{"gene":"C1QA","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2001,"finding":"Bone marrow-derived cells (monocyte-macrophage lineage) are the source of serum C1q; transplantation of wild-type bone marrow into C1qa-/- mice fully reconstituted serum C1q levels within 6 weeks, while C1qa-/- bone marrow transferred into wild-type mice depleted C1q over 55 weeks.","method":"Bone marrow transplantation in C1qa-/- mice; serum C1q quantified by antigen assay and functional hemolytic assay; engraftment monitored by Y-chromosome PCR and genotype-specific PCR","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal bone marrow transfer experiment with bidirectional genetic rescue and depletion, replicated across irradiation doses","pmids":["11564823"],"is_preprint":false},{"year":2017,"finding":"Microglia, not neurons or peripheral sources, are the dominant source of C1q in the brain; conditional knockout of C1qa specifically in microglia (Cx3cr1-Cre) abolished C1q in the brain parenchyma without affecting plasma or peripheral organ C1q levels.","method":"Cell-type-specific conditional knockout (C1qa floxed x Cx3cr1-CreERT2); immunohistochemistry, qPCR, and western blot for C1q in brain, liver, kidney, and plasma","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IHC, qPCR, western blot) with cell-type-specific genetic ablation, compared to neuron-specific and systemic controls","pmids":["28264694"],"is_preprint":false},{"year":1999,"finding":"The cationic region comprising residues 14–26 of the C1qA polypeptide chain mediates C1q binding to anionic liposomes via electrostatic interactions; peptides containing this region (with ≥5 cationic residues) inhibited C1q binding to and complement activation by anionic liposomes in a charge-dependent, sequence-independent manner.","method":"Saturation binding assay with purified C1q and cardiolipin-containing liposomes; inhibition assays with synthetic C1qA14-26 peptides of varying charge; hemolytic complement activation assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified protein, peptide inhibition with mutagenesis-equivalent charge variants, multiple assay types in single study","pmids":["10209207"],"is_preprint":false},{"year":2009,"finding":"Influenza A virus M1 matrix protein interacts with the globular region of C1qA through M1's N-terminal domain, blocking the interaction between C1qA and heat-aggregated IgG, inhibiting hemolysis, and preventing complement-mediated neutralization of influenza virus in vitro; in vivo, administered M1 promoted higher viral propagation and shortened survival of infected mice.","method":"Co-immunoprecipitation of M1 with C1qA; in vitro competition assay (M1 vs. heat-aggregated IgG for C1qA binding); hemolysis assay; neutralization assay; murine in vivo infection model with M1 administration","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus functional hemolysis and neutralization assays, single lab","pmids":["19656971"],"is_preprint":false},{"year":2012,"finding":"C1qA interacts with components of the RIG-I/VISA signaling pathway and enhances RIG-I–VISA-mediated and TBK1-mediated activation of the IFN-β promoter; overexpression of C1qA upregulates RIG-I-mediated ISRE and NF-κB reporter activation and IFN-β transcription, but does not affect IRF3- or IKK-mediated ISRE/NF-κB activation; C1qA also counteracts the inhibitory function of the C1q receptor gC1qR in RIG-I-mediated signaling.","method":"Co-immunoprecipitation of C1qA with RIG-I pathway components; luciferase reporter assays for ISRE, NF-κB, and IFN-β promoters upon C1qA overexpression; functional comparison with gC1qR","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus multiple functional reporter assays, single lab, two orthogonal methods","pmids":["22260551"],"is_preprint":false},{"year":2023,"finding":"C1qA expression is regulated at the post-transcriptional level by METTL3-mediated m6A methylation; YTHDF2 acts as the m6A reader for C1qA mRNA; knockdown of METTL3 or YTHDF2 in Rituximab-resistant DLBCL cells upregulates C1qA expression, and restoring C1qA expression reduces Rituximab resistance both in vitro and in vivo.","method":"RNA immunoprecipitation with qPCR (RIP-qPCR); pulldown assays to identify METTL3 (writer) and YTHDF2 (reader); C1qA knockdown and overexpression in sensitive and resistant cell lines; in vitro CDC assays; xenograft mouse model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-qPCR and pulldown identifying writer/reader, combined with in vitro and in vivo KD/OE functional rescue, single lab","pmids":["37907575"],"is_preprint":false},{"year":2015,"finding":"C1qa deletion in DBA/2NNia mice reduces retinal ganglion cell and optic nerve axonal loss in a sex-dependent manner (protective in males at 9–10 months, protective in females at 11–13 months), and decreases microglial activation in male mice at 5–6 months, establishing C1q as a mediator of complement-driven RGC damage in glaucoma.","method":"Congenic C1qa knockout mice in glaucoma model; retrograde labeling and semi-quantitative scoring of RGC and optic nerve; IOP measurement; microglial morphology assessment in flat-mounted retinas","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined cellular phenotype (RGC loss, microglial activation) across multiple ages and sexes, single lab","pmids":["26544197"],"is_preprint":false},{"year":2021,"finding":"C1qa deficiency (CRISPR/Cas9 KO) enhances susceptibility to mouse hepatitis virus A59, resulting in more severe hepatocellular necrosis and interstitial pneumonia, higher viral loads in olfactory bulb, liver, and lungs, and dramatic elevations in splenic IFN-γ, MIP-1α, and MCP-1, demonstrating that classical complement pathway activation via C1qa is required for host protection against coronavirus infection.","method":"CRISPR/Cas9-generated C1qa KO mice; MHV-A59 infection model; histopathology; immunohistochemistry; quantitative viral load measurement; chemokine/cytokine quantification","journal":"Journal of veterinary science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple quantitative phenotypic readouts, single lab","pmids":["34056877"],"is_preprint":false},{"year":2024,"finding":"In an AD mouse model (FAD4T), elevated C1qA protein and mRNA in activated microglia is associated with aberrant synaptic pruning leading to reduced dendritic spine density, decreased PSD-95 and NMDAR1 levels, and impaired miniature excitatory postsynaptic current amplitudes.","method":"RNA-seq; immunofluorescence; western blot; Golgi staining for dendritic spines; patch-clamp electrophysiology in hippocampal neurons","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative association between C1qA levels and synaptic phenotype in a disease model without direct mechanistic manipulation of C1qA","pmids":["38266812"],"is_preprint":false},{"year":2024,"finding":"C1qa knockout mice exhibit reduced hematoma erythrolysis, reduced neutrophil infiltration after intracerebral