{"gene":"VPS50","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2016,"finding":"VPS-50/mVPS50 is associated with synaptic and dense-core vesicles and controls vesicle acidification, likely through regulation of V-ATPase complex assembly, affecting neuropeptide levels and presynaptic neuronal function.","method":"C. elegans genetics, behavioral assays, subcellular fractionation/localization, murine homolog expression in neurons","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization to vesicles and functional acidification phenotype shown in both nematode and mouse, but V-ATPase assembly link is proposed rather than directly reconstituted","pmids":["26948874"],"is_preprint":false},{"year":2019,"finding":"VPS50 is a subunit of the EARP complex required for recycling of internalized transferrin receptors (TfRs) to the cell surface; a missense mutation p.Gly169Val delays transferrin recycling and alters VPS50 interaction with VPS53, representing a loss-of-function.","method":"In vitro transferrin recycling assay, co-immunoprecipitation (VPS50–VPS53 interaction), zebrafish knockdown rescue experiments, high-throughput sequencing","journal":"Molecular cytogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transferrin recycling assay and Co-IP with VPS53 in a single lab, supported by zebrafish rescue, but single study","pmids":["30828385"],"is_preprint":false},{"year":2021,"finding":"VPS50 is the unique subunit of the EARP heterotetrameric complex (shared subunits VPS51, VPS52, VPS53 with GARP); loss of VPS50 in patient fibroblasts reduces VPS52 and VPS53 protein levels, delays TfR recycling to the plasma membrane, and causes mislocalization of gamma-glutamyltransferase from bile canaliculi to basolateral membranes with abnormal tight junctions in hepatocytes, indicating a role in establishing cell polarity.","method":"Patient-derived fibroblast analysis, Western blot of VPS50/VPS52/VPS53 levels, transferrin receptor recycling assay, light and transmission electron microscopy of liver tissue","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Western blot, TfR recycling assay, electron microscopy) in patient-derived cells, independently corroborated by a second report (PMID:38876772)","pmids":["34037727"],"is_preprint":false},{"year":2024,"finding":"Knockout of VPS50 in mouse cortical neurons causes mislocalization of the V-ATPase V1 domain pump away from synaptic vesicles and impairs synaptic activity without changing synaptic vesicle number; mosaic KO in hippocampus alters synaptic transmission and plasticity and produces cognitive impairments, establishing VPS50 as an accessory factor for V-ATPase V1 recruitment to synaptic vesicles.","method":"CRISPR/Cas9 KO in cultured murine cortical neurons and in vivo hippocampus, immunofluorescence/localization of V-ATPase V1, electrophysiology (synaptic transmission and plasticity), behavioral assays","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with multiple orthogonal readouts (localization, electrophysiology, behavior) in both in vitro and in vivo mammalian systems, peer-reviewed publication confirming preprint findings","pmids":["38926759"],"is_preprint":false},{"year":2024,"finding":"Loss of VPS50 protein (confirmed in patient fibroblasts) leads to significantly reduced VPS53 and absent VPS52 protein levels, demonstrating that VPS50 is required for the stability of other EARP complex subunits.","method":"Western blot of patient-derived fibroblasts with biallelic VPS50 loss-of-function variants (structural variant + nonsense variant), long-read genome sequencing","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein quantification in patient-derived cells, single study, replicates finding from PMID:34037727","pmids":["38876772"],"is_preprint":false},{"year":2019,"finding":"Knockdown of CCDC132 (VPS50) in gastric cancer cells increases phosphorylation of p53 and Chk2 and elevates γ-H2AX, 53BP1, cleaved Caspase 3 and cleaved PARP levels, attenuating proliferation and tumorigenesis by facilitating DNA damage signaling.","method":"Lentiviral shRNA knockdown, PathScan stress/apoptosis signaling arrays, Western blot, xenograft tumor growth assay","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with pathway readout but no direct mechanistic link between VPS50/EARP function and DNA damage signaling established","pmids":["31814760"],"is_preprint":false}],"current_model":"VPS50 is the unique subunit of the EARP heterotetrameric complex (with shared subunits VPS51, VPS52, VPS53) that localizes to recycling endosomes and synaptic/dense-core vesicles, where it is required for endocytic recycling of transferrin receptors to the plasma membrane, stabilization of VPS52 and VPS53, and—by recruiting the V-ATPase V1 domain to synaptic vesicles—for proper vesicle acidification, synaptic neurotransmission, and establishment of hepatocyte cell polarity."