{"gene":"VPS13B","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2003,"finding":"COH1/VPS13B encodes a putative transmembrane protein of 4,022 amino acids with homology to Saccharomyces cerevisiae VPS13 protein, suggesting a role in vesicle-mediated sorting and intracellular protein transport; the gene spans 62 exons over ~864 kb on chromosome 8q22 and is widely expressed.","method":"Gene cloning, sequence analysis, homology to yeast VPS13","journal":"American journal of human genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational homology inference only, no direct functional experiment on the protein","pmids":["12730828"],"is_preprint":false},{"year":2011,"finding":"COH1/VPS13B is a peripheral Golgi membrane protein that co-localizes with the cis-Golgi matrix protein GM130; RNAi-mediated depletion causes fragmentation of the Golgi ribbon into ministacks, and fibroblasts from Cohen syndrome patients also display disrupted Golgi organization.","method":"Immunofluorescence co-localization with GM130, RNAi knockdown, cell fractionation, patient fibroblast analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (subcellular fractionation, RNAi phenotype, patient cells), replicated in two cell systems","pmids":["21865173"],"is_preprint":false},{"year":2014,"finding":"COH1/VPS13B associates with the Golgi complex in a manner dependent on the small GTPase RAB6: RAB6A/A' knockdown prevents COH1 Golgi localization, dominant-negative RAB6_T27N increases COH1 solubilization from membranes, and co-IP confirms physical interaction preferentially with constitutively active RAB6_Q72L. COH1 depletion in primary neurons impairs neurite outgrowth.","method":"RNAi knockdown, co-immunoprecipitation, dominant-negative and constitutively active RAB6 mutants, membrane fractionation, primary neuron knockdown assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, multiple RAB6 mutants, fractionation, and neuronal functional readout in one study","pmids":["25492866"],"is_preprint":false},{"year":2024,"finding":"Sec23IP (a protein at ER exit sites, ERES) acts as a VPS13B adaptor that recruits VPS13B to ERES-Golgi interfaces; VPS13B interacts directly with Sec23IP via its VPS13 adaptor binding domain (VAB). Disease-associated missense mutations in the VAB domain impair this interaction. Knockout of VPS13B or Sec23IP blocks formation of tubular ERGIC and delays ER export of procollagen.","method":"Co-immunoprecipitation, direct interaction assay, disease-mutation mutagenesis of VAB domain, VPS13B/Sec23IP knockout, live-cell imaging of ERGIC, procollagen secretion assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding with mutagenesis of disease variants, KO phenotype with multiple orthogonal readouts (ERGIC formation, procollagen trafficking)","pmids":["39352497"],"is_preprint":false},{"year":2024,"finding":"VPS13B localizes at the interface between proximal and distal Golgi subcompartments (cis-trans interface); VPS13B KO cells show delayed Golgi reformation after Brefeldin A treatment. FAM177A1, a Golgi protein, is a functional partner of VPS13B—loss of FAM177A1 phenocopies VPS13B KO in the BFA-reformation assay, and in zebrafish vps13b genetically interacts with fam177a1.","method":"Super-resolution microscopy (localization), Brefeldin A washout assay in KO cells, zebrafish genetic interaction (double mutant)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise localization by super-resolution, functional KO phenotype, genetic epistasis in zebrafish, FAM177A1 phenocopy; peer-reviewed publication","pmids":["39331042"],"is_preprint":false},{"year":2023,"finding":"VPS13B localizes to Golgi-lipid droplet contact sites and promotes formation of these contacts upon oleic acid stimulation; depletion of VPS13B moderately reduces Golgi-lipid droplet contacts and additionally causes Golgi fragmentation.","method":"3D high-resolution microscopy, oleic acid stimulation, VPS13B depletion","journal":"Contact (Thousand Oaks)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, imaging-based localization with depletion phenotype, but functional consequence of these contacts remains uncharacterized","pmids":["38090145"],"is_preprint":false},{"year":2020,"finding":"VPS13B loss-of-function (CRISPR KO in HeLa cells and patient iPSC-derived neurons) leads to accumulation of autophagic vacuoles and significantly increased autophagic flux; transcriptomic analysis shows upregulation of ATG4C and dysregulation of autophagosome organization genes.","method":"CRISPR/Cas9 KO, autophagic flux assays, iPSC-derived neuron differentiation, RNA sequencing","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with patient iPSC-derived neurons and orthogonal transcriptomic validation, single lab","pmids":["32375900"],"is_preprint":false},{"year":2025,"finding":"VPS13B localizes to Mitofusin 2-positive mitochondria via its C-terminal region and recruits phosphatidylinositol-4-phosphate (PI4P)-rich Golgi vesicles to mitochondrial fission sites. Loss of VPS13B causes elongated, fused mitochondria with reduced membrane potential and impaired mitophagy; depletion of PI4P likewise blocks fission despite normal DRP1 recruitment, indicating that lipid transfer by VPS13B is required for membrane fission.","method":"Live-cell imaging, subcellular fractionation, PI4P depletion, DRP1 recruitment assay, patient iPSC-derived neuron analysis, mitochondrial membrane potential and mitophagy assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, PI4P depletion epistasis, DRP1 assay, patient neurons), mechanistic chain from lipid transfer to fission established","pmids":["41402289"],"is_preprint":false},{"year":2026,"finding":"VPS13B KO causes aberrant lysosomal distribution, reduction in LAMP1-positive lysosomes, downregulation of lysosome-related genes (acidification and biogenesis), and loss of LysoTracker-positive acidic