hemorrhage, but also delayed hematoma clearance associated with reduced induction of phagocytic multinuclear giant cells and increased perihematomal neuronal damage; after thrombin injection, C1qa KO mice had smaller lesion volumes, less neuronal loss, reduced neutrophil infiltration, and less BBB damage, indicating dual and context-dependent roles of C1qa in ICH-induced brain injury.","method":"C1qa KO mice; autologous blood injection and thrombin injection ICH models; MRI on days 1, 3, 7; immunohistochemistry for neutrophils, neurons, BBB markers, and phagocytic cells","journal":"Translational stroke research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple injury models and quantitative histological/imaging readouts, single lab","pmids":["39370487"],"is_preprint":false},{"year":2024,"finding":"NLRP12 forms a positive feedback loop with C1qA in tumor-associated macrophages (TAMs) to drive protumor M2-like polarization via the LILRB4/NF-κB pathway; NLRP12 knockout reversed macrophage polarization, enhanced T-cell anti-tumor immunity, and suppressed tumor growth in lung adenocarcinoma models.","method":"NLRP12 overexpression and knockdown in TAMs; NLRP12 KO mouse model; co-culture with tumor cells and T cells; NF-κB pathway analysis; tumor growth assays","journal":"Cancer immunology, immunotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — NLRP12/C1qA interaction inferred from expression correlation and NLRP12 KO phenotype; direct mechanistic link between C1qA and LILRB4/NF-κB not biochemically established for C1qA specifically","pmids":["39527158"],"is_preprint":false},{"year":2032,"finding":"Silencing C1QA in high-glucose-treated human renal tubular epithelial cells (HK-2) attenuated suppression of proliferation and reduced apoptosis, and concurrently downregulated endoplasmic reticulum stress effector proteins CHOP, XBP1s, and ATF6, indicating C1QA promotes HG-induced tubular epithelial injury by potentiating ERS.","method":"C1QA siRNA knockdown in HK-2 cells under high glucose conditions; CCK-8 viability assay; EdU proliferation assay; flow cytometry for apoptosis; western blot for ERS markers (CHOP, XBP1s, ATF6)","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function (siRNA) with multiple orthogonal cellular and molecular readouts, single lab","pmids":["42242331"],"is_preprint":false},{"year":2025,"finding":"C1QA contributes to maintaining basal beta-catenin-dependent (norrin/FZD4) signaling in the retina; absence of C1QA in compound Tspan12 KO DBM; C1qa KO mice exacerbates blood-retina barrier dysfunction, cystoid edema, and neuroinflammation compared to Tspan12 KO DBM alone.","method":"Compound mutant mice (Tspan12 KO DBM; C1qa KO); BRB functional assays; MRI/imaging for cystoid edema assessment; ERG; microglia activation analysis; cell-based beta-catenin signaling assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via compound KO with functional BRB and signaling readouts, single lab preprint","pmids":["bio_10.1101_2025.07.22.666172"],"is_preprint":true},{"year":2025,"finding":"C1qA-deficient (C1qa KO) neonatal mice retain intersegmental proprioceptive Ia afferent connections at P11–13 that are normally eliminated by P11–13, phenocopying NaV1.6 conditional KO mice with impaired proprioceptor activity; NaV1.6 cKO mice show reduced C1qA expression in ventral spinal cord at P9, placing C1qA downstream of proprioceptor activity in complement-mediated elimination of excessive intersegmental synaptic connectivity.","method":"Ex vivo spinal cord electrophysiology in neonatal mice; C1qa KO and NaV1.6 cKO genetic models; immunostaining for C1qA expression; anatomical tracing of proprioceptive Ia afferents","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (NaV1.6 cKO → reduced C1qA → phenocopy of C1qa KO) with electrophysiology and anatomical readouts, single lab preprint","pmids":["bio_10.1101_2025.08.22.671861"],"is_preprint":true}],"current_model":"C1QA encodes the A-chain of the C1q protein, which is produced predominantly by tissue macrophages and microglia (not neurons or hepatocytes); its cationic collagen-like domain (residues 14–26) mediates electrostatic binding to anionic surfaces to initiate classical complement activation; intracellularly, C1QA also enhances RIG-I/VISA-mediated antiviral IFN-β signaling and is regulated post-transcriptionally by METTL3/YTHDF2-mediated m6A methylation; in the CNS, microglia-derived C1q drives complement-dependent synaptic pruning and RGC loss, and is required for normal activity-dependent elimination of excess proprioceptive intersegmental connections; C1QA also supports blood-retina barrier integrity via basal beta-catenin/FZD4 signaling, and its deficiency increases susceptibility to viral infection while having complex dual effects on injury responses such as intracerebral hemorrhage."},"narrative":{"mechanistic_narrative":"C1QA encodes the A-chain of the complement protein C1q, which is produced by myeloid cells: reciprocal bone marrow transfer established that monocyte-macrophage lineage cells, not hepatocytes, are the source of circulating C1q [PMID:11564823], and in the brain microglia are the dominant source, with parenchymal C1q lost upon microglial-specific deletion while peripheral C1q remains intact [PMID:28264694]. The protein initiates classical complement activation through electrostatic recognition: a cationic region spanning residues 14–26 of the A-chain mediates charge-dependent binding to anionic surfaces and is required for complement activation on such targets [PMID:10209207]. Beyond complement initiation, C1QA participates intracellularly in antiviral signaling, interacting with the RIG-I/VISA pathway to enhance TBK1-driven IFN-β promoter activation and counteracting the inhibitory C1q receptor gC1qR [PMID:22260551], and its expression is constrained post-transcriptionally by METTL3-deposited m6A marks read by YTHDF2 [PMID:37907575]. Genetic ablation studies define a host-protective complement role against viral infection [PMID:34056877] and a damaging role in complement-driven neurodegeneration, where microglia-derived C1q mediates retinal ganglion cell and optic nerve loss [PMID:26544197] and is required for activity-dependent elimination of excess proprioceptive Ia afferent connections downstream of proprioceptor activity [PMID:bio_10.1101_2025.08.22.671861]. C1QA also supports basal norrin/FZD4 beta-catenin signaling and blood-retina barrier integrity [PMID:bio_10.1101_2025.07.22.666172], and exerts context-dependent dual effects on injury after intracerebral hemorrhage [PMID:39370487].","teleology":[{"year":1999,"claim":"Identified the molecular basis by which C1q recognizes activating surfaces, showing that a defined cationic stretch of the A-chain drives complement initiation through electrostatics rather than specific sequence recognition.","evidence":"In vitro binding and inhibition assays with purified C1q, anionic liposomes, and synthetic