{"gene":"C6","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":1993,"finding":"The human C6 gene spans 18 exons; analysis of 17 exon boundaries revealed that the intron/exon organization of C6 (and related terminal complement components C7 and C9) does not follow the conventional pattern where recognized protein modules are bounded by class 1 introns, suggesting a more complex evolutionary history for terminal complement component genes than anticipated.","method":"Genomic DNA sequencing, exon boundary mapping, comparison with published C7 and C9 gene structures","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct sequencing of 17/18 exons with boundary classification; single study","pmids":["8512929"],"is_preprint":false},{"year":1995,"finding":"A naturally occurring carboxy-terminally truncated C6 molecule (14% shorter than normal C6), arising from an abnormal 5' splice donor site in intron 15 that creates an in-frame stop codon 17 codons downstream, retains bactericidal activity, demonstrating that the carboxy-terminal region of C6 is dispensable for membrane attack complex function.","method":"PCR amplification and sequencing of C6 genomic region; expression of C6 cDNA fragments as fusion proteins in pUEX system to map epitopes; hemolytic/bactericidal assays of patient serum","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1-2 — combined sequencing, epitope mapping by expressed fusion proteins, and functional bactericidal assay; replicated in three individuals from two families","pmids":["7535801"],"is_preprint":false},{"year":1995,"finding":"Haplotype analysis using seven DNA markers across the linked C6 and C7 loci revealed that complete C6 deficiency (C6*Q0) is associated with at least four haplotypes, with one common defective haplotype predominating in South African patients; subtotal C6 deficiency (C6*SD) shares a haplotype with combined C6/C7 deficiency, indicating the C6 gene defect alone does not explain the associated C7 deficiency.","method":"DNA marker haplotyping (7 markers spanning ~300 kbp of chromosome 5p12-14) in patients and family members; comparison with protein phenotyping","journal":"Annals of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multi-marker haplotyping in defined patient cohorts; single study but comprehensive marker coverage","pmids":["7625765"],"is_preprint":false},{"year":1995,"finding":"Three C6 DNA polymorphisms were localized precisely within the C6 gene: one in exon 3, one in intron 3, and one adjacent to exon 17; together with four C7 markers, these define 128 possible haplotypes across ~300 kbp of chromosome 5p12-14, and allelic associations between C6 and C7 markers are surprisingly weak.","method":"RFLP analysis, DNA sequencing, gene frequency estimation in North European Caucasian and Japanese populations","journal":"Annals of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization of polymorphisms within gene structure; population-level replication","pmids":["7625764"],"is_preprint":false},{"year":1977,"finding":"Genetic linkage analysis excludes linkage between the C6 locus and HLA region marker loci on chromosome 6, and also excludes linkage to PGM3; C6 electrophoretic variants (C6A and C6B) were identified with allele frequencies of 0.61 and 0.39 respectively in a Norwegian population, establishing C6 as a genetically polymorphic protein.","method":"High-voltage agarose gel electrophoresis and isoelectric focusing with hemolytic assay; LOD score linkage analysis in families","journal":"Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein typing plus formal linkage analysis; foundational mapping study","pmids":["885533"],"is_preprint":false},{"year":1997,"finding":"C6 deficiency in the PVG/c rat strain is not caused by a large gene deletion (Southern blot normal) but is associated with ~100-fold reduced C6 mRNA in liver; C6 mRNA of normal size (~3.3 kb) is present at low levels and C6 mRNA is also detectable in kidney by RT-PCR, indicating the defect likely involves a point mutation causing mRNA instability or aberrant transcription rather than a structural gene deletion.","method":"Northern blot analysis, RT-PCR with rat C6-specific primers cloned from liver cDNA library using human C6 as probe, Southern blot of genomic DNA, immunization to generate anti-rat C6 antibodies for antigen detection","journal":"Clinical and Experimental Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Northern, Southern, RT-PCR, immunological); single