compartments. Mechanistically, VPS13B KO alters TFEB mRNA levels and blunts TFEB nuclear translocation upon Torin1 treatment. Patient iPSC-derived induced neurons recapitulate loss of acidic lysosomal compartments.","method":"VPS13B KO HeLa cells, bulk RNA sequencing, qRT-PCR, LysoTracker assay, TFEB nuclear/cytoplasmic ratio imaging, patient iPSC-derived neuron differentiation","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with multiple orthogonal readouts and patient iPSC neurons, single lab, TFEB mechanistic link supported by transcriptional and localization data","pmids":["42104376"],"is_preprint":false},{"year":2026,"finding":"Loss of VPS13B in human gingival epithelial cells causes decreased cell-surface localization of CXADR (coxsackievirus and adenovirus receptor) with accumulation in lysosomes (shown by bafilomycin A1 treatment), resulting in increased epithelial permeability to LPS and PGN; rescue by CXADR-JAM1c-term chimera restores barrier function, indicating VPS13B regulates intracellular trafficking of CXADR to the plasma membrane.","method":"VPS13B KO cells, surface biotinylation/localization assay, bafilomycin A1 lysosomal block, CXADR-JAM1 chimera rescue, epithelial permeability assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with mechanistic rescue experiment and multiple readouts, single lab","pmids":["41730960"],"is_preprint":false},{"year":2020,"finding":"A VPS13B missense variant (p.Arg237Pro) shows diminished localization at the Golgi complex compared to wild-type, supporting loss of Golgi-targeting as a pathomechanism for missense mutations.","method":"Functional characterization of missense variant by immunofluorescence Golgi localization assay","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single assay (localization), single variant, but directly links disease mutation to Golgi-targeting mechanism established by prior work","pmids":["39723426"],"is_preprint":false},{"year":2025,"finding":"VPS13B KO in human pluripotent stem cell-derived cortical organoids results in reduced C18-N-acyl sphingolipids; treatment with cationic amphiphilic drugs (CADs) that cause lipid accumulation in acidic organelles restores Golgi morphology and sphingolipid levels, and partially rescues neurite outgrowth in CS organoids, linking VPS13B to lysosome-dependent sphingolipid regulation.","method":"VPS13B KO iPSC-derived cortical organoids, lipidomics, high-throughput microscopy-based Golgi morphology screen, pharmacological rescue (azelastine, raloxifene)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lipidomics + organoid rescue with two compounds, preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.09.04.674037"],"is_preprint":true},{"year":2020,"finding":"In a Vps13b exon 3 knockout mouse, cataracts develop with large vacuoles in the cortical lens area, epithelial-mesenchymal transition, and fibrosis, demonstrating that VPS13B is required for lens homeostasis.","method":"Vps13b knockout mouse (Vps13b∆Ex3/∆Ex3), histology, immunohistochemistry, western blot, slit-lamp examination","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with histological and molecular phenotyping, single lab","pmids":["32915983"],"is_preprint":false},{"year":2023,"finding":"Vps13b knockout mice show microcephaly, growth delay, hypotonia, impaired spatial memory, and enhanced sociability; neuroanatomical analysis reveals dentate gyrus size reduction and thinning of motor cortex layer VI; increased neuronal death occurs in infantile stages without progression in adulthood, suggesting VPS13B promotes neuronal survival early in life. Females are less severely affected than males.","method":"Vps13b KO mouse, 2D/3D brain histomorphology, behavioral tests (Morris water maze, open field, rotarod), immunohistochemistry for apoptosis markers","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comprehensive KO mouse phenotyping with multiple orthogonal methods, single lab","pmids":["37573958"],"is_preprint":false},{"year":2019,"finding":"Vps13b exon 2 deletion mutant mice show motor deficits (reduced open-field activity, shorter rotarod latency) and deficits in spatial learning (Morris water maze), recapitulating intellectual disability and hypotonia features of Cohen syndrome.","method":"Vps13b exon 2 deletion mouse, open field test, rotarod, Morris water maze, anxiety and social behavior tests","journal":"Experimental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined KO mouse with specific behavioral readouts, single lab","pmids":["31495077"],"is_preprint":false}],"current_model":"VPS13B/COH1 is a large peripheral membrane protein of the BLTP/VPS13 bridge-like lipid transfer family that localizes to the cis-trans Golgi interface where it is recruited by Sec23IP (via its VAB domain) to ER exit site-Golgi interfaces and by RAB6 (as a RAB6 effector); it promotes Golgi ribbon integrity, tubular ERGIC formation, and ER-to-Golgi cargo export (including procollagen), and additionally transfers PI4P-rich Golgi-derived lipid vesicles to mitochondrial fission sites (via its C-terminal mitofusin-2-binding region) to enable membrane fission and mitochondrial quality control; VPS13B also regulates intracellular trafficking of CXADR to the plasma membrane, lysosomal homeostasis through TFEB, and autophagy flux, with loss-of-function causing Golgi fragmentation, impaired mitochondrial fission, lysosomal dysfunction, and—in neurons—reduced neurite outgrowth, collectively underlying the multisystem features of Cohen syndrome."