{"gene":"THSD7A","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2010,"finding":"THSD7A is expressed at the leading edge of migrating HUVECs and co-localizes with αVβ3 integrin and paxillin; overexpression of a THSD7A C-terminal fragment inhibited HUVEC migration and tube formation, while suppression enhanced migration and tube formation, and the distribution was dispersed from focal adhesions after actin cytoskeleton disruption, implicating THSD7A in cytoskeletal organization.","method":"HUVEC overexpression/knockdown with migration and tube formation assays, immunolocalization with αVβ3 integrin and paxillin, actin disruption experiments","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype, co-localization with focal adhesion components, single lab with multiple orthogonal methods","pmids":["20020485"],"is_preprint":false},{"year":2011,"finding":"Full-length THSD7A is membrane-associated and N-glycosylated; a soluble form is released into culture medium. Soluble THSD7A promotes HUVEC migration, tube formation, filopodia formation, and vessel branching in zebrafish SIV assays. It increases FAK phosphorylation and alters vinculin distribution, indicating regulation of cytoskeletal reorganization via a FAK-dependent mechanism.","method":"HEK293T overexpression, glycosylation assays, HUVEC migration/tube formation/sprouting assays, zebrafish SIV assay, FAK phosphorylation immunoblot, vinculin localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (in vitro migration, tube formation, in vivo zebrafish), FAK phosphorylation measured biochemically, single lab","pmids":["22194972"],"is_preprint":false},{"year":2011,"finding":"Zebrafish Thsd7a is expressed along the ventral neural tube at sites correlating with angiogenic intersegmental vessel (ISV) growth paths; morpholino knockdown of Thsd7a causes lateral deviation of angiogenic endothelial cells and aberrant ISV patterning, establishing Thsd7a as a neural guidance molecule required for directed EC migration during embryonic angiogenesis.","method":"Morpholino knockdown in zebrafish, in situ hybridization, ISV patterning analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function morpholino with specific vascular phenotype in vivo, single lab","pmids":["21520329"],"is_preprint":false},{"year":2016,"finding":"Zebrafish thsd7a is expressed specifically in primary motor neurons; knockdown disrupts primary motor neuron formation and ISV sprouting. Thsd7a morphants phenocopy loss of Notch-dll4 signaling, and transcript profiling showed downregulation of notch1b and its downstream targets vegfr2/3 and nrarpb, placing Thsd7a upstream of Notch-dll4 signaling in angiogenic sprouting.","method":"Morpholino knockdown in Tg(kdr:EGFP/mnx1:TagRFP) double transgenic zebrafish, transcript profiling, phenotypic comparison with Notch-dll4 loss","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via morpholino in transgenic zebrafish, transcript profiling, single lab","pmids":["27484901"],"is_preprint":false},{"year":2018,"finding":"THSD7A knockdown in endothelial cells attenuates monocyte adhesion by decreasing expression of ICAM, L-selectin, and ITGB2, demonstrating a functional role for THSD7A in regulating monocyte-endothelial adhesion molecules.","method":"siRNA knockdown in endothelial cells, monocyte adhesion assay, ICAM/L-selectin/ITGB2 expression analysis","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and molecular readout (adhesion molecule expression), single lab","pmids":["29472232"],"is_preprint":false},{"year":2019,"finding":"The immunodominant B-cell epitope of THSD7A for autoantibodies in membranous nephropathy is located in a 28-mer sequence (T28mer) in the N-terminal domain, with sequence homology to the major PLA2R epitope. Kallikrein protease cleavage within this sequence abolishes antibody reactivity. Cross-reactivity of PLA2R and THSD7A autoantibodies was detected at the peptide but not the protein level.","method":"Western blot and slot blot with THSD7A protein fragments and peptides, bio-layer interferometry for real-time interaction, kallikrein protease cleavage, homology modelling, B-cell epitope prediction","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — epitope mapped by multiple orthogonal biochemical methods (fragment mapping, peptide binding, protease cleavage, BLI), single lab","pmids":["31395435"],"is_preprint":false},{"year":2022,"finding":"Immune complexes formed by predominantly IgG4 anti-THSD7A autoantibodies activate complement exclusively via the alternative pathway; C3b fixation is abolished in factor B-depleted sera, partially inhibited in C4-depleted sera, unchanged in C1q-depleted sera, and occurs in Mg-EGTA buffer, demonstrating that the classical and lectin pathways are dispensable while the alternative pathway is necessary and