},"narrative":{"mechanistic_narrative":"VPS50 is the defining subunit of the endosome-associated recycling protein (EARP) complex, a heterotetramer it forms with the GARP-shared subunits VPS51, VPS52, and VPS53, and it functions in endocytic recycling and vesicle acidification [PMID:34037727]. Within the complex VPS50 is structurally required for partner stability: its loss in patient fibroblasts reduces VPS53 and depletes VPS52 protein levels [PMID:34037727, PMID:38876772]. Functionally, EARP/VPS50 drives recycling of internalized transferrin receptors back to the plasma membrane, and a missense variant (p.Gly169Val) that weakens the VPS50–VPS53 interaction delays this recycling as a loss-of-function [PMID:30828385, PMID:34037727]. In neurons, VPS50 associates with synaptic and dense-core vesicles and acts as an accessory factor recruiting the V-ATPase V1 domain to synaptic vesicles, thereby controlling vesicle acidification, synaptic transmission and plasticity; its loss impairs neurotransmission and produces cognitive deficits without altering vesicle number [PMID:26948874, PMID:38926759]. In epithelial cells VPS50 establishes hepatocyte polarity, with its loss mislocalizing gamma-glutamyltransferase from bile canaliculi to basolateral membranes and disrupting tight junctions [PMID:34037727].","teleology":[{"year":2016,"claim":"Established the first cellular role for VPS50 by linking it to synaptic and dense-core vesicles and to vesicle acidification, framing it as a presynaptic regulator.","evidence":"C. elegans genetics, behavioral assays, subcellular fractionation, and murine homolog expression in neurons","pmids":["26948874"],"confidence":"Medium","gaps":["V-ATPase assembly link proposed, not biochemically reconstituted","molecular mechanism connecting VPS50 to acidification not defined","human/mammalian functional role not yet shown"]},{"year":2019,"claim":"Defined VPS50 as an EARP subunit required for transferrin receptor recycling and showed a disease-associated missense variant impairs recycling by altering the VPS50–VPS53 interaction.","evidence":"In vitro transferrin recycling assay, VPS50–VPS53 co-immunoprecipitation, and zebrafish knockdown-rescue","pmids":["30828385"],"confidence":"Medium","gaps":["single-lab study","full EARP complex composition not resolved here","no structural basis for the VPS50–VPS53 interface"]},{"year":2021,"claim":"Positioned VPS50 as the unique EARP subunit whose loss destabilizes VPS52/VPS53 and showed EARP function extends to establishing epithelial cell polarity in hepatocytes.","evidence":"Patient-derived fibroblast Western blot, TfR recycling assay, and light/electron microscopy of liver tissue","pmids":["34037727"],"confidence":"High","gaps":["mechanism linking endosomal recycling to tight-junction/polarity establishment unresolved","cargo beyond TfR and GGT not mapped"]},{"year":2024,"claim":"Confirmed in an independent patient cohort that VPS50 is required for stability of the other EARP subunits, reducing VPS53 and abolishing VPS52.","evidence":"Western blot of patient fibroblasts with biallelic loss-of-function variants and long-read genome sequencing","pmids":["38876772"],"confidence":"Medium","gaps":["single study replicating prior finding","does not address whether destabilization is transcriptional or post-translational"]},{"year":2024,"claim":"Provided the mechanistic basis for the acidification phenotype by showing VPS50 recruits the V-ATPase V1 domain to synaptic vesicles, linking it to synaptic transmission, plasticity, and cognition.","evidence":"CRISPR/Cas9 KO in cultured cortical neurons and in vivo hippocampus, V-ATPase V1 immunolocalization, electrophysiology, and behavioral assays","pmids":["38926759"],"confidence":"High","gaps":["direct physical interaction between VPS50 and V-ATPase V1 not biochemically demonstrated","how endosomal recycling activity connects to vesicular V1 recruitment unclear"]},{"year":null,"claim":"How EARP/VPS50 recognizes specific cargo and physically couples the V-ATPase V1 domain to vesicle membranes, and whether reported DNA-damage signaling effects reflect a genuine EARP-independent role, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["no reconstituted EARP–V-ATPase interaction","no structural model of the EARP tetramer","cargo-recognition determinants unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,3]}],"complexes":["EARP complex"],"partners":["VPS51","VPS52","VPS53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JG6","full_name":"Syndetin","aliases":["Coiled-coil domain-containing protein 132","EARP/GARPII complex subunit VPS50"],"length_aa":964,"mass_kda":111.2,"function":"Acts as a component of the EARP complex that is involved in endocytic recycling. The EARP complex associates with Rab4-positive endosomes and promotes recycling of internalized transferrin receptor (TFRC) to the plasma membrane. Within the EARP complex, required to tether the complex to recycling endosomes. Not involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN)","subcellular_location":"Recycling