},"narrative":{"mechanistic_narrative":"VPS13B/COH1 is a large peripheral membrane protein that operates at organelle membrane interfaces to maintain Golgi architecture and secretory trafficking, with loss of function underlying the multisystem features of Cohen syndrome [PMID:21865173, PMID:39352497]. It is a peripheral Golgi membrane protein that co-localizes with the cis-Golgi matrix protein GM130 and concentrates at the interface between proximal and distal Golgi subcompartments; its depletion fragments the Golgi ribbon into ministacks and delays Golgi reformation, a phenotype shared with its functional partner FAM177A1 [PMID:21865173, PMID:39331042]. Golgi recruitment is governed by two membrane determinants: the small GTPase RAB6, which binds VPS13B preferentially in its active form and is required for membrane association, and the ER-exit-site protein Sec23IP, which binds the VPS13B VAB domain to position the protein at ERES-Golgi interfaces where it drives tubular ERGIC formation and ER export of procollagen [PMID:25492866, PMID:39352497]. Beyond the Golgi, VPS13B localizes via its C-terminal Mitofusin-2-binding region to mitochondria, where it delivers PI4P-rich Golgi-derived vesicles to fission sites; this lipid transfer is required for membrane scission downstream of DRP1 recruitment, and its loss yields elongated, fused mitochondria with impaired mitophagy [PMID:41402289]. VPS13B additionally supports lysosomal homeostasis and TFEB-dependent lysosomal gene expression, regulates autophagic flux, and directs trafficking of the surface receptor CXADR to the plasma membrane to maintain epithelial barrier integrity [PMID:32375900, PMID:42104376, PMID:41730960]. Disease-associated missense variants act by disrupting Golgi targeting or the Sec23IP interaction [PMID:39352497, PMID:39723426], and Vps13b-null mice recapitulate Cohen syndrome features including microcephaly, behavioral and motor deficits, and cataracts [PMID:32915983, PMID:37573958].","teleology":[{"year":2003,"claim":"Established the existence and broad expression of COH1/VPS13B and, by homology to yeast VPS13, first implicated it in vesicle-mediated sorting and intracellular protein transport.","evidence":"Gene cloning and sequence/homology analysis","pmids":["12730828"],"confidence":"Low","gaps":["Computational homology only, no direct functional assay on the protein","No subcellular localization demonstrated","No interacting partners identified"]},{"year":2011,"claim":"Resolved where VPS13B acts by showing it is a peripheral Golgi membrane protein whose loss fragments the Golgi ribbon, directly linking it to Golgi structural integrity and to Cohen syndrome patient cell phenotypes.","evidence":"Immunofluorescence co-localization with GM130, RNAi, cell fractionation, patient fibroblasts","pmids":["21865173"],"confidence":"High","gaps":["Mechanism of Golgi recruitment unknown","No molecular partners identified","Functional consequence beyond morphology not addressed"]},{"year":2014,"claim":"Identified the first recruitment determinant by demonstrating RAB6-dependent Golgi association and a physical interaction preferential for active RAB6, and tied VPS13B loss to a neuronal phenotype (impaired neurite outgrowth).","evidence":"Co-IP with RAB6 mutants, dominant-negative/constitutively-active RAB6, membrane fractionation, primary neuron knockdown","pmids":["25492866"],"confidence":"High","gaps":["Whether RAB6 is the sole recruitment factor unknown","Molecular activity of VPS13B not defined","Link between Golgi role and neurite outgrowth mechanistically unresolved"]},{"year":2024,"claim":"Defined a second recruitment mechanism and a secretory function: Sec23IP binds the VAB domain to position VPS13B at ERES-Golgi interfaces enabling tubular ERGIC formation and procollagen export, and disease VAB mutations disrupt this binding.","evidence":"Co-IP, direct interaction assay, disease-variant VAB mutagenesis, VPS13B/Sec23IP KO, live ERGIC imaging, procollagen secretion","pmids":["39352497"],"confidence":"High","gaps":["How RAB6 and Sec23IP recruitment are coordinated unknown","Direct lipid transfer at ERES-Golgi not shown","Cargo selectivity beyond procollagen unclear"]},{"year":2024,"claim":"Pinpointed VPS13B to the cis-trans Golgi interface and identified FAM177A1 as a functional partner via phenocopy and zebrafish genetic interaction, extending the Golgi-integrity role to an in-vivo context.","evidence":"Super-resolution microscopy, Brefeldin A washout in KO cells, zebrafish double-mutant genetic interaction","pmids":["39331042"],"confidence":"High","gaps":["Biochemical nature of FAM177A1-VPS13B relationship unknown","Whether FAM177A1 affects recruitment or function not distinguished"]},{"year":2023,"claim":"Extended VPS13B's contact-site repertoire to Golgi-lipid droplet contacts that increase upon oleic acid stimulation, consistent with a lipid-transfer/contact role.","evidence":"3D high-resolution microscopy, oleic acid stimulation, depletion","pmids":["38090145"],"confidence":"Medium","gaps":["Functional consequence of Golgi-LD contacts uncharacterized","Single lab, imaging-based","No lipid flux measured at these contacts"]},{"year":2025,"claim":"Established a direct lipid-transfer mechanism at mitochondria: VPS13B delivers PI4P-rich Golgi vesicles to fission sites via its C-terminal MFN2-binding region, and this lipid transfer is required for membrane scission downstream of DRP1, linking VPS13B to mitochondrial quality control.","evidence":"Live imaging, fractionation, PI4P depletion epistasis, DRP1 recruitment assay, patient iPSC neurons, membrane potential/mitophagy assays","pmids":["41402289"],"confidence":"High","gaps":["Direct demonstration of VPS13B lipid-channel transfer activity in vitro not shown","How Golgi and mitochondrial pools are partitioned unknown"]},{"year":2020,"claim":"Connected VPS13B loss to autophagy dysregulation, showing increased autophagic flux and accumulation of autophagic vacuoles in KO cells and patient neurons.","evidence":"CRISPR KO, autophagic flux assays, iPSC-derived neurons, RNA-seq","pmids":["32375900"],"confidence":"Medium","gaps":["Whether autophagy change is primary or secondary to organelle defects unknown","Direct VPS13B role in autophagosome biology not