sufficient.","method":"In vitro complement fixation assays with factor B-, C4-, C1q-depleted sera and Mg-EGTA buffer; IgG subclass analysis of patient sera","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution complement assay with pathway-specific depletions, single lab but multiple depletion conditions","pmids":["35874690"],"is_preprint":false},{"year":2024,"finding":"Anti-THSD7A antibodies in a mouse MN model cause loss of slit diaphragm proteins (nephrin, NEPH1) at the protein level without transcriptional downregulation, induce transcriptomic/proteomic reconfiguration involving disrupted podocyte adhesion, cytoskeletal dynamics, upregulation of ubiquitin-proteasome components, cathepsins, and ADAM proteases. In C3-deficient mice, these proteolytic and SD protein changes persist, indicating complement-independent pathomechanisms. Podocyte-specific Thsd7a-KO mice are completely protected from MN development upon antibody transfer. Interactome analysis identified THSD7A in a complex with integrin α3, linking THSD7A to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling.","method":"Podocyte-specific Thsd7a-KO mice, anti-THSD7A antibody transfer MN model, transcriptome and proteome analyses, C3-deficient mice, interactome analysis (Co-IP/MS implied), in vitro primary podocyte exposure to antibody","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — KO mouse with complete protection phenotype, multi-omics (transcriptome + proteome), complement-deficient mice for pathway dissection, interactome analysis identifying integrin α3 complex, multiple orthogonal methods in a single rigorous study","pmids":["41746732"],"is_preprint":false},{"year":2024,"finding":"THSD7A is carried in exosomes (small extracellular vesicles) from both cancer cells and neurons; add-back of purified THSD7A to endoglin-knockdown cancer cells or exosome-inhibited neurons rescues filopodia defects. THSD7A induces filopodia formation through activation of the Rho GTPase Cdc42.","method":"Exosome inhibition and rescue experiments, proteomic analysis of cancer cell-derived SEVs, add-back of purified THSD7A protein, Cdc42 activity assays, filopodia quantification in cancer cells and neurons","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — purified protein add-back rescue, Cdc42 activation assay, multiple cell types tested, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2016,"finding":"VEGF-A upregulates THSD7A expression in cultured endothelial cells, particularly under T-helper type 2-prone conditions, suggesting VEGF-A as a transcriptional regulator of THSD7A outside the kidney relevant to MN pathogenesis.","method":"In vitro VEGF-A stimulation of cultured endothelial cells with measurement of THSD7A expression; immunohistochemistry of ALHE tumor tissue","journal":"American journal of kidney diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro stimulation experiment, single lab, no mechanistic follow-up","pmids":["30554801"],"is_preprint":false},{"year":2022,"finding":"Inhibition of super-enhancers reduces THSD7A expression in podocytes, and ERK inhibition enhances THSD7A expression, indicating that THSD7A transcription is regulated by super-enhancer activity and ERK signaling in podocytes.","method":"Super-enhancer inhibitor treatment and ERK inhibitor treatment in cultured podocytes with THSD7A expression quantification","journal":"Cell biochemistry and function","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single inhibitor experiments in vitro, single lab, no mechanistic dissection of pathway","pmids":["35670653"],"is_preprint":false},{"year":2024,"finding":"In a mouse model of THSD7A-associated MN, complement depletion with cobra venom factor only partially attenuated proteinuria and glomerular injury; anti-THSD7A antibody exposure in primary podocytes caused actin cytoskeleton disruption, podocyte hypermobility, oxidative stress, and apoptosis even after complement inactivation, establishing complement-independent autonomous podocyte injury as a pathomechanism.","method":"Mouse MN model with cobra venom factor complement depletion, in vitro primary podocyte exposure to anti-THSD7A antibody with complement inactivation, actin cytoskeleton imaging, oxidative stress and apoptosis assays","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo complement depletion plus in vitro podocyte assays with complement inactivation, multiple phenotypic readouts, single lab","pmids":["39086386"],"is_preprint":false}],"current_model":"THSD7A is a membrane-associated, N-glycosylated transmembrane protein expressed on podocytes and endothelial cells that forms a complex with integrin α3 to regulate cytoskeletal organization, focal adhesion dynamics, and cell migration via FAK and Cdc42 signaling; in the kidney, autoantibody binding to its N-terminal immunodominant epitope triggers complement-independent proteolytic disruption of slit diaphragm proteins (nephrin, NEPH1) and autonomous podocytopathy, as well as complement activation exclusively through the alternative pathway, together causing the proteinuria of membranous nephropathy, while in the vascular system its soluble form and exosome-associated form promote angiogenesis and filopodia formation downstream of VEGF-A and Notch-dll4 signaling."