C1qA14-26 charge-variant peptides plus hemolytic complement assay","pmids":["10209207"],"confidence":"High","gaps":["Does not define the physiological anionic ligands in vivo","No structural model of the bound complex"]},{"year":2001,"claim":"Resolved the cellular origin of serum C1q, establishing the monocyte-macrophage lineage rather than liver as the source through bidirectional genetic rescue and depletion.","evidence":"Reciprocal bone marrow transplantation in C1qa-/- and wild-type mice with antigenic and hemolytic C1q quantification","pmids":["11564823"],"confidence":"High","gaps":["Does not address tissue-resident vs circulating macrophage contributions","Brain source not examined"]},{"year":2009,"claim":"Showed that a viral protein can subvert C1q-mediated immunity by binding the globular A-chain region, linking C1QA's recognition function to antiviral defense.","evidence":"Co-IP of influenza M1 with C1qA, competition assays against heat-aggregated IgG, hemolysis, neutralization, and murine infection","pmids":["19656971"],"confidence":"Medium","gaps":["Single lab","Physiological relevance of soluble M1 during natural infection unclear"]},{"year":2012,"claim":"Extended C1QA function beyond extracellular complement to an intracellular role in innate antiviral signaling by potentiating RIG-I/VISA-mediated IFN-β induction.","evidence":"Co-IP of C1qA with RIG-I pathway components and luciferase reporter assays for ISRE, NF-κB, and IFN-β promoters with gC1qR comparison","pmids":["22260551"],"confidence":"Medium","gaps":["Largely overexpression-based","Endogenous intracellular C1qA pool not localized","Mechanism of pathway contact unresolved"]},{"year":2015,"claim":"Established C1q as a causal mediator of complement-driven neurodegeneration by showing C1qa deletion protects retinal ganglion cells and reduces microglial activation in glaucoma.","evidence":"Congenic C1qa KO in DBA/2NNia glaucoma model with RGC/optic nerve scoring, IOP, and microglial morphology","pmids":["26544197"],"confidence":"Medium","gaps":["Sex-dependent timing unexplained","Downstream complement effectors not dissected"]},{"year":2021,"claim":"Demonstrated that classical complement via C1qa is host-protective against viral infection, complementing the disease-promoting CNS roles.","evidence":"CRISPR/Cas9 C1qa KO mice infected with MHV-A59 with histopathology, viral load, and cytokine quantification","pmids":["34056877"],"confidence":"Medium","gaps":["Mechanism of protection (opsonization vs lysis) not separated","Single coronavirus model"]},{"year":2023,"claim":"Identified post-transcriptional control of C1QA via m6A, showing METTL3/YTHDF2 suppress C1qA and that restoring it overcomes Rituximab resistance.","evidence":"RIP-qPCR and pulldown identifying METTL3 writer and YTHDF2 reader, with C1QA KD/OE in DLBCL cells, CDC assays, and xenografts","pmids":["37907575"],"confidence":"Medium","gaps":["Single lab","m6A sites on C1QA mRNA not mapped"]},{"year":2024,"claim":"Implicated elevated microglial C1qA in aberrant synaptic pruning in Alzheimer's model brain, correlating it with spine and synaptic protein loss.","evidence":"RNA-seq, immunofluorescence, western blot, Golgi staining, and patch-clamp in FAD4T mice","pmids":["38266812"],"confidence":"Low","gaps":["Correlative without direct C1qA manipulation","Causality between C1qA and pruning not established in this model"]},{"year":2024,"claim":"Placed C1qA within a tumor-associated macrophage feedback loop promoting M2-like polarization and immune suppression.","evidence":"NLRP12 OE/KD and KO in TAMs with co-culture, NF-κB analysis, and tumor growth assays in lung adenocarcinoma","pmids":["39527158"],"confidence":"Low","gaps":["C1qA link inferred from correlation and NLRP12 phenotype","Direct C1qA-LILRB4/NF-κB biochemistry not shown"]},{"year":2024,"claim":"Revealed context-dependent dual roles of C1qa in intracerebral hemorrhage, both promoting erythrolysis/neutrophil infiltration and supporting protective hematoma clearance.","evidence":"C1qa KO mice in autologous blood and thrombin ICH models with MRI and immunohistochemistry","pmids":["39370487"],"confidence":"Medium","gaps":["Opposing effects across models not mechanistically reconciled","Cellular effectors downstream of C1q unclear"]},{"year":2025,"claim":"Defined a non-canonical C1QA contribution to maintaining basal norrin/FZD4 beta-catenin signaling and blood-retina barrier integrity through genetic epistasis.","evidence":"Compound Tspan12 KO; C1qa KO mice with BRB assays, ERG, edema imaging, and cell-based beta-catenin signaling (preprint)","pmids":["bio_10.1101_2025.07.22.666172"],"confidence":"Medium","gaps":["Preprint, single lab","Direct molecular link between C1qA and FZD4 signaling not established"]},{"year":2025,"claim":"Positioned C1qA downstream of proprioceptor activity in activity-dependent complement-mediated synapse elimination, showing it is required to prune excess intersegmental Ia afferent connections.","evidence":"Ex vivo spinal cord electrophysiology, C1qa KO and NaV1.6 cKO models, C1qA immunostaining, and Ia afferent tracing (preprint)","pmids":["bio_10.1101_2025.08.22.671861"],"confidence":"Medium","gaps":["Preprint, single lab","Mechanism linking activity to C1qA induction unknown"]},{"year":null,"claim":"How C1QA's distinct extracellular complement-initiating role and its intracellular antiviral and signaling functions are partitioned within and across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural basis for intracellular RIG-I pathway contacts","Determinants directing C1qA to synaptic vs vascular vs antiviral roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,7]}],"complexes":["C1 complex (C1q)"],"partners":["RIGI","GC1QR","METTL3","YTHDF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02745","full_name":"Complement C1q subcomponent subunit A","aliases":[],"length_aa":245,"mass_kda":26.0,"function":"Core component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:12847249, PubMed:19006321, PubMed:24626930, PubMed:29449492, PubMed:3258649, PubMed:34155115, PubMed:6249812, PubMed:6776418). The classical complement pathway is initiated by the C1Q subcomplex of the C1 complex, which specifically binds IgG or IgM immunoglobulins complexed with antigens, forming antigen-antibody complexes on the surface of pathogens: C1QA, together with C1QB and C1QC, specifically recognizes and binds the Fc regions of IgG or IgM via its C1q domain (PubMed:12847249, PubMed:19006321, PubMed:24626930, PubMed:29449492, PubMed:3258649, PubMed:6776418). Immunoglobulin-binding activates the proenzyme C1R, which cleaves C1S, initiating the proteolytic cascade of the complement system (PubMed:29449492). The C1Q subcomplex is activated by a hexamer of IgG complexed with antigens, while it is activated by a pentameric IgM (PubMed:19706439, PubMed:24626930, PubMed:29449492). The C1Q subcomplex also recognizes and binds phosphatidylserine exposed on