established"]},{"year":2020,"claim":"Provided functional validation of a disease pathomechanism by showing the p.Arg237Pro missense variant fails to localize to the Golgi.","evidence":"Immunofluorescence Golgi localization of missense variant","pmids":["39723426"],"confidence":"Medium","gaps":["Single variant, single assay","Structural basis of mislocalization not defined"]},{"year":2026,"claim":"Linked VPS13B to lysosomal homeostasis through TFEB, showing KO reduces acidic lysosomal compartments and blunts TFEB nuclear translocation, with recapitulation in patient neurons.","evidence":"KO HeLa, RNA-seq, qRT-PCR, LysoTracker, TFEB nuclear/cytoplasmic imaging, patient iPSC neurons","pmids":["42104376"],"confidence":"Medium","gaps":["Mechanism by which VPS13B influences TFEB unknown","Single lab","Direct vs indirect effect on lysosome biogenesis unresolved"]},{"year":2026,"claim":"Identified a surface-receptor trafficking role: VPS13B directs CXADR to the plasma membrane, and its loss diverts CXADR to lysosomes and compromises epithelial barrier function.","evidence":"KO cells, surface localization assay, bafilomycin A1, CXADR-JAM1 chimera rescue, permeability assay","pmids":["41730960"],"confidence":"Medium","gaps":["Whether CXADR trafficking defect is direct or downstream of Golgi/lysosome dysfunction unknown","Single lab","Generality across other surface cargo untested"]},{"year":2025,"claim":"Connected VPS13B to lysosome-dependent sphingolipid regulation, showing KO organoids have reduced C18 sphingolipids and that cationic amphiphilic drugs rescue Golgi morphology and partially restore neurite outgrowth.","evidence":"KO iPSC cortical organoids, lipidomics, Golgi morphology screen, pharmacological rescue (preprint)","pmids":["bio_10.1101_2025.09.04.674037"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Causal chain from sphingolipid loss to Golgi/neurite phenotype not fully established"]},{"year":2020,"claim":"Demonstrated an in-vivo requirement for VPS13B in lens homeostasis, with KO mice developing cataracts, vacuoles, EMT and fibrosis.","evidence":"Vps13b exon 3 KO mouse, histology, IHC, western blot, slit-lamp","pmids":["32915983"],"confidence":"Medium","gaps":["Cellular mechanism linking VPS13B loss to lens pathology unknown","Single lab"]},{"year":2023,"claim":"Defined the neurodevelopmental consequences of VPS13B loss in mice—microcephaly, growth delay, behavioral and memory deficits, and early-life neuronal death—supporting a role in neuronal survival.","evidence":"Vps13b KO mouse, brain histomorphology, behavioral battery, apoptosis IHC","pmids":["37573958","31495077"],"confidence":"Medium","gaps":["Mechanistic link from organelle defects to neuronal death not resolved","Sex-difference basis unknown"]},{"year":null,"claim":"How VPS13B's multiple recruitment cues (RAB6, Sec23IP, MFN2) and its proposed bridge-like lipid transfer activity are integrated to coordinate Golgi integrity, ER export, mitochondrial fission, and lysosomal/autophagy homeostasis remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vitro reconstitution of VPS13B lipid transfer activity","No structural model of full-length VPS13B at a membrane contact","Hierarchy/coordination among RAB6, Sec23IP and MFN2 recruitment undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[5]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[8,9]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[9]}],"complexes":[],"partners":["RAB6","SEC23IP","FAM177A1","MFN2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z7G8","full_name":"Intermembrane lipid transfer protein VPS13B","aliases":["Cohen syndrome protein 1","Vacuolar protein sorting-associated protein 13B"],"length_aa":4022,"mass_kda":448.7,"function":"Mediates the transfer of lipids between membranes at organelle contact sites (By similarity). Binds phosphatidylinositol 3-phosphate (By similarity). Functions as a tethering factor in the slow endocytic recycling pathway, to assist traffic between early and recycling endosomes (PubMed:24334764, PubMed:30962439, PubMed:32375900). Involved in the transport of proacrosomal vesicles to the nuclear dense lamina (NDL) during spermatid development (By similarity). Plays a role in the assembly of the Golgi apparatus, possibly by mediating trafficking to the Golgi membrane (PubMed:21865173). Plays a role in the development of the nervous system, and may be required for neuron projection development (PubMed:25492866, PubMed:32560273). May also play a role during adipose tissue development (PubMed:26358774). Required for maintenance of the ocular lens (By similarity)","subcellular_location":"Recycling endosome membrane; Cytoplasmic vesicle, secretory vesicle, acrosome membrane; Golgi apparatus, cis-Golgi network membrane; Endoplasmic reticulum-Golgi intermediate compartment membrane; Golgi apparatus, trans-Golgi network membrane; Early endosome membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q7Z7G8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS13B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VPS13B","total_profiled":1310},"omim":[{"mim_id":"619181","title":"FAMILY WITH SEQUENCE SIMILARITY 177, MEMBER A1; FAM177A1","url":"https://www.omim.org/entry/619181"},{"mim_id":"618921","title":"LACTAMASE, BETA-2; LACTB2","url":"https://www.omim.org/entry/618921"},{"mim_id":"607817","title":"VACUOLAR PROTEIN SORTING 13 HOMOLOG B; VPS13B","url":"https://www.omim.org/entry/607817"},{"mim_id":"601993","title":"NUCLEAR RECEPTOR COACTIVATOR 2; NCOA2","url":"https://www.omim.org/entry/601993"},{"mim_id":"216550","title":"COHEN SYNDROME; COH1","url":"https://www.omim.org/entry/216550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS13B"},"hgnc":{"alias_symbol":["BLTP5B"],"prev_symbol":["CHS1","COH1"]},"alphafold":{"accession":"Q7Z7G8","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z7G8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z7G8-5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z7G8-5-F1-predicted_aligned_error_v6.png","plddt_mean":71.