},"narrative":{"mechanistic_narrative":"THSD7A is a membrane-associated, N-glycosylated transmembrane protein that regulates cytoskeletal organization, focal adhesion dynamics, and directed cell migration in both endothelial cells and podocytes [PMID:20020485, PMID:22194972]. At the leading edge of migrating endothelial cells it co-localizes with αVβ3 integrin and paxillin, and it controls migration and capillary tube formation through a FAK-dependent mechanism that reorganizes vinculin and the actin cytoskeleton; a soluble form released from cells promotes filopodia formation, vessel sprouting, and branching, acting upstream of Notch-dll4 signaling during angiogenesis [PMID:22194972, PMID:27484901]. THSD7A drives filopodia formation by activating the Rho GTPase Cdc42 and is trafficked in exosomes. In the kidney, THSD7A is the target autoantigen of membranous nephropathy: autoantibodies bind an immunodominant 28-mer epitope in its N-terminal domain [PMID:31395435], and antibody binding triggers autonomous podocyte injury characterized by proteolytic loss of the slit diaphragm proteins nephrin and NEPH1, actin cytoskeleton disruption, and upregulation of ubiquitin-proteasome and ADAM/cathepsin proteases, with podocyte-specific Thsd7a-knockout mice fully protected from disease [PMID:41746732]. This podocytopathy proceeds independently of complement [PMID:41746732, PMID:39086386], while THSD7A immune complexes additionally activate complement exclusively through the alternative pathway [PMID:35874690]. Interactome analysis places THSD7A in a complex with integrin α3, linking it to the regulation of podocyte adhesion, cytoskeleton, and membrane signaling [PMID:41746732].","teleology":[{"year":2010,"claim":"Established THSD7A as a regulator of endothelial migration and cytoskeletal organization, defining its baseline cellular function before any disease association.","evidence":"HUVEC overexpression/knockdown with migration and tube formation assays plus co-localization with αVβ3 integrin and paxillin","pmids":["20020485"],"confidence":"Medium","gaps":["Did not define the molecular partner mediating focal adhesion localization","No in vivo validation in this study"]},{"year":2011,"claim":"Defined THSD7A as N-glycosylated and membrane-associated with a functional soluble form acting through FAK, connecting it to cytoskeletal reorganization in vitro and angiogenesis in vivo.","evidence":"HEK293T glycosylation assays, HUVEC migration/sprouting assays, zebrafish SIV assay, FAK phosphorylation immunoblot","pmids":["22194972"],"confidence":"Medium","gaps":["Receptor mediating soluble THSD7A signaling not identified","Mechanism of soluble form release unknown"]},{"year":2011,"claim":"Demonstrated that THSD7A acts as a neural guidance molecule directing endothelial cell migration during embryonic angiogenesis.","evidence":"Morpholino knockdown and in situ hybridization with ISV patterning analysis in zebrafish","pmids":["21520329"],"confidence":"Medium","gaps":["Morpholino specificity not confirmed with genetic mutant","Molecular signaling downstream of guidance unresolved"]},{"year":2016,"claim":"Placed THSD7A upstream of Notch-dll4 signaling in angiogenic sprouting, integrating it into a defined developmental pathway.","evidence":"Morpholino knockdown in transgenic zebrafish with transcript profiling and phenotypic epistasis comparison","pmids":["27484901"],"confidence":"Medium","gaps":["Direct biochemical link between THSD7A and Notch components not shown","Mechanism connecting motor neuron expression to vascular sprouting unclear"]},{"year":2018,"claim":"Extended THSD7A function to leukocyte-endothelial interactions by showing it regulates adhesion molecule expression.","evidence":"siRNA knockdown in endothelial cells with monocyte adhesion assay and ICAM/L-selectin/ITGB2 readouts","pmids":["29472232"],"confidence":"Medium","gaps":["Pathway linking THSD7A to adhesion molecule transcription unknown","No in vivo confirmation"]},{"year":2019,"claim":"Mapped the immunodominant membranous nephropathy autoantibody epitope to an N-terminal 28-mer, providing the molecular basis for autoantibody recognition.","evidence":"Fragment/peptide blotting, bio-layer interferometry, kallikrein cleavage, and homology modelling","pmids":["31395435"],"confidence":"Medium","gaps":["Structural conformation of the epitope not solved","Physiological role of