the surface of cells undergoing programmed cell death, possibly promoting activation of the complement system (PubMed:18250442)","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/P02745/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QA","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/C1QA","total_profiled":1310},"omim":[{"mim_id":"614330","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 2; C1QL2","url":"https://www.omim.org/entry/614330"},{"mim_id":"614285","title":"C1q- AND TUMOR NECROSIS FACTOR-RELATED PROTEIN 9; C1QTNF9","url":"https://www.omim.org/entry/614285"},{"mim_id":"614148","title":"C1q- AND TUMOR NECROSIS FACTOR-RELATED PROTEIN 9B; C1QTNF9B","url":"https://www.omim.org/entry/614148"},{"mim_id":"614147","title":"C1q- AND TUMOR NECROSIS FACTOR-RELATED PROTEIN 8; C1QTNF8","url":"https://www.omim.org/entry/614147"},{"mim_id":"613652","title":"C1q DEFICIENCY 1; C1QD1","url":"https://www.omim.org/entry/613652"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":604.1},{"tissue":"lymphoid tissue","ntpm":1056.2}],"url":"https://www.proteinatlas.org/search/C1QA"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P02745","domains":[{"cath_id":"2.60.120.40","chopping":"114-242","consensus_level":"high","plddt":94.9244,"start":114,"end":242}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02745","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02745-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02745-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QA","jax_strain_url":"https://www.jax.org/strain/search?query=C1QA"},"sequence":{"accession":"P02745","fasta_url":"https://rest.uniprot.org/uniprotkb/P02745.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02745/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02745"}},"corpus_meta":[{"pmid":"28264694","id":"PMC_28264694","title":"Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain.","date":"2017","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/28264694","citation_count":292,"is_preprint":false},{"pmid":"18927313","id":"PMC_18927313","title":"A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma.","date":"2008","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/18927313","citation_count":119,"is_preprint":false},{"pmid":"11564823","id":"PMC_11564823","title":"Reconstitution of the complement function in C1q-deficient (C1qa-/-) mice with wild-type bone marrow cells.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11564823","citation_count":96,"is_preprint":false},{"pmid":"33133060","id":"PMC_33133060","title":"Increased Macrophages and C1qA, C3, C4 Transcripts in the Midbrain of People With Schizophrenia.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33133060","citation_count":78,"is_preprint":false},{"pmid":"12630757","id":"PMC_12630757","title":"Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus.","date":"2003","source":"Lupus","url":"https://pubmed.ncbi.nlm.nih.gov/12630757","citation_count":66,"is_preprint":false},{"pmid":"10209207","id":"PMC_10209207","title":"C1q binding to liposomes is surface charge dependent and is inhibited by peptides consisting of residues 14-26 of the human C1qA chain in a sequence independent manner.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10209207","citation_count":56,"is_preprint":false},{"pmid":"19656971","id":"PMC_19656971","title":"Influenza A virus M1 blocks the classical complement pathway through interacting with C1qA.","date":"2009","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/19656971","citation_count":42,"is_preprint":false},{"pmid":"38266812","id":"PMC_38266812","title":"Cognitive impairment in Alzheimer's disease FAD4T mouse model: Synaptic loss facilitated by activated microglia via C1qA.","date":"2024","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38266812","citation_count":29,"is_preprint":false},{"pmid":"16465510","id":"PMC_16465510","title":"The pattern of clinical breast cancer metastasis correlates with a single nucleotide polymorphism in the C1qA component of complement.","date":"2006","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16465510","citation_count":26,"is_preprint":false},{"pmid":"22260551","id":"PMC_22260551","title":"The complement C1qA enhances retinoic acid-inducible gene-I-mediated immune signalling.","date":"2012","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22260551","citation_count":25,"is_preprint":false},{"pmid":"20332777","id":"PMC_20332777","title":"Common germ-line polymorphism of C1QA and breast cancer survival.","date":"2010","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20332777","citation_count":16,"is_preprint":false},{"pmid":"31019999","id":"PMC_31019999","title":"C1QA and C1QC modify age-at-onset in familial amyloid polyneuropathy patients.","date":"2019","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31019999","citation_count":15,"is_preprint":false},{"pmid":"20560256","id":"PMC_20560256","title":"Hereditary C1q deficiency: a new family with C1qA deficiency.","date":"2010","source":"The Turkish journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/20560256","citation_count":15,"is_preprint":false},{"pmid":"22236909","id":"PMC_22236909","title":"Association study of C1qA polymorphisms with systemic lupus erythematosus in a Han population.","date":"2012","source":"Lupus","url":"https://pubmed.ncbi.nlm.nih.gov/22236909","citation_count":14,"is_preprint":false},{"pmid":"22472776","id":"PMC_22472776","title":"Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency.","date":"2012","source":"Lupus","url":"https://pubmed.ncbi.nlm.nih.gov/22472776","citation_count":13,"is_preprint":false},{"pmid":"26544197","id":"PMC_26544197","title":"Differential Effects of C1qa Ablation on Glaucomatous Damage in Two Sexes in DBA/2NNia Mice.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26544197","citation_count":12,"is_preprint":false},{"pmid":"32556499","id":"PMC_32556499","title":"A regulatory variant in the C1Q gene cluster is associated with tuberculosis susceptibility and C1qA plasma levels in a South African population.","date":"2020","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/32556499","citation_count":11,"is_preprint":false},{"pmid":"38328228","id":"PMC_38328228","title":"C1QA is an invariant biomarker for tissue macrophages.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38328228","citation_count":10,"is_preprint":false},{"pmid":"37907575","id":"PMC_37907575","title":"METTL3-mediated m6A methylation of C1qA regulates the Rituximab resistance of diffuse large B-cell lymphoma cells.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37907575","citation_count":10,"is_preprint":false},{"pmid":"35733178","id":"PMC_35733178","title":"Potential biomarkers of spinal dural arteriovenous fistula: C4BPA and C1QA.","date":"2022","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/35733178","citation_count":10,"is_preprint":false},{"pmid":"38030709","id":"PMC_38030709","title":"C1QA and COMP: plasma-based biomarkers for early diagnosis of pancreatic neuroendocrine tumors.