{"gene":"TRAPPC10","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2006,"finding":"The TRAPPII-specific subunits Trs120 and Trs130 (orthologs of mammalian TRAPPC10) are required for switching the GEF specificity of the TRAPP complex from Ypt1 to Ypt31/32 at the late Golgi, thereby coordinating Golgi entry and exit.","method":"Genetic epistasis, GEF activity assays, intracellular localization of GTPases in yeast mutants","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — GEF specificity switch demonstrated biochemically and genetically, replicated in multiple subsequent studies","pmids":["17041589"],"is_preprint":false},{"year":2005,"finding":"Trs130p (yeast ortholog of TRAPPC10) is required for vesicle traffic from the early endosome to the late Golgi, and trs130 mutants accumulate aberrant membrane structures; Trs130p colocalizes with the late Golgi marker Sec7p.","method":"Temperature-sensitive mutant analysis, electron microscopy, fluorescence colocalization, secretion assays in yeast","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (EM, colocalization, trafficking assays) in a single study","pmids":["16314430"],"is_preprint":false},{"year":2009,"finding":"Mammalian TRAPPC10 (mTrs130) is a component of the mammalian TRAPPII complex, which is enriched on COPI-coated vesicles/buds, specifically activates Rab1, and binds to the COPI coat adaptor subunit gamma1COP; depletion of mTrs130 causes vesicle accumulation near the Golgi and cargo accumulation in an early Golgi compartment.","method":"shRNA knockdown, co-immunoprecipitation, immunoelectron microscopy, GEF activity assays in mammalian cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — reconstituted GEF activity, reciprocal Co-IP, EM localization, and functional KD phenotype in one study","pmids":["19656848"],"is_preprint":false},{"year":2011,"finding":"In mammalian cells, TRAPPC2 serves as an adaptor for TRAPPII complex formation by binding to TRAPPC9, which in turn binds to TRAPPC10; a disease-causing TRAPPC2 mutation (D47Y) abolishes interaction with TRAPPC9 and TRAPPC8, and disease-causing TRAPPC9 deletions all fail to interact with both TRAPPC2 and TRAPPC10.","method":"Co-immunoprecipitation in mammalian cells, disease mutant analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP interactions defined, multiple disease mutants tested, but single-lab study","pmids":["21858081"],"is_preprint":false},{"year":2016,"finding":"Mammalian TRAPPII (containing TRAPPC10) acts as a GEF for both Rab18 and Rab1; COPI interaction with TRAPPII is required for recruitment of Rab18 to lipid droplet surfaces; inactivation of TRAPPII-specific subunits via siRNA or CRISPR-Cas9 deletion causes aberrantly large lipid droplets and defective Rab18 recruitment to lipid droplets.","method":"siRNA depletion, CRISPR-Cas9 knockout, GEF activity assays, live-cell imaging, lipid droplet phenotype analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — GEF assay, CRISPR KO, and functional rescue with multiple orthogonal methods","pmids":["28003315"],"is_preprint":false},{"year":2018,"finding":"The TRAPPC2L missense variant (p.Asp37Tyr) ablates interaction between TRAPPC2L and TRAPPC10/Trs130; since TRAPPII activates RAB11, loss of this interaction leads to increased active RAB11 levels and altered RAB11 cellular morphology in patient fibroblasts.","method":"Yeast two-hybrid, patient fibroblast studies, membrane trafficking assays, RAB11 activation state measurement","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 — yeast two-hybrid and patient cell studies with functional readout, single lab","pmids":["30120216"],"is_preprint":false},{"year":2022,"finding":"Biallelic loss-of-function variants in TRAPPC10 cause a microcephalic neurodevelopmental disorder; mutant TRAPPC10 shows weakened interaction with TRAPPC2L; loss of TRAPPC10 leads to concomitant loss of TRAPPC9 protein levels and a membrane trafficking defect, both of which are rescued by wild-type but not mutant TRAPPC10 constructs; Trappc10-/- knockout mice display neuroanatomical brain defects and microcephaly.","method":"Patient cell studies (lymphoblastoid cells and knockout cell lines), Co-IP, membrane trafficking assays, TRAPPC10-/- mouse model, rescue experiments with wild-type vs. mutant constructs","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including KO cells, mouse model, rescue experiments, and interaction studies in one study","pmids":["35298461"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of the 22-subunit budding yeast TRAPPII complex (containing Trs130/TRAPPC10 ortholog) including a TRAPPII-Rab11 nucleotide exchange intermediate reveal that the Trs130 subunit provides a 'leg' that positions the active site distal to the membrane surface enabling steric gating against Rab1, and the Trs120 subunit acts as a 'lid' to enclose the active site for Rab11 access.","method":"Cryo-electron microscopy structure determination of TRAPPII-Rab11 complex","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure with mechanistic interpretation of substrate