kallikrein cleavage in vivo not established"]},{"year":2022,"claim":"Determined that THSD7A immune complexes activate complement exclusively through the alternative pathway, refining the effector mechanism of antibody-mediated injury.","evidence":"In vitro complement fixation assays with factor B-, C4-, C1q-depleted sera and Mg-EGTA buffer","pmids":["35874690"],"confidence":"Medium","gaps":["In vivo contribution of alternative pathway not quantified here","Trigger initiating alternative pathway on podocyte surface unresolved"]},{"year":2024,"claim":"Established THSD7A as causally required for membranous nephropathy and revealed a complement-independent, proteolytic podocytopathy with an integrin α3 partner.","evidence":"Podocyte-specific Thsd7a-KO mice, antibody-transfer MN model, multi-omics, C3-deficient mice, and interactome analysis","pmids":["41746732"],"confidence":"High","gaps":["Protease responsible for nephrin/NEPH1 loss not pinned to a single enzyme","Functional consequence of the THSD7A–integrin α3 interaction not directly tested by perturbation"]},{"year":2024,"claim":"Corroborated complement-independent autonomous podocyte injury, showing antibody binding alone drives cytoskeletal disruption, oxidative stress, and apoptosis.","evidence":"Mouse MN model with cobra venom factor complement depletion and primary podocyte assays with complement inactivation","pmids":["39086386"],"confidence":"Medium","gaps":["Relative contribution of complement-dependent versus -independent injury in patients unclear","Signaling cascade from antibody binding to apoptosis not fully mapped"]},{"year":2024,"claim":"Identified Cdc42 activation and exosomal trafficking as the mechanism by which THSD7A induces filopodia, unifying its cytoskeletal effects across cell types.","evidence":"Exosome inhibition/rescue, SEV proteomics, purified protein add-back, and Cdc42 activity assays (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Receptor coupling THSD7A to Cdc42 activation unidentified","Relevance of exosomal THSD7A to renal disease not tested"]},{"year":null,"claim":"How THSD7A signaling through integrin α3, FAK, and Cdc42 mechanistically connects autoantibody binding to slit diaphragm protein loss, and which protease executes nephrin/NEPH1 degradation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No single executor protease confirmed","No structural model of the THSD7A ectodomain or its complexes","Receptor/coreceptor for soluble and exosomal THSD7A unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,4]}],"complexes":[],"partners":["ITGA3","ITGAV","ITGB3","PXN","PTK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UPZ6","full_name":"Thrombospondin type-1 domain-containing protein 7A","aliases":[],"length_aa":1657,"mass_kda":185.4,"function":"Plays a role in actin cytoskeleton rearrangement The soluble form promotes endothelial cell migration and filopodia formation during sprouting angiogenesis via a FAK-dependent mechanism","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UPZ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/THSD7A","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/THSD7A","total_profiled":1310},"omim":[{"mim_id":"614692","title":"MEMBRANOUS NEPHROPATHY, SUSCEPTIBILITY TO; MBNP","url":"https://www.omim.org/entry/614692"},{"mim_id":"612249","title":"THROMBOSPONDIN TYPE-1 DOMAIN-CONTAINING PROTEIN 7A; THSD7A","url":"https://www.omim.org/entry/612249"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":7.0}],"url":"https://www.proteinatlas.org/search/THSD7A"},"hgnc":{"alias_symbol":["KIAA0960"],"prev_symbol":[]},"alphafold":{"accession":"Q9UPZ6","domains":[{"cath_id":"-","chopping":"60-136_147-182","consensus_level":"medium","plddt":75.6711,"start":60,"end":182},{"cath_id":"-","chopping":"962-975_994-1033_1287-1337","consensus_level":"high","plddt":79.1407,"start":962,"end":1337},{"cath_id":"-","chopping":"1527-1555","consensus_level":"high","plddt":74.8562,"start":1527,"end":1555}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPZ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPZ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPZ6-F1-predicted_aligned_error_v6.png","plddt_mean":67.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=THSD7A","jax_strain_url":"https://www.jax.org/strain/search?query=THSD7A"},"sequence":{"accession":"Q9UPZ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPZ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPZ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPZ6"}},"corpus_meta":[{"pmid":"28674044","id":"PMC_28674044","title":"PLA2R 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report.