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS13B","jax_strain_url":"https://www.jax.org/strain/search?query=VPS13B"},"sequence":{"accession":"Q7Z7G8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z7G8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z7G8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z7G8"}},"corpus_meta":[{"pmid":"12730828","id":"PMC_12730828","title":"Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12730828","citation_count":273,"is_preprint":false},{"pmid":"21865173","id":"PMC_21865173","title":"Cohen syndrome-associated protein, COH1, is a novel, giant Golgi matrix protein required for Golgi integrity.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21865173","citation_count":117,"is_preprint":false},{"pmid":"19401597","id":"PMC_19401597","title":"Surfome analysis as a fast track to vaccine discovery: identification of a novel protective antigen for Group B Streptococcus hypervirulent strain COH1.","date":"2009","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/19401597","citation_count":82,"is_preprint":false},{"pmid":"25492866","id":"PMC_25492866","title":"Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25492866","citation_count":76,"is_preprint":false},{"pmid":"15154116","id":"PMC_15154116","title":"Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome.","date":"2004","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15154116","citation_count":63,"is_preprint":false},{"pmid":"33547071","id":"PMC_33547071","title":"A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33547071","citation_count":53,"is_preprint":false},{"pmid":"16648375","id":"PMC_16648375","title":"Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome.","date":"2006","source":"Journal 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cloning, sequence analysis, homology to yeast VPS13\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational homology inference only, no direct functional experiment on the protein\",\n      \"pmids\": [\"12730828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"COH1/VPS13B is a peripheral Golgi membrane protein that co-localizes with the cis-Golgi matrix protein GM130; RNAi-mediated depletion causes fragmentation of the Golgi ribbon into ministacks, and fibroblasts from Cohen syndrome patients also display disrupted Golgi organization.\",\n      \"method\": \"Immunofluorescence co-localization with GM130, RNAi knockdown, cell fractionation, patient fibroblast analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (subcellular fractionation, RNAi phenotype, patient cells), replicated in two cell systems\",\n      \"pmids\": [\"21865173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COH1/VPS13B associates with the Golgi complex in a manner dependent on the small GTPase RAB6: RAB6A/A' knockdown prevents COH1 Golgi localization, dominant-negative RAB6_T27N increases COH1 solubilization from membranes, and co-IP confirms physical interaction preferentially with constitutively active RAB6_Q72L. COH1 depletion in primary neurons impairs neurite outgrowth.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, dominant-negative and constitutively active RAB6 mutants, membrane fractionation, primary neuron knockdown assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, multiple RAB6 mutants, fractionation, and neuronal functional readout in one study\",\n      \"pmids\": [\"25492866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sec23IP (a protein at ER exit sites, ERES) acts as a VPS13B adaptor that recruits VPS13B to ERES-Golgi interfaces; VPS13B interacts directly with Sec23IP via its VPS13 adaptor binding domain (VAB). Disease-associated missense mutations in the VAB domain impair this interaction. Knockout of VPS13B or Sec23IP blocks formation of tubular ERGIC and delays ER export of procollagen.\",\n      \"method\": \"Co-immunoprecipitation, direct interaction assay, disease-mutation mutagenesis of VAB domain, VPS13B/Sec23IP knockout, live-cell imaging of ERGIC, procollagen secretion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding with mutagenesis of disease variants, KO phenotype with multiple orthogonal readouts (ERGIC formation, procollagen trafficking)\",\n      \"pmids\": [\"39352497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VPS13B localizes at the interface between proximal and distal Golgi subcompartments (cis-trans interface); VPS13B KO cells show delayed Golgi reformation after Brefeldin A treatment. FAM177A1, a Golgi protein, is a functional partner of VPS13B—loss of FAM177A1 phenocopies VPS13B KO in the BFA-reformation assay, and in zebrafish vps13b genetically interacts with fam177a1.\",\n      \"method\": \"Super-resolution microscopy (localization), Brefeldin A washout assay in KO cells, zebrafish genetic interaction (double mutant)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise localization by super-resolution, functional KO phenotype, genetic epistasis in zebrafish, FAM177A1 phenocopy; peer-reviewed publication\",\n      \"pmids\": [\"39331042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VPS13B localizes to Golgi-lipid droplet contact sites and promotes formation of these contacts upon oleic acid stimulation; depletion of VPS13B moderately reduces Golgi-lipid droplet contacts and additionally causes Golgi fragmentation.\",\n      \"method\": \"3D high-resolution microscopy, oleic acid stimulation, VPS13B depletion\",\n      \"journal\": \"Contact (Thousand Oaks)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, imaging-based localization with depletion phenotype, but functional consequence of these contacts remains uncharacterized\",\n      \"pmids\": [\"38090145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VPS13B loss-of-function (CRISPR KO in HeLa cells and patient iPSC-derived neurons) leads to accumulation of autophagic vacuoles and significantly increased autophagic flux; transcriptomic analysis shows upregulation of ATG4C and dysregulation of autophagosome organization genes.