selectivity","pmids":["35559680"],"is_preprint":false},{"year":2021,"finding":"In the mammalian TRAPPII complex (containing TRAPPC9 and TRAPPC10), the complex has GEF activity toward Rab1 and Rab11 but not 18 other Rabs tested; TRAPPII and TRAPPIII show significant differences in protein dynamics at the Rab binding site as revealed by HDX-MS; both complexes have enhanced GEF activity on lipid membranes with conformational changes accompanying membrane association.","method":"Biochemical GEF assays against panel of 20 Rabs, hydrogen-deuterium exchange mass spectrometry (HDX-MS), electron microscopy, membrane-reconstituted GEF assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods in a single rigorous study","pmids":["34229011"],"is_preprint":false},{"year":2002,"finding":"Genetic interactions link TRS130 (yeast TRAPPC10 ortholog) with ARF1 and YPT31/32: a synthetic lethal trs130 allele requires ARF1 for viability, and high-copy YPT31/YPT32 suppresses lethality from TRS130 or TRS120 deletion, positioning Ypt31/32 downstream of TRS130 in the trafficking pathway.","method":"Synthetic lethal genetic screen, high-copy suppressor analysis, yeast genetics","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis by suppressor analysis, multiple alleles tested","pmids":["12210902"],"is_preprint":false},{"year":2012,"finding":"Genetic epistasis in yeast demonstrates that Trs130 (TRAPPC10 ortholog) functions specifically with Ypt31/32 (not Ypt1): overexpression of Ypt31 but not Ypt1 suppresses growth and GFP-Snc1 transport phenotypes of trs130ts mutants, placing TRAPPII/Trs130 in the Ypt31/32 pathway.","method":"Temperature-sensitive mutant analysis, GFP-Snc1 transport assay, genetic suppression in yeast","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic epistasis with defined cargo readout","pmids":["22426882"],"is_preprint":false},{"year":2012,"finding":"Trs130 (TRAPPC10 ortholog) participates in autophagy by regulating transport of Atg8 and Atg9 to the pre-autophagosomal structure; genetic analysis places Trs130 downstream of Atg5 and upstream of Atg1, Atg13, Atg9, and Atg14; overexpression of Ypt31/32 but not Ypt1 rescues autophagy defects in trs130ts mutants.","method":"Temperature-sensitive mutant analysis, GFP-Atg8/Atg9 localization, Ape1 maturation assay, genetic epistasis in yeast","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple markers and genetic epistasis to place pathway position","pmids":["23078654"],"is_preprint":false},{"year":2024,"finding":"Loss of TRAPPC6B reduces levels of TRAPP II complex-specific members TRAPPC9 and TRAPPC10 in patient fibroblasts; co-immunoprecipitation shows TRAPPC6B co-precipitates preferentially with TRAPP II over TRAPP III, establishing TRAPPC10 as specifically enriched in the TRAPP II complex.","method":"Patient fibroblast protein level analysis, co-immunoprecipitation, Golgi trafficking assay with rescue","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and functional rescue experiments establish TRAPPC10 as TRAPP II-specific","pmids":["37713627"],"is_preprint":false}],"current_model":"TRAPPC10 (mammalian ortholog of yeast Trs130) is a core structural and functional subunit of the TRAPPII complex that interacts with TRAPPC9 (via TRAPPC2 as adaptor) and TRAPPC2L, positions the TRAPP catalytic core via a 'leg' domain to enable steric gating of substrate selectivity, and confers GEF activity specifically toward Rab11 (and Rab1/Rab18) to regulate late Golgi trafficking, endosome-to-Golgi recycling, lipid droplet homeostasis, and autophagy; biallelic loss of TRAPPC10 destabilizes TRAPPC9 and causes membrane trafficking defects resulting in microcephalic neurodevelopmental disorder."},"narrative":{"teleology":[{"year":2002,"claim":"Genetic suppressor analysis first positioned Trs130 (TRAPPC10 ortholog) in the Ypt31/32 (Rab11) trafficking pathway by showing that high-copy YPT31/32 suppresses TRS130 deletion lethality and that TRS130 genetically interacts with ARF1, establishing TRAPPC10 as a regulator upstream of Rab11-family GTPases.","evidence":"Synthetic lethal screen and high-copy suppressor analysis in budding yeast","pmids":["12210902"],"confidence":"Medium","gaps":["Genetic placement did not demonstrate direct GEF activity","Mammalian relevance not yet addressed","Mechanism of Trs130 action unknown"]},{"year":2005,"claim":"Demonstration that Trs130 is required for vesicle traffic from the early endosome to the late Golgi established the specific trafficking step controlled by this subunit, with electron microscopy revealing aberrant membrane accumulation in trs130 mutants.","evidence":"Temperature-sensitive mutant analysis, electron microscopy, fluorescence colocalization, and secretion assays in yeast","pmids":["16314430"],"confidence":"High","gaps":["Whether Trs130 directly acts on Rab GTPases remained untested","No structural information on how Trs130 contributes to TRAPPII function"]},{"year":2006,"claim":"The key mechanistic insight that TRAPPII-specific subunits including Trs130 switch the TRAPP complex's GEF specificity from Ypt1 (Rab1) to Ypt31/32 (Rab11) resolved how a shared catalytic core can serve two distinct Rab substrates at different Golgi compartments.","evidence":"GEF activity assays and genetic epistasis in budding yeast","pmids":["17041589"],"confidence":"High","gaps":["Structural basis for specificity switching unknown","Mammalian TRAPPII Rab specificity not yet tested"]},{"year":2009,"claim":"Extension to mammalian cells showed that TRAPPC10 is a component of mammalian TRAPPII enriched on COPI-coated vesicles, that the complex activates Rab1, and that TRAPPC10 depletion causes vesicle accumulation and cargo mistargeting near the Golgi, translating the yeast findings to mammalian Golgi trafficking.","evidence":"shRNA knockdown, co-immunoprecipitation, immunoelectron microscopy, and GEF assays in mammalian cells","pmids":["19656848"],"confidence":"High","gaps":["Mammalian TRAPPII Rab11 GEF activity not yet demonstrated","COPI interaction mechanism not structurally resolved"]},{"year":2011,"claim":"Mapping the intra-complex assembly revealed that TRAPPC2 acts as an adaptor bridging TRAPPC9 to the TRAPP core, and TRAPPC9 in turn binds TRAPPC10, explaining how disease-causing mutations in TRAPPC2 or TRAPPC9 disrupt TRAPPII assembly.","evidence":"Co-immunoprecipitation with wild-type and disease-mutant constructs in mammalian cells","pmids":["21858081"],"confidence":"Medium","gaps":["Single-lab Co-IP study without reciprocal or structural validation of the TRAPPC9–TRAPPC10 interface","Stoichiometry of the complex not determined"]},{"year":2012,"claim":"Refined genetic epistasis confirmed that Trs130 functions specifically in the Ypt31/32 (not Ypt1) pathway, and further showed that TRAPPII/Trs130 participates in autophagy by regulating Atg8/Atg9 transport to the pre-autophagosomal structure downstream of Atg5 and upstream of Atg1.","evidence":"Temperature-sensitive mutant analysis, GFP-Snc1 and GFP-Atg8/Atg9 transport assays, Ape1 maturation, and genetic suppression in yeast","pmids":["22426882","23078654"],"confidence":"Medium","gaps":["Mammalian autophagy role of TRAPPC10 not tested","Molecular mechanism linking Rab activation to autophagosome biogenesis unclear"]},{"year":2016,"claim":"Discovery that mammalian TRAPPII acts as a GEF for Rab18 and that TRAPPII-specific subunit loss causes aberrantly large lipid droplets expanded the functional repertoire of TRAPPC10-containing TRAPPII beyond Golgi trafficking to lipid droplet homeostasis.","evidence":"siRNA depletion, CRISPR-Cas9 knockout, GEF assays, live-cell imaging, and lipid droplet phenotype analysis in mammalian cells","pmids":["28003315"],"confidence":"High","gaps":["Whether TRAPPC10 directly contacts Rab18 or only positions the catalytic core unknown","Physiological significance of lipid droplet defect in vivo not established"]},{"year":2018,"claim":"Identification of a TRAPPC2L disease variant that ablates interaction with TRAPPC10 and leads to increased active RAB11 in patient cells provided the first human genetic evidence that the TRAPPC2L–TRAPPC10 interaction regulates RAB11 activation state.","evidence":"Yeast two-hybrid, patient fibroblast studies, RAB11 activation measurement","pmids":["30120216"],"confidence":"Medium","gaps":["Single-family study; mechanism by which loss of TRAPPC2L–TRAPPC10 interaction increases active RAB11 is counterintuitive and not fully explained","No structural data on TRAPPC2L–TRAPPC10 interface"]},{"year":2021,"claim":"Comprehensive biochemical profiling established that mammalian TRAPPII containing TRAPPC10 has GEF activity toward Rab1 and Rab11 (but not 18 other Rabs) and that membrane association enhances activity with conformational changes, resolving the mammalian Rab specificity profile.","evidence":"GEF assays against 20 Rabs, hydrogen-deuterium exchange mass spectrometry, electron microscopy, and membrane-reconstituted assays","pmids":["34229011"],"confidence":"High","gaps":["Discrepancy with earlier Rab18 GEF activity claim not fully reconciled","Membrane-induced conformational changes not mapped to specific subunits"]},{"year":2022,"claim":"Cryo-EM structures of the TRAPPII–Rab11 complex revealed the structural basis for substrate selectivity: TRAPPC10's 'leg' domain elevates the catalytic core from the membrane surface, sterically excluding Rab1 and permitting Rab11 access, while Trs120 acts as a 'lid' enclosing the active site.","evidence":"Cryo-EM structure determination of the 22-subunit yeast TRAPPII complex including a Rab11 exchange intermediate","pmids":["35559680"],"confidence":"High","gaps":["Mammalian TRAPPII structure not yet solved","Dynamic conformational gating during catalysis not captured"]},{"year":2022,"claim":"Biallelic TRAPPC10 loss-of-function variants were shown to cause microcephalic neurodevelopmental disorder, with loss of TRAPPC10 destabilizing TRAPPC9, disrupting membrane trafficking, and producing microcephaly in knockout mice — establishing TRAPPC10 as a disease gene.","evidence":"Patient lymphoblastoid cells, knockout cell lines, Co-IP, trafficking assays, rescue with wild-type