laboratory","pmids":["9276537"],"is_preprint":false},{"year":2001,"finding":"C6 mRNA expression is significantly reduced in esophageal carcinoma tissues compared to paired normal esophageal epithelium, and similar reductions occur in colon and kidney cancers; Southern blot analysis showed no gene deletion in cancer cell lines, suggesting transcriptional downregulation rather than genomic loss underlies reduced C6 expression in tumors.","method":"Differential display of tumor/normal pairs, in situ hybridization, semi-quantitative RT-PCR in 10 tumor/normal pairs, Southern blot, tumor/normal expression array analysis","journal":"European Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (differential display, ISH, RT-PCR, Southern) in paired human specimens; single study","pmids":["11378347"],"is_preprint":false},{"year":2020,"finding":"C6 knockout mice exhibit defective innate immune responses including impaired PMN surface adhesion molecule expression, superoxide generation, reactive oxygen species production, histone release, and phagocytosis; C6-deficient PMNs and macrophages have defective NLRP3 inflammasome activation. C6-/- mice subjected to polymicrobial sepsis show improved survival with reduced proinflammatory cytokines/chemokines, attenuated cardiac dysfunction, and reduced lung injury in LPS-induced acute lung injury, indicating C6-dependent MAC formation drives organ damage during sepsis.","method":"C6 knockout mouse model; flow cytometry for surface molecules; superoxide/ROS assays; phagocytosis assays; NLRP3 inflammasome activation assays in PMNs and macrophages; cecal ligation puncture polymicrobial sepsis model; LPS-induced acute lung injury model; ELISA for cytokines/chemokines/histones","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple orthogonal cellular and in vivo phenotypic readouts across two disease models; single laboratory but comprehensive","pmids":["32444389"],"is_preprint":false}],"current_model":"Complement C6 is a terminal complement component encoded on chromosome 5p12-14 whose 18-exon gene produces a mosaic protein that, when incorporated into the membrane attack complex, drives cell lysis and innate immune activation; a carboxy-terminally truncated C6 retains bactericidal activity, liver is the primary site of C6 mRNA expression, C6 mRNA is transcriptionally downregulated in several carcinomas without genomic deletion, and genetic ablation of C6 in mice establishes that MAC-dependent C6 activity is required for normal PMN/macrophage innate immune functions (adhesion, ROS, phagocytosis, NLRP3 inflammasome) and drives organ injury in sepsis and acute lung injury."},"narrative":{"teleology":[{"year":1977,"claim":"Establishing that C6 is a genetically polymorphic serum protein whose locus is unlinked to the MHC region addressed the fundamental question of where C6 maps and whether it co-segregates with other immune loci.","evidence":"High-voltage agarose electrophoresis, isoelectric focusing with hemolytic overlay, and LOD score linkage analysis in Norwegian families","pmids":["885533"],"confidence":"Medium","gaps":["Chromosomal assignment was not determined in this study","Functional consequences of C6 allelic variants (C6A vs C6B) not characterized"]},{"year":1993,"claim":"Determination that the C6 gene spans 18 exons whose boundaries do not follow the expected class 1 intron/module pattern resolved the structural genomic organization and challenged assumptions about how terminal complement component genes evolved.","evidence":"Genomic DNA sequencing and exon boundary classification across 17 of 18 exon junctions","pmids":["8512929"],"confidence":"Medium","gaps":["One exon boundary was not characterized","Promoter and regulatory elements upstream of the gene were not defined"]},{"year":1995,"claim":"Discovery that a naturally occurring C-terminally truncated C6 retains bactericidal function demonstrated that the distal ~14% of the protein is dispensable for MAC assembly and lytic activity, redefining the minimal functional unit of C6.","evidence":"PCR/sequencing of a splice-site mutation in intron 15 creating premature stop codon; hemolytic and bactericidal assays of patient serum; replicated across three individuals from two families","pmids":["7535801"],"confidence":"High","gaps":["Whether the truncated C6 has altered kinetics of MAC insertion or assembly was not assessed","Structural basis for dispensability of the C-terminal region is unknown"]},{"year":1995,"claim":"Multi-marker haplotyping across the C6/C7 locus