\",\n      \"method\": \"CRISPR/Cas9 KO, autophagic flux assays, iPSC-derived neuron differentiation, RNA sequencing\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with patient iPSC-derived neurons and orthogonal transcriptomic validation, single lab\",\n      \"pmids\": [\"32375900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS13B localizes to Mitofusin 2-positive mitochondria via its C-terminal region and recruits phosphatidylinositol-4-phosphate (PI4P)-rich Golgi vesicles to mitochondrial fission sites. Loss of VPS13B causes elongated, fused mitochondria with reduced membrane potential and impaired mitophagy; depletion of PI4P likewise blocks fission despite normal DRP1 recruitment, indicating that lipid transfer by VPS13B is required for membrane fission.\",\n      \"method\": \"Live-cell imaging, subcellular fractionation, PI4P depletion, DRP1 recruitment assay, patient iPSC-derived neuron analysis, mitochondrial membrane potential and mitophagy assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, PI4P depletion epistasis, DRP1 assay, patient neurons), mechanistic chain from lipid transfer to fission established\",\n      \"pmids\": [\"41402289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"VPS13B KO causes aberrant lysosomal distribution, reduction in LAMP1-positive lysosomes, downregulation of lysosome-related genes (acidification and biogenesis), and loss of LysoTracker-positive acidic compartments. Mechanistically, VPS13B KO alters TFEB mRNA levels and blunts TFEB nuclear translocation upon Torin1 treatment. Patient iPSC-derived induced neurons recapitulate loss of acidic lysosomal compartments.\",\n      \"method\": \"VPS13B KO HeLa cells, bulk RNA sequencing, qRT-PCR, LysoTracker assay, TFEB nuclear/cytoplasmic ratio imaging, patient iPSC-derived neuron differentiation\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with multiple orthogonal readouts and patient iPSC neurons, single lab, TFEB mechanistic link supported by transcriptional and localization data\",\n      \"pmids\": [\"42104376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of VPS13B in human gingival epithelial cells causes decreased cell-surface localization of CXADR (coxsackievirus and adenovirus receptor) with accumulation in lysosomes (shown by bafilomycin A1 treatment), resulting in increased epithelial permeability to LPS and PGN; rescue by CXADR-JAM1c-term chimera restores barrier function, indicating VPS13B regulates intracellular trafficking of CXADR to the plasma membrane.\",\n      \"method\": \"VPS13B KO cells, surface biotinylation/localization assay, bafilomycin A1 lysosomal block, CXADR-JAM1 chimera rescue, epithelial permeability assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with mechanistic rescue experiment and multiple readouts, single lab\",\n      \"pmids\": [\"41730960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A VPS13B missense variant (p.Arg237Pro) shows diminished localization at the Golgi complex compared to wild-type, supporting loss of Golgi-targeting as a pathomechanism for missense mutations.\",\n      \"method\": \"Functional characterization of missense variant by immunofluorescence Golgi localization assay\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single assay (localization), single variant, but directly links disease mutation to Golgi-targeting mechanism established by prior work\",\n      \"pmids\": [\"39723426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS13B KO in human pluripotent stem cell-derived cortical organoids results in reduced C18-N-acyl sphingolipids; treatment with cationic amphiphilic drugs (CADs) that cause lipid accumulation in acidic organelles restores Golgi morphology and sphingolipid levels, and partially rescues neurite outgrowth in CS organoids, linking VPS13B to lysosome-dependent sphingolipid regulation.\",\n      \"method\": \"VPS13B KO iPSC-derived cortical organoids, lipidomics, high-throughput microscopy-based Golgi morphology screen, pharmacological rescue (azelastine, raloxifene)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lipidomics + organoid rescue with two compounds, preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.04.674037\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In a Vps13b exon 3 knockout mouse, cataracts develop with large vacuoles in the cortical lens area, epithelial-mesenchymal transition, and fibrosis, demonstrating that VPS13B is required for lens homeostasis.\",\n      \"method\": \"Vps13b knockout mouse (Vps13b∆Ex3/∆Ex3), histology, immunohistochemistry, western blot, slit-lamp examination\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with histological and molecular phenotyping, single lab\",\n      \"pmids\": [\"32915983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Vps13b knockout mice show microcephaly, growth delay, hypotonia, impaired spatial memory, and enhanced sociability; neuroanatomical analysis reveals dentate gyrus size reduction and thinning of motor cortex layer VI; increased neuronal death occurs in infantile stages without progression in adulthood, suggesting VPS13B promotes neuronal survival early in life. Females are less severely affected than males.\",\n      \"method\": \"Vps13b KO mouse, 2D/3D brain histomorphology, behavioral tests (Morris water maze, open field, rotarod), immunohistochemistry for apoptosis markers\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive KO mouse phenotyping with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37573958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Vps13b exon 2 deletion mutant mice show motor deficits (reduced open-field activity, shorter rotarod latency) and deficits in spatial learning (Morris water maze), recapitulating intellectual disability and hypotonia features of Cohen syndrome.