vs. mutant constructs, and Trappc10−/− mouse model","pmids":["35298461"],"confidence":"High","gaps":["Specific neuronal cell types and developmental stages most affected not determined","Whether trafficking defect or specific Rab dysregulation underlies neuronal pathology unclear"]},{"year":2024,"claim":"Demonstration that TRAPPC6B loss reduces TRAPPC9 and TRAPPC10 protein levels, and that TRAPPC6B co-precipitates preferentially with TRAPPII, further defined TRAPPC10 as specifically enriched in the TRAPPII complex and showed upstream dependencies for its stability.","evidence":"Patient fibroblast protein analysis, co-immunoprecipitation, Golgi trafficking rescue assay","pmids":["37713627"],"confidence":"Medium","gaps":["Mechanism by which TRAPPC6B stabilizes TRAPPII-specific subunits is unclear","Whether TRAPPC6B loss phenocopies TRAPPC10 loss in neurons not tested"]},{"year":null,"claim":"Key unresolved questions include the high-resolution structure of mammalian TRAPPII, the reconciliation of conflicting Rab18 GEF data, the specific neuronal mechanisms underlying TRAPPC10-associated microcephaly, and whether TRAPPC10 has functions independent of the TRAPPII complex.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mammalian TRAPPII cryo-EM structure","Rab18 vs. Rab11 GEF specificity discrepancy across studies unresolved","Cell-type-specific roles in brain development not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,7,8]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6]}],"complexes":["TRAPPII"],"partners":["TRAPPC9","TRAPPC2","TRAPPC2L","TRAPPC6B","RAB11","RAB1","RAB18"],"other_free_text":[]},"mechanistic_narrative":"TRAPPC10 is a TRAPPII complex-specific subunit that confers Rab GTPase exchange factor (GEF) substrate selectivity, directing the TRAPP catalytic core toward Rab11 (Ypt31/32 in yeast) at the late Golgi to coordinate intra-Golgi trafficking, endosome-to-Golgi recycling, lipid droplet homeostasis, and autophagy [PMID:17041589, PMID:16314430, PMID:28003315, PMID:23078654]. Cryo-EM structures show that TRAPPC10 provides a 'leg' domain that positions the active site distal to the membrane, sterically gating against Rab1 and enabling selective Rab11 activation, while the mammalian TRAPPII complex also activates Rab1 and Rab18 in biochemical assays [PMID:35559680, PMID:34229011, PMID:28003315]. TRAPPC10 assembles into TRAPPII through TRAPPC9 (bridged by TRAPPC2) and TRAPPC2L, and loss of TRAPPC10 destabilizes TRAPPC9 and impairs membrane trafficking [PMID:21858081, PMID:35298461, PMID:30120216]. Biallelic loss-of-function variants in TRAPPC10 cause a microcephalic neurodevelopmental disorder, confirmed by patient cell rescue experiments and Trappc10-knockout mice displaying microcephaly and neuroanatomical defects [PMID:35298461]."},"prefetch_data":{"uniprot":{"accession":"P48553","full_name":"Trafficking protein particle complex subunit 10","aliases":["Epilepsy holoprosencephaly candidate 1 protein","EHOC-1","Protein GT334","Trafficking protein particle complex subunit TMEM1","Transport protein particle subunit TMEM1","TRAPP subunit TMEM1"],"length_aa":1259,"mass_kda":142.2,"function":"Specific subunit of the TRAPP (transport protein particle) II complex, a highly conserved vesicle tethering complex that functions in late Golgi trafficking as a membrane tether","subcellular_location":"Golgi apparatus, cis-Golgi network","url":"https://www.uniprot.org/uniprotkb/P48553/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRAPPC10","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":[{"gene":"TRAPPC2","stoichiometry":10.0},{"gene":"TRAPPC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRAPPC10","total_profiled":1310},"omim":[{"mim_id":"620027","title":"NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SHORT STATURE, AND SPEECH DELAY; NEDMISS","url":"https://www.omim.org/entry/620027"},{"mim_id":"618331","title":"ENCEPHALOPATHY, PROGRESSIVE, EARLY-ONSET, WITH EPISODIC RHABDOMYOLYSIS; PEERB","url":"https://www.omim.org/entry/618331"},{"mim_id":"610970","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 2L; TRAPPC2L","url":"https://www.omim.org/entry/610970"},{"mim_id":"602103","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 10; TRAPPC10","url":"https://www.omim.org/entry/602103"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRAPPC10"},"hgnc":{"alias_symbol":["EHOC-1","TRS130"],"prev_symbol":["TMEM1"]},"alphafold":{"accession":"P48553","domains":[{"cath_id":"3.40.50","chopping":"21-212","consensus_level":"high","plddt":83.0633,"start":21,"end":212},{"cath_id":"-","chopping":"220-474","consensus_level":"medium","plddt":90.6413,"start":220,"end":474},{"cath_id":"2.60.40.10","chopping":"579-661_720-782","consensus_level":"high","plddt":78.411,"start":579,"end":782},{"cath_id":"2.60.40.10","chopping":"955-1054","consensus_level":"high","plddt":81.2664,"start":955,"end":1054},{"cath_id":"2.60.40.10","chopping":"1060-1170_1225-1247","consensus_level":"medium","plddt":82.3307,"start":1060,"end":1247},{"cath_id":"2.60.40","chopping":"797-885","consensus_level":"high","plddt":80.9497,"start":797,"end":885}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48553","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48553-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48553-F1-predicted_aligned_error_v6.png","plddt_mean":79.