revealed that complete C6 deficiency arises from multiple independent mutations, with subtotal C6 deficiency sharing a haplotype with combined C6/C7 deficiency, clarifying the genetic heterogeneity underlying C6 deficiency states.","evidence":"DNA marker haplotyping using 7 markers spanning ~300 kbp of chromosome 5p12-14 in South African and other patient cohorts","pmids":["7625765","7625764"],"confidence":"Medium","gaps":["Causative mutations for each deficiency haplotype were not identified","Mechanism linking the C6 defect haplotype to associated C7 deficiency was not resolved"]},{"year":1997,"claim":"Finding that C6 deficiency in the PVG/c rat arises from ~100-fold reduced mRNA rather than gene deletion established that regulatory or mRNA stability defects can abolish C6 protein without structural gene loss, and identified liver as the primary expression site.","evidence":"Northern blot, RT-PCR, and Southern blot in PVG/c rat liver and kidney; comparison with wild-type","pmids":["9276537"],"confidence":"Medium","gaps":["The causative point mutation or regulatory lesion was not identified","Contribution of extrahepatic C6 expression (e.g. kidney) to circulating levels was not quantified"]},{"year":2001,"claim":"Demonstrating that C6 mRNA is transcriptionally downregulated in esophageal, colon, and kidney carcinomas without genomic deletion raised the possibility that tumors evade complement-mediated surveillance by silencing terminal complement components.","evidence":"Differential display, in situ hybridization, semi-quantitative RT-PCR in 10 paired human tumor/normal specimens, and Southern blot in cancer cell lines","pmids":["11378347"],"confidence":"Medium","gaps":["Mechanism of transcriptional downregulation (promoter methylation, transcription factor loss) was not identified","Functional consequence of C6 loss for tumor immune evasion was not tested experimentally"]},{"year":2020,"claim":"Genetic ablation of C6 in mice revealed that MAC-dependent C6 activity is required for multiple innate immune effector functions and is a major driver of organ damage in sepsis and acute lung injury, establishing C6/MAC as a double-edged sword in innate immunity.","evidence":"C6 knockout mice assessed by flow cytometry, ROS/superoxide assays, phagocytosis assays, NLRP3 inflammasome activation in PMNs and macrophages, cecal ligation puncture sepsis model, and LPS-induced acute lung injury model","pmids":["32444389"],"confidence":"High","gaps":["Whether C6/MAC effects on innate cells are direct (sublytic MAC signaling) or indirect (via downstream mediators) was not resolved","Findings from a single laboratory; independent replication in other KO or inhibitor models pending","Relevance of mouse C6 KO phenotypes to human C6 deficiency states not formally demonstrated"]},{"year":null,"claim":"Key unresolved questions include the precise mechanism by which MAC/sublytic MAC activates NLRP3 inflammasome in innate immune cells, the structural basis for the dispensability of the C6 C-terminal domain, and the epigenetic mechanism responsible for C6 silencing in carcinomas.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of C6 within the assembled MAC pore at atomic resolution","Sublytic vs lytic MAC signaling pathways downstream of C6 incorporation not delineated","Therapeutic potential of C6 inhibition in sepsis not tested in clinical settings"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,7]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,4,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7]}],"complexes":["Membrane attack complex (MAC, C5b-9)"],"partners":["C5B","C7","C8","C9"],"other_free_text":[]},"mechanistic_narrative":"Complement component C6 is a terminal complement protein that assembles into the membrane attack complex (MAC) to mediate cell lysis and shape innate immune responses. The C6 gene spans 18 exons on chromosome 5p12-14 with a mosaic domain architecture whose intron/exon boundaries do not conform to the conventional module-class 1 intron paradigm, suggesting a complex evolutionary origin for terminal complement components [PMID:8512929]. A naturally occurring carboxy-terminal truncation (loss of ~14% of the protein) retains bactericidal activity, demonstrating that the C-terminal region is dispensable for MAC-dependent killing [PMID:7535801]. Genetic ablation of C6 in mice reveals that MAC-dependent C6 activity is required for normal PMN and macrophage innate immune functions—including adhesion molecule expression, superoxide generation, phagocytosis, and NLRP3 inflammasome activation—and drives organ injury in sepsis and acute lung injury models [PMID:32444389]."