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38030709","citation_count":9,"is_preprint":false},{"pmid":"36212588","id":"PMC_36212588","title":"In silico analysis of missense variants of the C1qA gene related to infection and autoimmune diseases.","date":"2022","source":"Journal of Taibah University Medical Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36212588","citation_count":9,"is_preprint":false},{"pmid":"36544679","id":"PMC_36544679","title":"Multi-omics profiling identifies C1QA/B+ macrophages with multiple immune checkpoints associated with esophageal squamous cell carcinoma (ESCC) liver metastasis.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36544679","citation_count":8,"is_preprint":false},{"pmid":"39527158","id":"PMC_39527158","title":"NLRP12/C1qA positive feedback in tumor-associated macrophages regulates immunosuppression through LILRB4/NF-κB pathway in lung adenocarcinoma.","date":"2024","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/39527158","citation_count":6,"is_preprint":false},{"pmid":"34056877","id":"PMC_34056877","title":"C1qa deficiency in mice increases susceptibility to mouse hepatitis virus A59 infection.","date":"2021","source":"Journal of veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/34056877","citation_count":5,"is_preprint":false},{"pmid":"39370487","id":"PMC_39370487","title":"The Role of Complement C1qa in Experimental Intracerebral Hemorrhage.","date":"2024","source":"Translational stroke research","url":"https://pubmed.ncbi.nlm.nih.gov/39370487","citation_count":3,"is_preprint":false},{"pmid":"38447782","id":"PMC_38447782","title":"Identification of the C1qDC gene family in grass carp (Ctenopharyngodon idellus) and the response of C1qA, C1qB, and C1qC to GCRV infection in vivo and in vitro.","date":"2024","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38447782","citation_count":3,"is_preprint":false},{"pmid":"39086409","id":"PMC_39086409","title":"Correlation between Complement C1q A Chain (C1QA) and Macrophages in the Progression of Carotid Atherosclerosis.","date":"2024","source":"Iranian journal of public health","url":"https://pubmed.ncbi.nlm.nih.gov/39086409","citation_count":1,"is_preprint":false},{"pmid":"39096524","id":"PMC_39096524","title":"Monogenic lupus with neuroregression in an infant due to rare compound heterozygous variants in C1QA gene: Case-based review.","date":"2025","source":"Modern rheumatology case reports","url":"https://pubmed.ncbi.nlm.nih.gov/39096524","citation_count":1,"is_preprint":false},{"pmid":"41997300","id":"PMC_41997300","title":"Mechanotransduction unifies healthy nondiabetic wound healing over time by promoting a Cd14+/C1qa+ fibroblast subpopulation.","date":"2026","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/41997300","citation_count":1,"is_preprint":false},{"pmid":"41383891","id":"PMC_41383891","title":"Investigation of miR-335-5p and Its Target Gene C1QA Associated with the Complement System in Conversion from Clinically Isolated Syndrome to Multiple Sclerosis.","date":"2025","source":"Noro psikiyatri arsivi","url":"https://pubmed.ncbi.nlm.nih.gov/41383891","citation_count":0,"is_preprint":false},{"pmid":"42242331","id":"PMC_42242331","title":"Single-cell-based analysis establishes C1QA-mediated promotion of high glucose-induced tubular epithelial injury via ERS in DN.","date":"2026","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/42242331","citation_count":0,"is_preprint":false},{"pmid":"42147803","id":"PMC_42147803","title":"Homozygous C1qA Deficiency Presenting as Early-Onset Systemic Lupus Erythematosus: A Case Report With a Literature Review.","date":"2026","source":"Case reports in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42147803","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.17.683046","title":"Single-cell RNA sequencing and large-scale bulk combination with machine learning reveal gastric cancer-related macrophage heterogeneity","date":"2025-10-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.17.683046","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.22.666172","title":"C1q limits cystoid edema by maintaining basal beta-catenin-dependent signaling and blood-retina barrier function","date":"2025-07-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.22.666172","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.06.25339648","title":"Peripheral transcriptomic signature of chronic antibody-mediated rejection in kidney transplantation: a dual effect for  <i>MMP9</i>  over time","date":"2025-11-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.06.25339648","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.22.671861","title":"Activity-driven proprioceptive synaptic refinement in the developing spinal cord by complement signaling mechanisms","date":"2025-08-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.22.671861","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.23.655738","title":"Effects of C3aR activated mast cells in eosinophilic esophagitis","date":"2025-05-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.23.655738","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.10.25331295","title":"Inflammatory Markers are Associated with Ischemic Stroke among Indigenous Africans: Evidence from the SIREN Study","date":"2025-08-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.10.25331295","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.07.637193","title":"Single-cell analysis of the human retina reveals stage-linked microglial states and neural-immune circuit rewiring in diabetic retinopathy","date":"2025-02-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.07.637193","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.17.24315623","title":"Identification of Shared and Unique Key Biomarkers of Alcohol Liver Cirrhosis and Non-Alcoholic Steatohepatitis Through Machine Learning Network-Based Algorithms","date":"2024-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.17.24315623","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.29.610301","title":"Single-Cell Analysis Reveals Critical Role of Macrophage Epsin in Regulating Origin of Foam Cell in Atherosclerosis","date":"2024-09-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.29.610301","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.30.605701","title":"Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation","date":"2024-07-31","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.30.605701","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.16.649149","title":"A Single-Cell Atlas Of Human Pediatric Liver Reveals Age-Related Hepatic Gene Signatures","date":"2025-04-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.16.649149","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25936,"output_tokens":4110,"usd":0.069729,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11884,"output_tokens":3586,"usd":0.074535,"stage2_stop_reason":"end_turn"},"total_usd":0.144264,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Bone marrow-derived cells (monocyte-macrophage lineage) are the source of serum C1q; transplantation of wild-type bone marrow into C1qa-/- mice fully reconstituted serum C1q levels within 6 weeks, while C1qa-/- bone marrow transferred into wild-type mice depleted C1q over 55 weeks.