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRAPPC10","jax_strain_url":"https://www.jax.org/strain/search?query=TRAPPC10"},"sequence":{"accession":"P48553","fasta_url":"https://rest.uniprot.org/uniprotkb/P48553.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48553/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48553"}},"corpus_meta":[{"pmid":"17041589","id":"PMC_17041589","title":"TRAPPII 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N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/25800836","citation_count":4,"is_preprint":false},{"pmid":"39560797","id":"PMC_39560797","title":"Introducing a novel TRAPPC10 gene variant as a potential cause of developmental delay and intellectual disability in an Iranian family.","date":"2024","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/39560797","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18371,"output_tokens":3221,"usd":0.051714},"stage2":{"model":"claude-opus-4-6","input_tokens":6594,"output_tokens":3294,"usd":0.17298},"total_usd":0.224694,"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\": 2006,\n      \"finding\": \"The TRAPPII-specific subunits Trs120 and Trs130 (orthologs of mammalian TRAPPC10) are required for switching the GEF specificity of the TRAPP complex from Ypt1 to Ypt31/32 at the late Golgi, thereby coordinating Golgi entry and exit.\",\n      \"method\": \"Genetic epistasis, GEF activity assays, intracellular localization of GTPases in yeast mutants\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — GEF specificity switch demonstrated biochemically and genetically, replicated in multiple subsequent studies\",\n      \"pmids\": [\"17041589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Trs130p (yeast ortholog of TRAPPC10) is required for vesicle traffic from the early endosome to the late Golgi, and trs130 mutants accumulate aberrant membrane structures; Trs130p colocalizes with the late Golgi marker Sec7p.\",\n      \"method\": \"Temperature-sensitive mutant analysis, electron microscopy, fluorescence colocalization, secretion assays in yeast\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (EM, colocalization, trafficking assays) in a single study\",\n      \"pmids\": [\"16314430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mammalian TRAPPC10 (mTrs130) is a component of the mammalian TRAPPII complex, which is enriched on COPI-coated vesicles/buds, specifically activates Rab1, and binds to the COPI coat adaptor subunit gamma1COP; depletion of mTrs130 causes vesicle accumulation near the Golgi and cargo accumulation in an early Golgi compartment.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, immunoelectron microscopy, GEF activity assays in mammalian cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstituted GEF activity, reciprocal Co-IP, EM localization, and functional KD phenotype in one study\",\n      \"pmids\": [\"19656848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In mammalian cells, TRAPPC2 serves as an adaptor for TRAPPII complex formation by binding to TRAPPC9, which in turn binds to TRAPPC10; a disease-causing TRAPPC2 mutation (D47Y) abolishes interaction with TRAPPC9 and TRAPPC8, and disease-causing TRAPPC9 deletions all fail to interact with both TRAPPC2 and TRAPPC10.\",\n      \"method\": \"Co-immunoprecipitation in mammalian cells, disease mutant analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP interactions defined, multiple disease mutants tested, but single-lab study\",\n      \"pmids\": [\"21858081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mammalian TRAPPII (containing TRAPPC10) acts as a GEF for both Rab18 and Rab1; COPI interaction with TRAPPII is required for recruitment of Rab18 to lipid droplet surfaces; inactivation of TRAPPII-specific subunits via siRNA or CRISPR-Cas9 deletion causes aberrantly large lipid droplets and defective Rab18 recruitment to lipid droplets.\",\n      \"method\": \"siRNA depletion, CRISPR-Cas9 knockout, GEF activity assays, live-cell imaging, lipid droplet phenotype analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — GEF assay, CRISPR KO, and functional rescue with multiple orthogonal methods\",\n      \"pmids\": [\"28003315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The TRAPPC2L missense variant (p.Asp37Tyr) ablates interaction between TRAPPC2L and TRAPPC10/Trs130; since TRAPPII activates RAB11, loss of this interaction leads to increased active RAB11 levels and altered RAB11 cellular morphology in patient fibroblasts.