endosome; Membrane","url":"https://www.uniprot.org/uniprotkb/Q96JG6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS50","classification":"Not Classified","n_dependent_lines":38,"n_total_lines":1208,"dependency_fraction":0.03145695364238411},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VPS50","total_profiled":1310},"omim":[{"mim_id":"619685","title":"NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SEIZURES, AND NEONATAL CHOLESTASIS; NEDMSC","url":"https://www.omim.org/entry/619685"},{"mim_id":"616465","title":"VPS50, EARP/GARPII COMPLEX SUBUNIT; VPS50","url":"https://www.omim.org/entry/616465"},{"mim_id":"615850","title":"VPS53 SUBUNIT OF GARP COMPLEX; VPS53","url":"https://www.omim.org/entry/615850"},{"mim_id":"615738","title":"VPS51 SUBUNIT OF GARP COMPLEX; VPS51","url":"https://www.omim.org/entry/615738"},{"mim_id":"603443","title":"VPS52 SUBUNIT OF GARP COMPLEX; VPS52","url":"https://www.omim.org/entry/603443"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS50"},"hgnc":{"alias_symbol":["KIAA1861","FLJ20097","DKFZp313I2429","VPS54L"],"prev_symbol":["CCDC132"]},"alphafold":{"accession":"Q96JG6","domains":[{"cath_id":"-","chopping":"215-357_368-434","consensus_level":"medium","plddt":70.593,"start":215,"end":434},{"cath_id":"-","chopping":"468-491_603-687_704-776","consensus_level":"high","plddt":80.8757,"start":468,"end":776},{"cath_id":"-","chopping":"790-902","consensus_level":"medium","plddt":88.095,"start":790,"end":902},{"cath_id":"-","chopping":"913-964","consensus_level":"medium","plddt":77.2502,"start":913,"end":964},{"cath_id":"1.20.5","chopping":"51-61_70-194","consensus_level":"high","plddt":76.6061,"start":51,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JG6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JG6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JG6-F1-predicted_aligned_error_v6.png","plddt_mean":70.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS50","jax_strain_url":"https://www.jax.org/strain/search?query=VPS50"},"sequence":{"accession":"Q96JG6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JG6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JG6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JG6"}},"corpus_meta":[{"pmid":"26948874","id":"PMC_26948874","title":"The Conserved VPS-50 Protein Functions in Dense-Core Vesicle Maturation and Acidification and Controls Animal Behavior.","date":"2016","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/26948874","citation_count":24,"is_preprint":false},{"pmid":"24238327","id":"PMC_24238327","title":"Novel antilisterial bacteriocin licheniocin 50.2 from Bacillus licheniformis VPS50.2 isolated from soil sample.","date":"2013","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24238327","citation_count":20,"is_preprint":false},{"pmid":"26370181","id":"PMC_26370181","title":"Association between CCDC132, FDX1 and TNFSF13 gene polymorphisms and the risk of IgA nephropathy.","date":"2015","source":"Nephrology (Carlton, Vic.)","url":"https://pubmed.ncbi.nlm.nih.gov/26370181","citation_count":17,"is_preprint":false},{"pmid":"30828385","id":"PMC_30828385","title":"The rare mutation in the endosome-associated recycling protein gene VPS50 is associated with human neural tube defects.","date":"2019","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/30828385","citation_count":10,"is_preprint":false},{"pmid":"21472204","id":"PMC_21472204","title":"CCDC132 is highly expressed in atopic dermatitis T cells.","date":"2010","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/21472204","citation_count":10,"is_preprint":false},{"pmid":"34037727","id":"PMC_34037727","title":"Biallelic variants in VPS50 cause a neurodevelopmental disorder with neonatal cholestasis.","date":"2021","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34037727","citation_count":8,"is_preprint":false},{"pmid":"31814760","id":"PMC_31814760","title":"Knockdown Of CCDC132 Attenuates Gastric Cancer Cells Proliferation And Tumorigenesis By Facilitating DNA Damage Signaling.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31814760","citation_count":4,"is_preprint":false},{"pmid":"38926759","id":"PMC_38926759","title":"Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior.","date":"2024","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/38926759","citation_count":2,"is_preprint":false},{"pmid":"38876772","id":"PMC_38876772","title":"Complex structural variation and nonsense variant in trans cause VPS50-related disorder.","date":"2024","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38876772","citation_count":1,"is_preprint":false},{"pmid":"37461727","id":"PMC_37461727","title":"Deletion of VPS50 protein in mice brain impairs synaptic function and behavior.