\",\n      \"method\": \"Bone marrow transplantation in C1qa-/- mice; serum C1q quantified by antigen assay and functional hemolytic assay; engraftment monitored by Y-chromosome PCR and genotype-specific PCR\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal bone marrow transfer experiment with bidirectional genetic rescue and depletion, replicated across irradiation doses\",\n      \"pmids\": [\"11564823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Microglia, not neurons or peripheral sources, are the dominant source of C1q in the brain; conditional knockout of C1qa specifically in microglia (Cx3cr1-Cre) abolished C1q in the brain parenchyma without affecting plasma or peripheral organ C1q levels.\",\n      \"method\": \"Cell-type-specific conditional knockout (C1qa floxed x Cx3cr1-CreERT2); immunohistochemistry, qPCR, and western blot for C1q in brain, liver, kidney, and plasma\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IHC, qPCR, western blot) with cell-type-specific genetic ablation, compared to neuron-specific and systemic controls\",\n      \"pmids\": [\"28264694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The cationic region comprising residues 14–26 of the C1qA polypeptide chain mediates C1q binding to anionic liposomes via electrostatic interactions; peptides containing this region (with ≥5 cationic residues) inhibited C1q binding to and complement activation by anionic liposomes in a charge-dependent, sequence-independent manner.\",\n      \"method\": \"Saturation binding assay with purified C1q and cardiolipin-containing liposomes; inhibition assays with synthetic C1qA14-26 peptides of varying charge; hemolytic complement activation assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified protein, peptide inhibition with mutagenesis-equivalent charge variants, multiple assay types in single study\",\n      \"pmids\": [\"10209207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Influenza A virus M1 matrix protein interacts with the globular region of C1qA through M1's N-terminal domain, blocking the interaction between C1qA and heat-aggregated IgG, inhibiting hemolysis, and preventing complement-mediated neutralization of influenza virus in vitro; in vivo, administered M1 promoted higher viral propagation and shortened survival of infected mice.\",\n      \"method\": \"Co-immunoprecipitation of M1 with C1qA; in vitro competition assay (M1 vs. heat-aggregated IgG for C1qA binding); hemolysis assay; neutralization assay; murine in vivo infection model with M1 administration\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus functional hemolysis and neutralization assays, single lab\",\n      \"pmids\": [\"19656971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"C1qA interacts with components of the RIG-I/VISA signaling pathway and enhances RIG-I–VISA-mediated and TBK1-mediated activation of the IFN-β promoter; overexpression of C1qA upregulates RIG-I-mediated ISRE and NF-κB reporter activation and IFN-β transcription, but does not affect IRF3- or IKK-mediated ISRE/NF-κB activation; C1qA also counteracts the inhibitory function of the C1q receptor gC1qR in RIG-I-mediated signaling.\",\n      \"method\": \"Co-immunoprecipitation of C1qA with RIG-I pathway components; luciferase reporter assays for ISRE, NF-κB, and IFN-β promoters upon C1qA overexpression; functional comparison with gC1qR\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus multiple functional reporter assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"22260551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"C1qA expression is regulated at the post-transcriptional level by METTL3-mediated m6A methylation; YTHDF2 acts as the m6A reader for C1qA mRNA; knockdown of METTL3 or YTHDF2 in Rituximab-resistant DLBCL cells upregulates C1qA expression, and restoring C1qA expression reduces Rituximab resistance both in vitro and in vivo.\",\n      \"method\": \"RNA immunoprecipitation with qPCR (RIP-qPCR); pulldown assays to identify METTL3 (writer) and YTHDF2 (reader); C1qA knockdown and overexpression in sensitive and resistant cell lines; in vitro CDC assays; xenograft mouse model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-qPCR and pulldown identifying writer/reader, combined with in vitro and in vivo KD/OE functional rescue, single lab\",\n      \"pmids\": [\"37907575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"C1qa deletion in DBA/2NNia mice reduces retinal ganglion cell and optic nerve axonal loss in a sex-dependent manner (protective in males at 9–10 months, protective in females at 11–13 months), and decreases microglial activation in male mice at 5–6 months, establishing C1q as a mediator of complement-driven RGC damage in glaucoma.\",\n      \"method\": \"Congenic C1qa knockout mice in glaucoma model; retrograde labeling and semi-quantitative scoring of RGC and optic nerve; IOP measurement; microglial morphology assessment in flat-mounted retinas\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined cellular phenotype (RGC loss, microglial activation) across multiple ages and sexes, single lab\",\n      \"pmids\": [\"26544197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1qa deficiency (CRISPR/Cas9 KO) enhances susceptibility to mouse hepatitis virus A59, resulting in more severe hepatocellular necrosis and interstitial pneumonia, higher viral loads in olfactory bulb, liver, and lungs, and dramatic elevations in splenic IFN-γ, MIP-1α, and MCP-1, demonstrating that classical complement pathway activation via C1qa is required for host protection against coronavirus infection.\",\n      \"method\": \"CRISPR/Cas9-generated C1qa KO mice; MHV-A59 infection model; histopathology; immunohistochemistry; quantitative viral load measurement; chemokine/cytokine quantification\",\n      \"journal\": \"Journal of veterinary science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple quantitative phenotypic readouts, single lab\",\n      \"pmids\": [\"34056877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In an AD mouse model (FAD4T), elevated C1qA protein and mRNA in activated microglia is associated with aberrant synaptic pruning leading to reduced dendritic spine density, decreased PSD-95 and NMDAR1 levels, and impaired miniature excitatory postsynaptic current amplitudes.