\",\n      \"method\": \"Vps13b exon 2 deletion mouse, open field test, rotarod, Morris water maze, anxiety and social behavior tests\",\n      \"journal\": \"Experimental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined KO mouse with specific behavioral readouts, single lab\",\n      \"pmids\": [\"31495077\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS13B/COH1 is a large peripheral membrane protein of the BLTP/VPS13 bridge-like lipid transfer family that localizes to the cis-trans Golgi interface where it is recruited by Sec23IP (via its VAB domain) to ER exit site-Golgi interfaces and by RAB6 (as a RAB6 effector); it promotes Golgi ribbon integrity, tubular ERGIC formation, and ER-to-Golgi cargo export (including procollagen), and additionally transfers PI4P-rich Golgi-derived lipid vesicles to mitochondrial fission sites (via its C-terminal mitofusin-2-binding region) to enable membrane fission and mitochondrial quality control; VPS13B also regulates intracellular trafficking of CXADR to the plasma membrane, lysosomal homeostasis through TFEB, and autophagy flux, with loss-of-function causing Golgi fragmentation, impaired mitochondrial fission, lysosomal dysfunction, and—in neurons—reduced neurite outgrowth, collectively underlying the multisystem features of Cohen syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS13B/COH1 is a large peripheral membrane protein that operates at organelle membrane interfaces to maintain Golgi architecture and secretory trafficking, with loss of function underlying the multisystem features of Cohen syndrome [#1, #3]. It is a peripheral Golgi membrane protein that co-localizes with the cis-Golgi matrix protein GM130 and concentrates at the interface between proximal and distal Golgi subcompartments; its depletion fragments the Golgi ribbon into ministacks and delays Golgi reformation, a phenotype shared with its functional partner FAM177A1 [#1, #4]. Golgi recruitment is governed by two membrane determinants: the small GTPase RAB6, which binds VPS13B preferentially in its active form and is required for membrane association, and the ER-exit-site protein Sec23IP, which binds the VPS13B VAB domain to position the protein at ERES-Golgi interfaces where it drives tubular ERGIC formation and ER export of procollagen [#2, #3]. Beyond the Golgi, VPS13B localizes via its C-terminal Mitofusin-2-binding region to mitochondria, where it delivers PI4P-rich Golgi-derived vesicles to fission sites; this lipid transfer is required for membrane scission downstream of DRP1 recruitment, and its loss yields elongated, fused mitochondria with impaired mitophagy [#7]. VPS13B additionally supports lysosomal homeostasis and TFEB-dependent lysosomal gene expression, regulates autophagic flux, and directs trafficking of the surface receptor CXADR to the plasma membrane to maintain epithelial barrier integrity [#6, #8, #9]. Disease-associated missense variants act by disrupting Golgi targeting or the Sec23IP interaction [#3, #10], and Vps13b-null mice recapitulate Cohen syndrome features including microcephaly, behavioral and motor deficits, and cataracts [#12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the existence and broad expression of COH1/VPS13B and, by homology to yeast VPS13, first implicated it in vesicle-mediated sorting and intracellular protein transport.\",\n      \"evidence\": \"Gene cloning and sequence/homology analysis\",\n      \"pmids\": [\"12730828\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational homology only, no direct functional assay on the protein\", \"No subcellular localization demonstrated\", \"No interacting partners identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved where VPS13B acts by showing it is a peripheral Golgi membrane protein whose loss fragments the Golgi ribbon, directly linking it to Golgi structural integrity and to Cohen syndrome patient cell phenotypes.\",\n      \"evidence\": \"Immunofluorescence co-localization with GM130, RNAi, cell fractionation, patient fibroblasts\",\n      \"pmids\": [\"21865173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Golgi recruitment unknown\", \"No molecular partners identified\", \"Functional consequence beyond morphology not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the first recruitment determinant by demonstrating RAB6-dependent Golgi association and a physical interaction preferential for active RAB6, and tied VPS13B loss to a neuronal phenotype (impaired neurite outgrowth).\",\n      \"evidence\": \"Co-IP with RAB6 mutants, dominant-negative/constitutively-active RAB6, membrane fractionation, primary neuron knockdown\",\n      \"pmids\": [\"25492866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAB6 is the sole recruitment factor unknown\", \"Molecular activity of VPS13B not defined\", \"Link between Golgi role and neurite outgrowth mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a second recruitment mechanism and a secretory function: Sec23IP binds the VAB domain to position VPS13B at ERES-Golgi interfaces enabling tubular ERGIC formation and procollagen export, and disease VAB mutations disrupt this binding.\",\n      \"evidence\": \"Co-IP, direct interaction assay, disease-variant VAB mutagenesis, VPS13B/Sec23IP KO, live ERGIC imaging, procollagen secretion\",\n      \"pmids\": [\"39352497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB6 and Sec23IP recruitment are coordinated unknown\", \"Direct lipid transfer at ERES-Golgi not shown\", \"Cargo selectivity beyond procollagen unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pinpointed VPS13B to the cis-trans Golgi interface and identified FAM177A1 as a functional partner via phenocopy and zebrafish genetic interaction, extending the Golgi-integrity role to an in-vivo context.