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37461727","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7271,"output_tokens":1649,"usd":0.023274,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8424,"output_tokens":2116,"usd":0.04751,"stage2_stop_reason":"end_turn"},"total_usd":0.070784,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"VPS-50/mVPS50 is associated with synaptic and dense-core vesicles and controls vesicle acidification, likely through regulation of V-ATPase complex assembly, affecting neuropeptide levels and presynaptic neuronal function.\",\n      \"method\": \"C. elegans genetics, behavioral assays, subcellular fractionation/localization, murine homolog expression in neurons\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization to vesicles and functional acidification phenotype shown in both nematode and mouse, but V-ATPase assembly link is proposed rather than directly reconstituted\",\n      \"pmids\": [\"26948874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VPS50 is a subunit of the EARP complex required for recycling of internalized transferrin receptors (TfRs) to the cell surface; a missense mutation p.Gly169Val delays transferrin recycling and alters VPS50 interaction with VPS53, representing a loss-of-function.\",\n      \"method\": \"In vitro transferrin recycling assay, co-immunoprecipitation (VPS50–VPS53 interaction), zebrafish knockdown rescue experiments, high-throughput sequencing\",\n      \"journal\": \"Molecular cytogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transferrin recycling assay and Co-IP with VPS53 in a single lab, supported by zebrafish rescue, but single study\",\n      \"pmids\": [\"30828385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VPS50 is the unique subunit of the EARP heterotetrameric complex (shared subunits VPS51, VPS52, VPS53 with GARP); loss of VPS50 in patient fibroblasts reduces VPS52 and VPS53 protein levels, delays TfR recycling to the plasma membrane, and causes mislocalization of gamma-glutamyltransferase from bile canaliculi to basolateral membranes with abnormal tight junctions in hepatocytes, indicating a role in establishing cell polarity.\",\n      \"method\": \"Patient-derived fibroblast analysis, Western blot of VPS50/VPS52/VPS53 levels, transferrin receptor recycling assay, light and transmission electron microscopy of liver tissue\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Western blot, TfR recycling assay, electron microscopy) in patient-derived cells, independently corroborated by a second report (PMID:38876772)\",\n      \"pmids\": [\"34037727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockout of VPS50 in mouse cortical neurons causes mislocalization of the V-ATPase V1 domain pump away from synaptic vesicles and impairs synaptic activity without changing synaptic vesicle number; mosaic KO in hippocampus alters synaptic transmission and plasticity and produces cognitive impairments, establishing VPS50 as an accessory factor for V-ATPase V1 recruitment to synaptic vesicles.\",\n      \"method\": \"CRISPR/Cas9 KO in cultured murine cortical neurons and in vivo hippocampus, immunofluorescence/localization of V-ATPase V1, electrophysiology (synaptic transmission and plasticity), behavioral assays\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with multiple orthogonal readouts (localization, electrophysiology, behavior) in both in vitro and in vivo mammalian systems, peer-reviewed publication confirming preprint findings\",\n      \"pmids\": [\"38926759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of VPS50 protein (confirmed in patient fibroblasts) leads to significantly reduced VPS53 and absent VPS52 protein levels, demonstrating that VPS50 is required for the stability of other EARP complex subunits.\",\n      \"method\": \"Western blot of patient-derived fibroblasts with biallelic VPS50 loss-of-function variants (structural variant + nonsense variant), long-read genome sequencing\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein quantification in patient-derived cells, single study, replicates finding from PMID:34037727\",\n      \"pmids\": [\"38876772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of CCDC132 (VPS50) in gastric cancer cells increases phosphorylation of p53 and Chk2 and elevates γ-H2AX, 53BP1, cleaved Caspase 3 and cleaved PARP levels, attenuating proliferation and tumorigenesis by facilitating DNA damage signaling.