\",\n      \"method\": \"RNA-seq; immunofluorescence; western blot; Golgi staining for dendritic spines; patch-clamp electrophysiology in hippocampal neurons\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative association between C1qA levels and synaptic phenotype in a disease model without direct mechanistic manipulation of C1qA\",\n      \"pmids\": [\"38266812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1qa knockout mice exhibit reduced hematoma erythrolysis, reduced neutrophil infiltration after intracerebral hemorrhage, but also delayed hematoma clearance associated with reduced induction of phagocytic multinuclear giant cells and increased perihematomal neuronal damage; after thrombin injection, C1qa KO mice had smaller lesion volumes, less neuronal loss, reduced neutrophil infiltration, and less BBB damage, indicating dual and context-dependent roles of C1qa in ICH-induced brain injury.\",\n      \"method\": \"C1qa KO mice; autologous blood injection and thrombin injection ICH models; MRI on days 1, 3, 7; immunohistochemistry for neutrophils, neurons, BBB markers, and phagocytic cells\",\n      \"journal\": \"Translational stroke research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple injury models and quantitative histological/imaging readouts, single lab\",\n      \"pmids\": [\"39370487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NLRP12 forms a positive feedback loop with C1qA in tumor-associated macrophages (TAMs) to drive protumor M2-like polarization via the LILRB4/NF-κB pathway; NLRP12 knockout reversed macrophage polarization, enhanced T-cell anti-tumor immunity, and suppressed tumor growth in lung adenocarcinoma models.\",\n      \"method\": \"NLRP12 overexpression and knockdown in TAMs; NLRP12 KO mouse model; co-culture with tumor cells and T cells; NF-κB pathway analysis; tumor growth assays\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — NLRP12/C1qA interaction inferred from expression correlation and NLRP12 KO phenotype; direct mechanistic link between C1qA and LILRB4/NF-κB not biochemically established for C1qA specifically\",\n      \"pmids\": [\"39527158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2032,\n      \"finding\": \"Silencing C1QA in high-glucose-treated human renal tubular epithelial cells (HK-2) attenuated suppression of proliferation and reduced apoptosis, and concurrently downregulated endoplasmic reticulum stress effector proteins CHOP, XBP1s, and ATF6, indicating C1QA promotes HG-induced tubular epithelial injury by potentiating ERS.\",\n      \"method\": \"C1QA siRNA knockdown in HK-2 cells under high glucose conditions; CCK-8 viability assay; EdU proliferation assay; flow cytometry for apoptosis; western blot for ERS markers (CHOP, XBP1s, ATF6)\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function (siRNA) with multiple orthogonal cellular and molecular readouts, single lab\",\n      \"pmids\": [\"42242331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C1QA contributes to maintaining basal beta-catenin-dependent (norrin/FZD4) signaling in the retina; absence of C1QA in compound Tspan12 KO DBM; C1qa KO mice exacerbates blood-retina barrier dysfunction, cystoid edema, and neuroinflammation compared to Tspan12 KO DBM alone.\",\n      \"method\": \"Compound mutant mice (Tspan12 KO DBM; C1qa KO); BRB functional assays; MRI/imaging for cystoid edema assessment; ERG; microglia activation analysis; cell-based beta-catenin signaling assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via compound KO with functional BRB and signaling readouts, single lab preprint\",\n      \"pmids\": [\"bio_10.1101_2025.07.22.666172\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C1qA-deficient (C1qa KO) neonatal mice retain intersegmental proprioceptive Ia afferent connections at P11–13 that are normally eliminated by P11–13, phenocopying NaV1.6 conditional KO mice with impaired proprioceptor activity; NaV1.6 cKO mice show reduced C1qA expression in ventral spinal cord at P9, placing C1qA downstream of proprioceptor activity in complement-mediated elimination of excessive intersegmental synaptic connectivity.\",\n      \"method\": \"Ex vivo spinal cord electrophysiology in neonatal mice; C1qa KO and NaV1.6 cKO genetic models; immunostaining for C1qA expression; anatomical tracing of proprioceptive Ia afferents\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (NaV1.6 cKO → reduced C1qA → phenocopy of C1qa KO) with electrophysiology and anatomical readouts, single lab preprint\",\n      \"pmids\": [\"bio_10.1101_2025.08.22.671861\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"C1QA encodes the A-chain of the C1q protein, which is produced predominantly by tissue macrophages and microglia (not neurons or hepatocytes); its cationic collagen-like domain (residues 14–26) mediates electrostatic binding to anionic surfaces to initiate classical complement activation; intracellularly, C1QA also enhances RIG-I/VISA-mediated antiviral IFN-β signaling and is regulated post-transcriptionally by METTL3/YTHDF2-mediated m6A methylation; in the CNS, microglia-derived C1q drives complement-dependent synaptic pruning and RGC loss, and is required for normal activity-dependent elimination of excess proprioceptive intersegmental connections; C1QA also supports blood-retina barrier integrity via basal beta-catenin/FZD4 signaling, and its deficiency increases susceptibility to viral infection while having complex dual effects on injury responses such as intracerebral hemorrhage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QA encodes the A-chain of the complement protein C1q, which is produced by myeloid cells: reciprocal bone marrow transfer established that monocyte-macrophage lineage cells, not hepatocytes, are the source of circulating C1q [#0], and in the brain microglia are the dominant source, with parenchymal C1q lost upon microglial-specific deletion while peripheral C1q remains intact [#1]. The protein initiates classical complement activation through electrostatic recognition: a cationic region spanning residues 14\\u201326 of the A-chain mediates charge-dependent binding to anionic surfaces and is required for complement activation on such targets [#2]. Beyond complement initiation, C1QA participates intracellularly in antiviral signaling, interacting with the RIG-I/VISA pathway to enhance TBK1-driven IFN-\\u03b2 promoter activation and counteracting the inhibitory C1q receptor gC1qR [#4], and its expression is constrained post-transcriptionally by METTL3-deposited m6A marks read by YTHDF2 [#5]. Genetic ablation studies define a host-protective complement role against viral infection [#7] and a damaging role in complement-driven neurodegeneration, where microglia-derived C1q mediates retinal ganglion cell and optic nerve loss [#6] and is required for activity-dependent elimination of excess proprioceptive Ia afferent connections downstream of proprioceptor activity [#13]. C1QA also supports basal norrin/FZD4 beta-catenin signaling and blood-retina barrier integrity [#12], and exerts context-dependent dual effects on injury after intracerebral hemorrhage [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified the molecular basis by which C1q recognizes activating surfaces, showing that a defined cationic stretch of the A-chain drives complement initiation through electrostatics rather than specific sequence recognition.