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37832087","citation_count":3,"is_preprint":false},{"pmid":"33413188","id":"PMC_33413188","title":"Diagnostic performance of glomerular PLA2R and THSD7A antibodies in biopsy confirmed primary membranous nephropathy in South Africans.","date":"2021","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/33413188","citation_count":2,"is_preprint":false},{"pmid":"41746732","id":"PMC_41746732","title":"Functional characterization of podocyte-expressed THSD7A in experimental membranous nephropathy.","date":"2026","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/41746732","citation_count":1,"is_preprint":false},{"pmid":"35670653","id":"PMC_35670653","title":"Comprehensively characterizing cellular changes and the expression of THSD7A and PLA2R1 under multiple in vitro models of podocyte injury.","date":"2022","source":"Cell biochemistry and 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arkhiv","url":"https://pubmed.ncbi.nlm.nih.gov/38158964","citation_count":1,"is_preprint":false},{"pmid":"40489000","id":"PMC_40489000","title":"Phenotype-dependent heterogeneity of THSD7A expression in gastric cancer tissue in a patient with THSD7A-associated membranous nephropathy.","date":"2025","source":"CEN case reports","url":"https://pubmed.ncbi.nlm.nih.gov/40489000","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.20.604139","title":"Secreted exosomes induce filopodia formation","date":"2024-07-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.20.604139","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21723,"output_tokens":3360,"usd":0.057785,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10910,"output_tokens":3328,"usd":0.068875,"stage2_stop_reason":"end_turn"},"total_usd":0.12666,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"THSD7A is expressed at the leading edge of migrating HUVECs and co-localizes with αVβ3 integrin and paxillin; overexpression of a THSD7A C-terminal fragment inhibited HUVEC migration and tube formation, while suppression enhanced migration and tube formation, and the distribution was dispersed from focal adhesions after actin cytoskeleton disruption, implicating THSD7A in cytoskeletal organization.\",\n      \"method\": \"HUVEC overexpression/knockdown with migration and tube formation assays, immunolocalization with αVβ3 integrin and paxillin, actin disruption experiments\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype, co-localization with focal adhesion components, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20020485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Full-length THSD7A is membrane-associated and N-glycosylated; a soluble form is released into culture medium. Soluble THSD7A promotes HUVEC migration, tube formation, filopodia formation, and vessel branching in zebrafish SIV assays. It increases FAK phosphorylation and alters vinculin distribution, indicating regulation of cytoskeletal reorganization via a FAK-dependent mechanism.\",\n      \"method\": \"HEK293T overexpression, glycosylation assays, HUVEC migration/tube formation/sprouting assays, zebrafish SIV assay, FAK phosphorylation immunoblot, vinculin localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (in vitro migration, tube formation, in vivo zebrafish), FAK phosphorylation measured biochemically, single lab\",\n      \"pmids\": [\"22194972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Zebrafish Thsd7a is expressed along the ventral neural tube at sites correlating with angiogenic intersegmental vessel (ISV) growth paths; morpholino knockdown of Thsd7a causes lateral deviation of angiogenic endothelial cells and aberrant ISV patterning, establishing Thsd7a as a neural guidance molecule required for directed EC migration during embryonic angiogenesis.\",\n      \"method\": \"Morpholino knockdown in zebrafish, in situ hybridization, ISV patterning analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function morpholino with specific vascular phenotype in vivo, single lab\",\n      \"pmids\": [\"21520329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Zebrafish thsd7a is expressed specifically in primary motor neurons; knockdown disrupts primary motor neuron formation and ISV sprouting. Thsd7a morphants phenocopy loss of Notch-dll4 signaling, and transcript profiling showed downregulation of notch1b and its downstream targets vegfr2/3 and nrarpb, placing Thsd7a upstream of Notch-dll4 signaling in angiogenic sprouting.\",\n      \"method\": \"Morpholino knockdown in Tg(kdr:EGFP/mnx1:TagRFP) double transgenic zebrafish, transcript profiling, phenotypic comparison with Notch-dll4 loss\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via morpholino in transgenic zebrafish, transcript profiling, single lab\",\n      \"pmids\": [\"27484901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"THSD7A knockdown in endothelial cells attenuates monocyte adhesion by decreasing expression of ICAM, L-selectin, and ITGB2, demonstrating a functional role for THSD7A in regulating monocyte-endothelial adhesion molecules.