\",\n      \"evidence\": \"Super-resolution microscopy, Brefeldin A washout in KO cells, zebrafish double-mutant genetic interaction\",\n      \"pmids\": [\"39331042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical nature of FAM177A1-VPS13B relationship unknown\", \"Whether FAM177A1 affects recruitment or function not distinguished\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended VPS13B's contact-site repertoire to Golgi-lipid droplet contacts that increase upon oleic acid stimulation, consistent with a lipid-transfer/contact role.\",\n      \"evidence\": \"3D high-resolution microscopy, oleic acid stimulation, depletion\",\n      \"pmids\": [\"38090145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Golgi-LD contacts uncharacterized\", \"Single lab, imaging-based\", \"No lipid flux measured at these contacts\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a direct lipid-transfer mechanism at mitochondria: VPS13B delivers PI4P-rich Golgi vesicles to fission sites via its C-terminal MFN2-binding region, and this lipid transfer is required for membrane scission downstream of DRP1, linking VPS13B to mitochondrial quality control.\",\n      \"evidence\": \"Live imaging, fractionation, PI4P depletion epistasis, DRP1 recruitment assay, patient iPSC neurons, membrane potential/mitophagy assays\",\n      \"pmids\": [\"41402289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of VPS13B lipid-channel transfer activity in vitro not shown\", \"How Golgi and mitochondrial pools are partitioned unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected VPS13B loss to autophagy dysregulation, showing increased autophagic flux and accumulation of autophagic vacuoles in KO cells and patient neurons.\",\n      \"evidence\": \"CRISPR KO, autophagic flux assays, iPSC-derived neurons, RNA-seq\",\n      \"pmids\": [\"32375900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether autophagy change is primary or secondary to organelle defects unknown\", \"Direct VPS13B role in autophagosome biology not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided functional validation of a disease pathomechanism by showing the p.Arg237Pro missense variant fails to localize to the Golgi.\",\n      \"evidence\": \"Immunofluorescence Golgi localization of missense variant\",\n      \"pmids\": [\"39723426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single variant, single assay\", \"Structural basis of mislocalization not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked VPS13B to lysosomal homeostasis through TFEB, showing KO reduces acidic lysosomal compartments and blunts TFEB nuclear translocation, with recapitulation in patient neurons.\",\n      \"evidence\": \"KO HeLa, RNA-seq, qRT-PCR, LysoTracker, TFEB nuclear/cytoplasmic imaging, patient iPSC neurons\",\n      \"pmids\": [\"42104376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which VPS13B influences TFEB unknown\", \"Single lab\", \"Direct vs indirect effect on lysosome biogenesis unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a surface-receptor trafficking role: VPS13B directs CXADR to the plasma membrane, and its loss diverts CXADR to lysosomes and compromises epithelial barrier function.\",\n      \"evidence\": \"KO cells, surface localization assay, bafilomycin A1, CXADR-JAM1 chimera rescue, permeability assay\",\n      \"pmids\": [\"41730960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CXADR trafficking defect is direct or downstream of Golgi/lysosome dysfunction unknown\", \"Single lab\", \"Generality across other surface cargo untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected VPS13B to lysosome-dependent sphingolipid regulation, showing KO organoids have reduced C18 sphingolipids and that cationic amphiphilic drugs rescue Golgi morphology and partially restore neurite outgrowth.\",\n      \"evidence\": \"KO iPSC cortical organoids, lipidomics, Golgi morphology screen, pharmacological rescue (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.04.674037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Causal chain from sphingolipid loss to Golgi/neurite phenotype not fully established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated an in-vivo requirement for VPS13B in lens homeostasis, with KO mice developing cataracts, vacuoles, EMT and fibrosis.\",\n      \"evidence\": \"Vps13b exon 3 KO mouse, histology, IHC, western blot, slit-lamp\",\n      \"pmids\": [\"32915983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular mechanism linking VPS13B loss to lens pathology unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the neurodevelopmental consequences of VPS13B loss in mice—microcephaly, growth delay, behavioral and memory deficits, and early-life neuronal death—supporting a role in neuronal survival.\",\n      \"evidence\": \"Vps13b KO mouse, brain histomorphology, behavioral battery, apoptosis IHC\",\n      \"pmids\": [\"37573958\", \"31495077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from organelle defects to neuronal death not resolved\", \"Sex-difference basis unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS13B's multiple recruitment cues (RAB6, Sec23IP, MFN2) and its proposed bridge-like lipid transfer activity are integrated to coordinate Golgi integrity, ER export, mitochondrial fission, and lysosomal/autophagy homeostasis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of VPS13B lipid transfer activity\", \"No structural model of full-length VPS13B at a membrane contact\", \"Hierarchy/coordination among RAB6, Sec23IP and MFN2 recruitment undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB6\", \"SEC23IP\", \"FAM177A1\", \"MFN2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}