\",\n      \"method\": \"Yeast two-hybrid, patient fibroblast studies, membrane trafficking assays, RAB11 activation state measurement\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid and patient cell studies with functional readout, single lab\",\n      \"pmids\": [\"30120216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic loss-of-function variants in TRAPPC10 cause a microcephalic neurodevelopmental disorder; mutant TRAPPC10 shows weakened interaction with TRAPPC2L; loss of TRAPPC10 leads to concomitant loss of TRAPPC9 protein levels and a membrane trafficking defect, both of which are rescued by wild-type but not mutant TRAPPC10 constructs; Trappc10-/- knockout mice display neuroanatomical brain defects and microcephaly.\",\n      \"method\": \"Patient cell studies (lymphoblastoid cells and knockout cell lines), Co-IP, membrane trafficking assays, TRAPPC10-/- mouse model, rescue experiments with wild-type vs. mutant constructs\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including KO cells, mouse model, rescue experiments, and interaction studies in one study\",\n      \"pmids\": [\"35298461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of the 22-subunit budding yeast TRAPPII complex (containing Trs130/TRAPPC10 ortholog) including a TRAPPII-Rab11 nucleotide exchange intermediate reveal that the Trs130 subunit provides a 'leg' that positions the active site distal to the membrane surface enabling steric gating against Rab1, and the Trs120 subunit acts as a 'lid' to enclose the active site for Rab11 access.\",\n      \"method\": \"Cryo-electron microscopy structure determination of TRAPPII-Rab11 complex\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure with mechanistic interpretation of substrate selectivity\",\n      \"pmids\": [\"35559680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In the mammalian TRAPPII complex (containing TRAPPC9 and TRAPPC10), the complex has GEF activity toward Rab1 and Rab11 but not 18 other Rabs tested; TRAPPII and TRAPPIII show significant differences in protein dynamics at the Rab binding site as revealed by HDX-MS; both complexes have enhanced GEF activity on lipid membranes with conformational changes accompanying membrane association.\",\n      \"method\": \"Biochemical GEF assays against panel of 20 Rabs, hydrogen-deuterium exchange mass spectrometry (HDX-MS), electron microscopy, membrane-reconstituted GEF assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical methods in a single rigorous study\",\n      \"pmids\": [\"34229011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Genetic interactions link TRS130 (yeast TRAPPC10 ortholog) with ARF1 and YPT31/32: a synthetic lethal trs130 allele requires ARF1 for viability, and high-copy YPT31/YPT32 suppresses lethality from TRS130 or TRS120 deletion, positioning Ypt31/32 downstream of TRS130 in the trafficking pathway.\",\n      \"method\": \"Synthetic lethal genetic screen, high-copy suppressor analysis, yeast genetics\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis by suppressor analysis, multiple alleles tested\",\n      \"pmids\": [\"12210902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Genetic epistasis in yeast demonstrates that Trs130 (TRAPPC10 ortholog) functions specifically with Ypt31/32 (not Ypt1): overexpression of Ypt31 but not Ypt1 suppresses growth and GFP-Snc1 transport phenotypes of trs130ts mutants, placing TRAPPII/Trs130 in the Ypt31/32 pathway.\",\n      \"method\": \"Temperature-sensitive mutant analysis, GFP-Snc1 transport assay, genetic suppression in yeast\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis with defined cargo readout\",\n      \"pmids\": [\"22426882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Trs130 (TRAPPC10 ortholog) participates in autophagy by regulating transport of Atg8 and Atg9 to the pre-autophagosomal structure; genetic analysis places Trs130 downstream of Atg5 and upstream of Atg1, Atg13, Atg9, and Atg14; overexpression of Ypt31/32 but not Ypt1 rescues autophagy defects in trs130ts mutants.\",\n      \"method\": \"Temperature-sensitive mutant analysis, GFP-Atg8/Atg9 localization, Ape1 maturation assay, genetic epistasis in yeast\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple markers and genetic epistasis to place pathway position\",\n      \"pmids\": [\"23078654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of TRAPPC6B reduces levels of TRAPP II complex-specific members TRAPPC9 and TRAPPC10 in patient fibroblasts; co-immunoprecipitation shows TRAPPC6B co-precipitates preferentially with TRAPP II over TRAPP III, establishing TRAPPC10 as specifically enriched in the TRAPP II complex.\",\n      \"method\": \"Patient fibroblast protein level analysis, co-immunoprecipitation, Golgi trafficking assay with rescue\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and functional rescue experiments establish TRAPPC10 as TRAPP II-specific\",\n      \"pmids\": [\"37713627\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRAPPC10 (mammalian ortholog of yeast Trs130) is a core structural and functional subunit of the TRAPPII complex that interacts with TRAPPC9 (via TRAPPC2 as adaptor) and TRAPPC2L, positions the TRAPP catalytic core via a 'leg' domain to enable steric gating of substrate selectivity, and confers GEF activity specifically toward Rab11 (and Rab1/Rab18) to regulate late Golgi trafficking, endosome-to-Golgi recycling, lipid droplet homeostasis, and autophagy; biallelic loss of TRAPPC10 destabilizes TRAPPC9 and causes membrane trafficking defects resulting in microcephalic neurodevelopmental disorder.