\",\n      \"method\": \"siRNA knockdown in endothelial cells, monocyte adhesion assay, ICAM/L-selectin/ITGB2 expression analysis\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and molecular readout (adhesion molecule expression), single lab\",\n      \"pmids\": [\"29472232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The immunodominant B-cell epitope of THSD7A for autoantibodies in membranous nephropathy is located in a 28-mer sequence (T28mer) in the N-terminal domain, with sequence homology to the major PLA2R epitope. Kallikrein protease cleavage within this sequence abolishes antibody reactivity. Cross-reactivity of PLA2R and THSD7A autoantibodies was detected at the peptide but not the protein level.\",\n      \"method\": \"Western blot and slot blot with THSD7A protein fragments and peptides, bio-layer interferometry for real-time interaction, kallikrein protease cleavage, homology modelling, B-cell epitope prediction\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — epitope mapped by multiple orthogonal biochemical methods (fragment mapping, peptide binding, protease cleavage, BLI), single lab\",\n      \"pmids\": [\"31395435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Immune complexes formed by predominantly IgG4 anti-THSD7A autoantibodies activate complement exclusively via the alternative pathway; C3b fixation is abolished in factor B-depleted sera, partially inhibited in C4-depleted sera, unchanged in C1q-depleted sera, and occurs in Mg-EGTA buffer, demonstrating that the classical and lectin pathways are dispensable while the alternative pathway is necessary and sufficient.\",\n      \"method\": \"In vitro complement fixation assays with factor B-, C4-, C1q-depleted sera and Mg-EGTA buffer; IgG subclass analysis of patient sera\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution complement assay with pathway-specific depletions, single lab but multiple depletion conditions\",\n      \"pmids\": [\"35874690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Anti-THSD7A antibodies in a mouse MN model cause loss of slit diaphragm proteins (nephrin, NEPH1) at the protein level without transcriptional downregulation, induce transcriptomic/proteomic reconfiguration involving disrupted podocyte adhesion, cytoskeletal dynamics, upregulation of ubiquitin-proteasome components, cathepsins, and ADAM proteases. In C3-deficient mice, these proteolytic and SD protein changes persist, indicating complement-independent pathomechanisms. Podocyte-specific Thsd7a-KO mice are completely protected from MN development upon antibody transfer. Interactome analysis identified THSD7A in a complex with integrin α3, linking THSD7A to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling.\",\n      \"method\": \"Podocyte-specific Thsd7a-KO mice, anti-THSD7A antibody transfer MN model, transcriptome and proteome analyses, C3-deficient mice, interactome analysis (Co-IP/MS implied), in vitro primary podocyte exposure to antibody\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — KO mouse with complete protection phenotype, multi-omics (transcriptome + proteome), complement-deficient mice for pathway dissection, interactome analysis identifying integrin α3 complex, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"41746732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"THSD7A is carried in exosomes (small extracellular vesicles) from both cancer cells and neurons; add-back of purified THSD7A to endoglin-knockdown cancer cells or exosome-inhibited neurons rescues filopodia defects. THSD7A induces filopodia formation through activation of the Rho GTPase Cdc42.\",\n      \"method\": \"Exosome inhibition and rescue experiments, proteomic analysis of cancer cell-derived SEVs, add-back of purified THSD7A protein, Cdc42 activity assays, filopodia quantification in cancer cells and neurons\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — purified protein add-back rescue, Cdc42 activation assay, multiple cell types tested, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"VEGF-A upregulates THSD7A expression in cultured endothelial cells, particularly under T-helper type 2-prone conditions, suggesting VEGF-A as a transcriptional regulator of THSD7A outside the kidney relevant to MN pathogenesis.\",\n      \"method\": \"In vitro VEGF-A stimulation of cultured endothelial cells with measurement of THSD7A expression; immunohistochemistry of ALHE tumor tissue\",\n      \"journal\": \"American journal of kidney diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro stimulation experiment, single lab, no mechanistic follow-up\",\n      \"pmids\": [\"30554801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inhibition of super-enhancers reduces THSD7A expression in podocytes, and ERK inhibition enhances THSD7A expression, indicating that THSD7A transcription is regulated by super-enhancer activity and ERK signaling in podocytes.