\",\n      \"method\": \"Lentiviral shRNA knockdown, PathScan stress/apoptosis signaling arrays, Western blot, xenograft tumor growth assay\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with pathway readout but no direct mechanistic link between VPS50/EARP function and DNA damage signaling established\",\n      \"pmids\": [\"31814760\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS50 is the unique subunit of the EARP heterotetrameric complex (with shared subunits VPS51, VPS52, VPS53) that localizes to recycling endosomes and synaptic/dense-core vesicles, where it is required for endocytic recycling of transferrin receptors to the plasma membrane, stabilization of VPS52 and VPS53, and—by recruiting the V-ATPase V1 domain to synaptic vesicles—for proper vesicle acidification, synaptic neurotransmission, and establishment of hepatocyte cell polarity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS50 is the defining subunit of the endosome-associated recycling protein (EARP) complex, a heterotetramer it forms with the GARP-shared subunits VPS51, VPS52, and VPS53, and it functions in endocytic recycling and vesicle acidification [#2]. Within the complex VPS50 is structurally required for partner stability: its loss in patient fibroblasts reduces VPS53 and depletes VPS52 protein levels [#2, #4]. Functionally, EARP/VPS50 drives recycling of internalized transferrin receptors back to the plasma membrane, and a missense variant (p.Gly169Val) that weakens the VPS50\\u2013VPS53 interaction delays this recycling as a loss-of-function [#1, #2]. In neurons, VPS50 associates with synaptic and dense-core vesicles and acts as an accessory factor recruiting the V-ATPase V1 domain to synaptic vesicles, thereby controlling vesicle acidification, synaptic transmission and plasticity; its loss impairs neurotransmission and produces cognitive deficits without altering vesicle number [#0, #3]. In epithelial cells VPS50 establishes hepatocyte polarity, with its loss mislocalizing gamma-glutamyltransferase from bile canaliculi to basolateral membranes and disrupting tight junctions [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the first cellular role for VPS50 by linking it to synaptic and dense-core vesicles and to vesicle acidification, framing it as a presynaptic regulator.\",\n      \"evidence\": \"C. elegans genetics, behavioral assays, subcellular fractionation, and murine homolog expression in neurons\",\n      \"pmids\": [\"26948874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"V-ATPase assembly link proposed, not biochemically reconstituted\", \"molecular mechanism connecting VPS50 to acidification not defined\", \"human/mammalian functional role not yet shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined VPS50 as an EARP subunit required for transferrin receptor recycling and showed a disease-associated missense variant impairs recycling by altering the VPS50\\u2013VPS53 interaction.\",\n      \"evidence\": \"In vitro transferrin recycling assay, VPS50\\u2013VPS53 co-immunoprecipitation, and zebrafish knockdown-rescue\",\n      \"pmids\": [\"30828385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single-lab study\", \"full EARP complex composition not resolved here\", \"no structural basis for the VPS50\\u2013VPS53 interface\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned VPS50 as the unique EARP subunit whose loss destabilizes VPS52/VPS53 and showed EARP function extends to establishing epithelial cell polarity in hepatocytes.\",\n      \"evidence\": \"Patient-derived fibroblast Western blot, TfR recycling assay, and light/electron microscopy of liver tissue\",\n      \"pmids\": [\"34037727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism linking endosomal recycling to tight-junction/polarity establishment unresolved\", \"cargo beyond TfR and GGT not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed in an independent patient cohort that VPS50 is required for stability of the other EARP subunits, reducing VPS53 and abolishing VPS52.\",\n      \"evidence\": \"Western blot of patient fibroblasts with biallelic loss-of-function variants and long-read genome sequencing\",\n      \"pmids\": [\"38876772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single study replicating prior finding\", \"does not address whether destabilization is transcriptional or post-translational\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the mechanistic basis for the acidification phenotype by showing VPS50 recruits the V-ATPase V1 domain to synaptic vesicles, linking it to synaptic transmission, plasticity, and cognition.\",\n      \"evidence\": \"CRISPR/Cas9 KO in cultured cortical neurons and in vivo hippocampus, V-ATPase V1 immunolocalization, electrophysiology, and behavioral assays\",\n      \"pmids\": [\"38926759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct physical interaction between VPS50 and V-ATPase V1 not biochemically demonstrated\", \"how endosomal recycling activity connects to vesicular V1 recruitment unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EARP/VPS50 recognizes specific cargo and physically couples the V-ATPase V1 domain to vesicle membranes, and whether reported DNA-damage signaling effects reflect a genuine EARP-independent role, remain unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no reconstituted EARP\\u2013V-ATPase interaction\", \"no structural model of the EARP tetramer\", \"cargo-recognition determinants unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [\"EARP complex\"],\n    \"partners\": [\"VPS51\", \"VPS52\", \"VPS53\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}