No protein partners identified\", \"No structural information\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Subcellular localization placed the protein at the ER-Golgi interface and showed disease mutations mislocalize it, linking trafficking compartment to function.\",\n      \"evidence\": \"transient transfection of tagged constructs in COS-7 cells with fluorescence microscopy\",\n      \"pmids\": [\"11031107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Partial ERGIC overlap only; precise residence not resolved\", \"Overexpression of tagged constructs may not reflect endogenous distribution\", \"Mechanism of C-terminal targeting unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Patient cartilage ultrastructure provided in vivo evidence that loss of function perturbs the secretory pathway in the disease-relevant cell type.\",\n      \"evidence\": \"histological/ultrastructural analysis of SEDT patient articular cartilage\",\n      \"pmids\": [\"11326333\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single patient pathological observation without biochemical assay\", \"Cannot distinguish direct from secondary effects on ER/Golgi morphology\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The crystal structure revealed an unexpected SNARE-like fold and rationalized disease mutations as either structure-disrupting or surface interaction-disrupting, predicting an adaptor/protein-interaction function.\",\n      \"evidence\": \"X-ray crystallography at 2.4 A with disease-mutation mapping\",\n      \"pmids\": [\"12361953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Predicted partner protein for the D47Y surface not identified in this work\", \"Functional consequence of the SNARE-like fold untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Cross-species complementation established functional conservation with yeast Trs20 and parsed which disease residues affect core TRAPP function versus other activities.\",\n      \"evidence\": \"yeast trs20 knockout complementation with multiple human disease alleles\",\n      \"pmids\": [\"14597397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the molecular interactions affected by non-complementing alleles\", \"Yeast viability readout does not resolve which trafficking step is impaired\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining direct binding to TRAPPC9 and TRAPPC8 identified TRAPPC2 as the mutually exclusive adaptor for mammalian TRAPPII versus TRAPPIII assembly and pinpointed Asp47 as the critical interaction residue.\",\n      \"evidence\": \"reciprocal Co-IP of endogenous and overexpressed TRAPP subunits with disease-mutant mapping in mammalian cells\",\n      \"pmids\": [\"21858081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of mutual exclusivity not resolved\", \"Functional consequence for mammalian Rab-GEF activity not measured here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Yeast work connected the adaptor role to enzymatic output, showing Trs20-Trs120 interaction is required for TRAPPII assembly and its Ypt32-GEF activity, which the D46Y mutation selectively abolishes while sparing TRAPPI.\",\n      \"evidence\": \"Co-IP and in vitro Ypt32-GEF assay with D46Y mutant in yeast\",\n      \"pmids\": [\"23465091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian GEF activity not directly tested\", \"Whether D47Y similarly affects mammalian Rab substrates not shown here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"TRAPPC2 was linked to autophagy and to SNARE binding, with D47Y weakening Syntaxin 5 interaction and the yeast equivalent destabilizing TRAPPIII to block selective and non-selective autophagy.\",\n      \"evidence\": \"mammalian Co-IP of TRAPPC2-Syntaxin 5, yeast size-exclusion chromatography and autophagy assays with D46Y\",\n      \"pmids\": [\"23898804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of mammalian Syntaxin 5 binding in autophagy not established\", \"Anterograde traffic was unaffected by D46Y in yeast, leaving the secretion defect mechanism in disease cells unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reconstitution and live-cell imaging showed Trs20 mediates recruitment of core TRAPP to the pre-autophagosomal structure via Trs85, providing a spatial mechanism for its autophagy function.\",\n      \"evidence\": \"in vitro reconstitution with recombinant proteins, co-precipitation, live-cell colocalization, and autophagy assays in trs20ts yeast\",\n      \"pmids\": [\"24329977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PAS recruitment demonstrated in yeast; mammalian autophagosome recruitment not directly shown\", \"Rab substrate engaged at the PAS not defined here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Loss-of-function in chondrocytes tied TRAPPC2 directly to the disease-relevant cargo, reducing COL2A1 expression and collagen II secretion.\",\n      \"evidence\": \"siRNA knockdown in SW1353 cells and primary human chondrocytes with Western blot/ELISA, plus characterization of a nonsense variant\",\n      \"pmids\": [\"37693308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether reduced secretion reflects TRAPPII or TRAPPIII dysfunction not dissected\", \"Single lab; mechanism linking TRAPP adaptor role to collagen trafficking not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A humanized yeast model confirmed cross-species functional replacement, providing a tractable platform for variant analysis.\",\n      \"evidence\": \"CRISPR/Cas9 humanization replacing yeast TRS20 with human TRAPPC2 and viability assay (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.08.04.605925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single study\", \"Does not itself define disease variant mechanisms\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How disrupted TRAPPII/III assembly in human chondrocytes mechanistically produces the specific procollagen secretion defect and skeletal phenotype remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct demonstration that mammalian D47Y impairs Rab-GEF activity in chondrocytes\", \"Mammalian Rab substrate(s) downstream of TRAPPC2 not identified in the corpus\", \"Connection between Syntaxin 5 binding and procollagen export untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 4, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"TRAPP\", \"TRAPPII\", \"TRAPPIII\"],\n    \"partners\": [\"TRAPPC9\", \"TRAPPC8\", \"STX5\", \"TRS120\", \"TRS85\", \"TRAPPC10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}