\",\n      \"method\": \"Super-enhancer inhibitor treatment and ERK inhibitor treatment in cultured podocytes with THSD7A expression quantification\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single inhibitor experiments in vitro, single lab, no mechanistic dissection of pathway\",\n      \"pmids\": [\"35670653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a mouse model of THSD7A-associated MN, complement depletion with cobra venom factor only partially attenuated proteinuria and glomerular injury; anti-THSD7A antibody exposure in primary podocytes caused actin cytoskeleton disruption, podocyte hypermobility, oxidative stress, and apoptosis even after complement inactivation, establishing complement-independent autonomous podocyte injury as a pathomechanism.\",\n      \"method\": \"Mouse MN model with cobra venom factor complement depletion, in vitro primary podocyte exposure to anti-THSD7A antibody with complement inactivation, actin cytoskeleton imaging, oxidative stress and apoptosis assays\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo complement depletion plus in vitro podocyte assays with complement inactivation, multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"39086386\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THSD7A is a membrane-associated, N-glycosylated transmembrane protein expressed on podocytes and endothelial cells that forms a complex with integrin α3 to regulate cytoskeletal organization, focal adhesion dynamics, and cell migration via FAK and Cdc42 signaling; in the kidney, autoantibody binding to its N-terminal immunodominant epitope triggers complement-independent proteolytic disruption of slit diaphragm proteins (nephrin, NEPH1) and autonomous podocytopathy, as well as complement activation exclusively through the alternative pathway, together causing the proteinuria of membranous nephropathy, while in the vascular system its soluble form and exosome-associated form promote angiogenesis and filopodia formation downstream of VEGF-A and Notch-dll4 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THSD7A is a membrane-associated, N-glycosylated transmembrane protein that regulates cytoskeletal organization, focal adhesion dynamics, and directed cell migration in both endothelial cells and podocytes [#0, #1]. At the leading edge of migrating endothelial cells it co-localizes with αVβ3 integrin and paxillin, and it controls migration and capillary tube formation through a FAK-dependent mechanism that reorganizes vinculin and the actin cytoskeleton; a soluble form released from cells promotes filopodia formation, vessel sprouting, and branching, acting upstream of Notch-dll4 signaling during angiogenesis [#1, #3]. THSD7A drives filopodia formation by activating the Rho GTPase Cdc42 and is trafficked in exosomes [#8]. In the kidney, THSD7A is the target autoantigen of membranous nephropathy: autoantibodies bind an immunodominant 28-mer epitope in its N-terminal domain [#5], and antibody binding triggers autonomous podocyte injury characterized by proteolytic loss of the slit diaphragm proteins nephrin and NEPH1, actin cytoskeleton disruption, and upregulation of ubiquitin-proteasome and ADAM/cathepsin proteases, with podocyte-specific Thsd7a-knockout mice fully protected from disease [#7]. This podocytopathy proceeds independently of complement [#7, #11], while THSD7A immune complexes additionally activate complement exclusively through the alternative pathway [#6]. Interactome analysis places THSD7A in a complex with integrin α3, linking it to the regulation of podocyte adhesion, cytoskeleton, and membrane signaling [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established THSD7A as a regulator of endothelial migration and cytoskeletal organization, defining its baseline cellular function before any disease association.\",\n      \"evidence\": \"HUVEC overexpression/knockdown with migration and tube formation assays plus co-localization with αVβ3 integrin and paxillin\",\n      \"pmids\": [\"20020485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular partner mediating focal adhesion localization\", \"No in vivo validation in this study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined THSD7A as N-glycosylated and membrane-associated with a functional soluble form acting through FAK, connecting it to cytoskeletal reorganization in vitro and angiogenesis in vivo.