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRAPPC10 is a TRAPPII complex-specific subunit that confers Rab GTPase exchange factor (GEF) substrate selectivity, directing the TRAPP catalytic core toward Rab11 (Ypt31/32 in yeast) at the late Golgi to coordinate intra-Golgi trafficking, endosome-to-Golgi recycling, lipid droplet homeostasis, and autophagy [PMID:17041589, PMID:16314430, PMID:28003315, PMID:23078654]. Cryo-EM structures show that TRAPPC10 provides a 'leg' domain that positions the active site distal to the membrane, sterically gating against Rab1 and enabling selective Rab11 activation, while the mammalian TRAPPII complex also activates Rab1 and Rab18 in biochemical assays [PMID:35559680, PMID:34229011, PMID:28003315]. TRAPPC10 assembles into TRAPPII through TRAPPC9 (bridged by TRAPPC2) and TRAPPC2L, and loss of TRAPPC10 destabilizes TRAPPC9 and impairs membrane trafficking [PMID:21858081, PMID:35298461, PMID:30120216]. Biallelic loss-of-function variants in TRAPPC10 cause a microcephalic neurodevelopmental disorder, confirmed by patient cell rescue experiments and Trappc10-knockout mice displaying microcephaly and neuroanatomical defects [PMID:35298461].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic suppressor analysis first positioned Trs130 (TRAPPC10 ortholog) in the Ypt31/32 (Rab11) trafficking pathway by showing that high-copy YPT31/32 suppresses TRS130 deletion lethality and that TRS130 genetically interacts with ARF1, establishing TRAPPC10 as a regulator upstream of Rab11-family GTPases.\",\n      \"evidence\": \"Synthetic lethal screen and high-copy suppressor analysis in budding yeast\",\n      \"pmids\": [\"12210902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genetic placement did not demonstrate direct GEF activity\", \"Mammalian relevance not yet addressed\", \"Mechanism of Trs130 action unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that Trs130 is required for vesicle traffic from the early endosome to the late Golgi established the specific trafficking step controlled by this subunit, with electron microscopy revealing aberrant membrane accumulation in trs130 mutants.\",\n      \"evidence\": \"Temperature-sensitive mutant analysis, electron microscopy, fluorescence colocalization, and secretion assays in yeast\",\n      \"pmids\": [\"16314430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Trs130 directly acts on Rab GTPases remained untested\", \"No structural information on how Trs130 contributes to TRAPPII function\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The key mechanistic insight that TRAPPII-specific subunits including Trs130 switch the TRAPP complex's GEF specificity from Ypt1 (Rab1) to Ypt31/32 (Rab11) resolved how a shared catalytic core can serve two distinct Rab substrates at different Golgi compartments.\",\n      \"evidence\": \"GEF activity assays and genetic epistasis in budding yeast\",\n      \"pmids\": [\"17041589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for specificity switching unknown\", \"Mammalian TRAPPII Rab specificity not yet tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extension to mammalian cells showed that TRAPPC10 is a component of mammalian TRAPPII enriched on COPI-coated vesicles, that the complex activates Rab1, and that TRAPPC10 depletion causes vesicle accumulation and cargo mistargeting near the Golgi, translating the yeast findings to mammalian Golgi trafficking.\",\n      \"evidence\": \"shRNA knockdown, co-immunoprecipitation, immunoelectron microscopy, and GEF assays in mammalian cells\",\n      \"pmids\": [\"19656848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian TRAPPII Rab11 GEF activity not yet demonstrated\", \"COPI interaction mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping the intra-complex assembly revealed that TRAPPC2 acts as an adaptor bridging TRAPPC9 to the TRAPP core, and TRAPPC9 in turn binds TRAPPC10, explaining how disease-causing mutations in TRAPPC2 or TRAPPC9 disrupt TRAPPII assembly.\",\n      \"evidence\": \"Co-immunoprecipitation with wild-type and disease-mutant constructs in mammalian cells\",\n      \"pmids\": [\"21858081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP study without reciprocal or structural validation of the TRAPPC9–TRAPPC10 interface\", \"Stoichiometry of the complex not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Refined genetic epistasis confirmed that Trs130 functions specifically in the Ypt31/32 (not Ypt1) pathway, and further showed that TRAPPII/Trs130 participates in autophagy by regulating Atg8/Atg9 transport to the pre-autophagosomal structure downstream of Atg5 and upstream of Atg1.