\",\n      \"evidence\": \"In vitro binding and inhibition assays with purified C1q, anionic liposomes, and synthetic C1qA14-26 charge-variant peptides plus hemolytic complement assay\",\n      \"pmids\": [\"10209207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the physiological anionic ligands in vivo\", \"No structural model of the bound complex\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved the cellular origin of serum C1q, establishing the monocyte-macrophage lineage rather than liver as the source through bidirectional genetic rescue and depletion.\",\n      \"evidence\": \"Reciprocal bone marrow transplantation in C1qa-/- and wild-type mice with antigenic and hemolytic C1q quantification\",\n      \"pmids\": [\"11564823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address tissue-resident vs circulating macrophage contributions\", \"Brain source not examined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that a viral protein can subvert C1q-mediated immunity by binding the globular A-chain region, linking C1QA's recognition function to antiviral defense.\",\n      \"evidence\": \"Co-IP of influenza M1 with C1qA, competition assays against heat-aggregated IgG, hemolysis, neutralization, and murine infection\",\n      \"pmids\": [\"19656971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological relevance of soluble M1 during natural infection unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended C1QA function beyond extracellular complement to an intracellular role in innate antiviral signaling by potentiating RIG-I/VISA-mediated IFN-\\u03b2 induction.\",\n      \"evidence\": \"Co-IP of C1qA with RIG-I pathway components and luciferase reporter assays for ISRE, NF-\\u03baB, and IFN-\\u03b2 promoters with gC1qR comparison\",\n      \"pmids\": [\"22260551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Largely overexpression-based\", \"Endogenous intracellular C1qA pool not localized\", \"Mechanism of pathway contact unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established C1q as a causal mediator of complement-driven neurodegeneration by showing C1qa deletion protects retinal ganglion cells and reduces microglial activation in glaucoma.\",\n      \"evidence\": \"Congenic C1qa KO in DBA/2NNia glaucoma model with RGC/optic nerve scoring, IOP, and microglial morphology\",\n      \"pmids\": [\"26544197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sex-dependent timing unexplained\", \"Downstream complement effectors not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that classical complement via C1qa is host-protective against viral infection, complementing the disease-promoting CNS roles.\",\n      \"evidence\": \"CRISPR/Cas9 C1qa KO mice infected with MHV-A59 with histopathology, viral load, and cytokine quantification\",\n      \"pmids\": [\"34056877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of protection (opsonization vs lysis) not separated\", \"Single coronavirus model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified post-transcriptional control of C1QA via m6A, showing METTL3/YTHDF2 suppress C1qA and that restoring it overcomes Rituximab resistance.\",\n      \"evidence\": \"RIP-qPCR and pulldown identifying METTL3 writer and YTHDF2 reader, with C1QA KD/OE in DLBCL cells, CDC assays, and xenografts\",\n      \"pmids\": [\"37907575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"m6A sites on C1QA mRNA not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated elevated microglial C1qA in aberrant synaptic pruning in Alzheimer's model brain, correlating it with spine and synaptic protein loss.\",\n      \"evidence\": \"RNA-seq, immunofluorescence, western blot, Golgi staining, and patch-clamp in FAD4T mice\",\n      \"pmids\": [\"38266812\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative without direct C1qA manipulation\", \"Causality between C1qA and pruning not established in this model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed C1qA within a tumor-associated macrophage feedback loop promoting M2-like polarization and immune suppression.\",\n      \"evidence\": \"NLRP12 OE/KD and KO in TAMs with co-culture, NF-\\u03baB analysis, and tumor growth assays in lung adenocarcinoma\",\n      \"pmids\": [\"39527158\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"C1qA link inferred from correlation and NLRP12 phenotype\", \"Direct C1qA-LILRB4/NF-\\u03baB biochemistry not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed context-dependent dual roles of C1qa in intracerebral hemorrhage, both promoting erythrolysis/neutrophil infiltration and supporting protective hematoma clearance.\",\n      \"evidence\": \"C1qa KO mice in autologous blood and thrombin ICH models with MRI and immunohistochemistry\",\n      \"pmids\": [\"39370487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing effects across models not mechanistically reconciled\", \"Cellular effectors downstream of C1q unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a non-canonical C1QA contribution to maintaining basal norrin/FZD4 beta-catenin signaling and blood-retina barrier integrity through genetic epistasis.\",\n      \"evidence\": \"Compound Tspan12 KO; C1qa KO mice with BRB assays, ERG, edema imaging, and cell-based beta-catenin signaling (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.22.666172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Direct molecular link between C1qA and FZD4 signaling not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned C1qA downstream of proprioceptor activity in activity-dependent complement-mediated synapse elimination, showing it is required to prune excess intersegmental Ia afferent connections.\",\n      \"evidence\": \"Ex vivo spinal cord electrophysiology, C1qa KO and NaV1.6 cKO models, C1qA immunostaining, and Ia afferent tracing (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.22.671861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Mechanism linking activity to C1qA induction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How C1QA's distinct extracellular complement-initiating role and its intracellular antiviral and signaling functions are partitioned within and across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural basis for intracellular RIG-I pathway contacts\", \"Determinants directing C1qA to synaptic vs vascular vs antiviral roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 7]}\n    ],\n    \"complexes\": [\"C1 complex (C1q)\"],\n    \"partners\": [\"RIGI\", \"gC1qR\", \"METTL3\", \"YTHDF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":5,"faith_pct":80.0}}