\",\n      \"evidence\": \"HEK293T glycosylation assays, HUVEC migration/sprouting assays, zebrafish SIV assay, FAK phosphorylation immunoblot\",\n      \"pmids\": [\"22194972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating soluble THSD7A signaling not identified\", \"Mechanism of soluble form release unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that THSD7A acts as a neural guidance molecule directing endothelial cell migration during embryonic angiogenesis.\",\n      \"evidence\": \"Morpholino knockdown and in situ hybridization with ISV patterning analysis in zebrafish\",\n      \"pmids\": [\"21520329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino specificity not confirmed with genetic mutant\", \"Molecular signaling downstream of guidance unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed THSD7A upstream of Notch-dll4 signaling in angiogenic sprouting, integrating it into a defined developmental pathway.\",\n      \"evidence\": \"Morpholino knockdown in transgenic zebrafish with transcript profiling and phenotypic epistasis comparison\",\n      \"pmids\": [\"27484901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between THSD7A and Notch components not shown\", \"Mechanism connecting motor neuron expression to vascular sprouting unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended THSD7A function to leukocyte-endothelial interactions by showing it regulates adhesion molecule expression.\",\n      \"evidence\": \"siRNA knockdown in endothelial cells with monocyte adhesion assay and ICAM/L-selectin/ITGB2 readouts\",\n      \"pmids\": [\"29472232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway linking THSD7A to adhesion molecule transcription unknown\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped the immunodominant membranous nephropathy autoantibody epitope to an N-terminal 28-mer, providing the molecular basis for autoantibody recognition.\",\n      \"evidence\": \"Fragment/peptide blotting, bio-layer interferometry, kallikrein cleavage, and homology modelling\",\n      \"pmids\": [\"31395435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural conformation of the epitope not solved\", \"Physiological role of kallikrein cleavage in vivo not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Determined that THSD7A immune complexes activate complement exclusively through the alternative pathway, refining the effector mechanism of antibody-mediated injury.\",\n      \"evidence\": \"In vitro complement fixation assays with factor B-, C4-, C1q-depleted sera and Mg-EGTA buffer\",\n      \"pmids\": [\"35874690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution of alternative pathway not quantified here\", \"Trigger initiating alternative pathway on podocyte surface unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established THSD7A as causally required for membranous nephropathy and revealed a complement-independent, proteolytic podocytopathy with an integrin α3 partner.\",\n      \"evidence\": \"Podocyte-specific Thsd7a-KO mice, antibody-transfer MN model, multi-omics, C3-deficient mice, and interactome analysis\",\n      \"pmids\": [\"41746732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for nephrin/NEPH1 loss not pinned to a single enzyme\", \"Functional consequence of the THSD7A–integrin α3 interaction not directly tested by perturbation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Corroborated complement-independent autonomous podocyte injury, showing antibody binding alone drives cytoskeletal disruption, oxidative stress, and apoptosis.\",\n      \"evidence\": \"Mouse MN model with cobra venom factor complement depletion and primary podocyte assays with complement inactivation\",\n      \"pmids\": [\"39086386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of complement-dependent versus -independent injury in patients unclear\", \"Signaling cascade from antibody binding to apoptosis not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified Cdc42 activation and exosomal trafficking as the mechanism by which THSD7A induces filopodia, unifying its cytoskeletal effects across cell types.\",\n      \"evidence\": \"Exosome inhibition/rescue, SEV proteomics, purified protein add-back, and Cdc42 activity assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Receptor coupling THSD7A to Cdc42 activation unidentified\", \"Relevance of exosomal THSD7A to renal disease not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How THSD7A signaling through integrin α3, FAK, and Cdc42 mechanistically connects autoantibody binding to slit diaphragm protein loss, and which protease executes nephrin/NEPH1 degradation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No single executor protease confirmed\", \"No structural model of the THSD7A ectodomain or its complexes\", \"Receptor/coreceptor for soluble and exosomal THSD7A unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGA3\", \"ITGAV\", \"ITGB3\", \"PXN\", \"PTK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}