\",\n      \"evidence\": \"Temperature-sensitive mutant analysis, GFP-Snc1 and GFP-Atg8/Atg9 transport assays, Ape1 maturation, and genetic suppression in yeast\",\n      \"pmids\": [\"22426882\", \"23078654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian autophagy role of TRAPPC10 not tested\", \"Molecular mechanism linking Rab activation to autophagosome biogenesis unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that mammalian TRAPPII acts as a GEF for Rab18 and that TRAPPII-specific subunit loss causes aberrantly large lipid droplets expanded the functional repertoire of TRAPPC10-containing TRAPPII beyond Golgi trafficking to lipid droplet homeostasis.\",\n      \"evidence\": \"siRNA depletion, CRISPR-Cas9 knockout, GEF assays, live-cell imaging, and lipid droplet phenotype analysis in mammalian cells\",\n      \"pmids\": [\"28003315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRAPPC10 directly contacts Rab18 or only positions the catalytic core unknown\", \"Physiological significance of lipid droplet defect in vivo not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of a TRAPPC2L disease variant that ablates interaction with TRAPPC10 and leads to increased active RAB11 in patient cells provided the first human genetic evidence that the TRAPPC2L–TRAPPC10 interaction regulates RAB11 activation state.\",\n      \"evidence\": \"Yeast two-hybrid, patient fibroblast studies, RAB11 activation measurement\",\n      \"pmids\": [\"30120216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-family study; mechanism by which loss of TRAPPC2L–TRAPPC10 interaction increases active RAB11 is counterintuitive and not fully explained\", \"No structural data on TRAPPC2L–TRAPPC10 interface\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Comprehensive biochemical profiling established that mammalian TRAPPII containing TRAPPC10 has GEF activity toward Rab1 and Rab11 (but not 18 other Rabs) and that membrane association enhances activity with conformational changes, resolving the mammalian Rab specificity profile.\",\n      \"evidence\": \"GEF assays against 20 Rabs, hydrogen-deuterium exchange mass spectrometry, electron microscopy, and membrane-reconstituted assays\",\n      \"pmids\": [\"34229011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrepancy with earlier Rab18 GEF activity claim not fully reconciled\", \"Membrane-induced conformational changes not mapped to specific subunits\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cryo-EM structures of the TRAPPII–Rab11 complex revealed the structural basis for substrate selectivity: TRAPPC10's 'leg' domain elevates the catalytic core from the membrane surface, sterically excluding Rab1 and permitting Rab11 access, while Trs120 acts as a 'lid' enclosing the active site.\",\n      \"evidence\": \"Cryo-EM structure determination of the 22-subunit yeast TRAPPII complex including a Rab11 exchange intermediate\",\n      \"pmids\": [\"35559680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian TRAPPII structure not yet solved\", \"Dynamic conformational gating during catalysis not captured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Biallelic TRAPPC10 loss-of-function variants were shown to cause microcephalic neurodevelopmental disorder, with loss of TRAPPC10 destabilizing TRAPPC9, disrupting membrane trafficking, and producing microcephaly in knockout mice — establishing TRAPPC10 as a disease gene.\",\n      \"evidence\": \"Patient lymphoblastoid cells, knockout cell lines, Co-IP, trafficking assays, rescue with wild-type vs. mutant constructs, and Trappc10−/− mouse model\",\n      \"pmids\": [\"35298461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific neuronal cell types and developmental stages most affected not determined\", \"Whether trafficking defect or specific Rab dysregulation underlies neuronal pathology unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that TRAPPC6B loss reduces TRAPPC9 and TRAPPC10 protein levels, and that TRAPPC6B co-precipitates preferentially with TRAPPII, further defined TRAPPC10 as specifically enriched in the TRAPPII complex and showed upstream dependencies for its stability.\",\n      \"evidence\": \"Patient fibroblast protein analysis, co-immunoprecipitation, Golgi trafficking rescue assay\",\n      \"pmids\": [\"37713627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TRAPPC6B stabilizes TRAPPII-specific subunits is unclear\", \"Whether TRAPPC6B loss phenocopies TRAPPC10 loss in neurons not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of mammalian TRAPPII, the reconciliation of conflicting Rab18 GEF data, the specific neuronal mechanisms underlying TRAPPC10-associated microcephaly, and whether TRAPPC10 has functions independent of the TRAPPII complex.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mammalian TRAPPII cryo-EM structure\", \"Rab18 vs. Rab11 GEF specificity discrepancy across studies unresolved\", \"Cell-type-specific roles in brain development not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"TRAPPII\"],\n    \"partners\": [\"TRAPPC9\", \"TRAPPC2\", \"TRAPPC2L\", \"TRAPPC6B\", \"RAB11\", \"RAB1\", \"RAB18\"],\n    \"other_free_text\": []\n  }\n}\n```"}