},"prefetch_data":{"uniprot":{"accession":"P13671","full_name":"Complement component C6","aliases":[],"length_aa":934,"mass_kda":104.8,"function":"Component of the membrane attack complex (MAC), a multiprotein complex activated by the complement cascade, which inserts into a target cell membrane and forms a pore, leading to target cell membrane rupture and cell lysis (PubMed:22267737, PubMed:22832194, PubMed:26841837, PubMed:27052168, PubMed:30552328). The MAC is initiated by proteolytic cleavage of C5 into complement C5b in response to the classical, alternative, lectin and GZMK complement pathways (PubMed:30552328, PubMed:39914456, PubMed:39814882). The complement pathways consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:30552328). Together with component C5b, involved in MAC complex assembly: complement C5b and C6 associate with the outer leaflet of target cell membrane, reducing the energy for membrane bending (PubMed:30552328, PubMed:32569291)","subcellular_location":"Secreted; Target cell membrane","url":"https://www.uniprot.org/uniprotkb/P13671/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C6","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/C6","total_profiled":1310},"omim":[{"mim_id":"620300","title":"MITOCHONDRIAL TRIFUNCTIONAL PROTEIN DEFICIENCY 2; MTPD2","url":"https://www.omim.org/entry/620300"},{"mim_id":"619872","title":"IMMUNODEFICIENCY 101 (VARICELLA ZOSTER VIRUS-SPECIFIC); IMD101","url":"https://www.omim.org/entry/619872"},{"mim_id":"619327","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 15; LRRC15","url":"https://www.omim.org/entry/619327"},{"mim_id":"617455","title":"POLYMERASE III, RNA, SUBUNIT F; POLR3F","url":"https://www.omim.org/entry/617455"},{"mim_id":"617363","title":"TRANSMEMBRANE PROTEIN 132A; TMEM132A","url":"https://www.omim.org/entry/617363"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":588.3}],"url":"https://www.proteinatlas.org/search/C6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P13671","domains":[{"cath_id":"2.20.100.10","chopping":"25-76","consensus_level":"medium","plddt":84.0248,"start":25,"end":76},{"cath_id":"-","chopping":"180-262_294-519","consensus_level":"medium","plddt":83.2556,"start":180,"end":519},{"cath_id":"2.10.70.10","chopping":"646-702","consensus_level":"medium","plddt":85.0316,"start":646,"end":702},{"cath_id":"2.10.70.10","chopping":"704-764","consensus_level":"medium","plddt":77.8443,"start":704,"end":764}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13671","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13671-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13671-F1-predicted_aligned_error_v6.png","plddt_mean":79.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C6","jax_strain_url":"https://www.jax.org/strain/search?query=C6"},"sequence":{"accession":"P13671","fasta_url":"https://rest.uniprot.org/uniprotkb/P13671.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13671/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13671"}},"corpus_meta":[{"pmid":"9771884","id":"PMC_9771884","title":"Delta9-tetrahydrocannabinol 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complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528301","id":"PMC_14528301","title":"HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528301","citation_count":679,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26472760","id":"PMC_26472760","title":"Gene essentiality and synthetic lethality in haploid human cells.","date":"2015","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26472760","citation_count":657,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14527406","id":"PMC_14527406","title":"HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/14527406","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12750511","id":"PMC_12750511","title":"Hypermutation of HIV-1 DNA in the absence of the Vif protein.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12750511","citation_count":570,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21565611","id":"PMC_21565611","title":"Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways.","date":"2011","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21565611","citation_count":507,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47111,"output_tokens":1454,"usd":0.081572},"stage2":{"model":"claude-opus-4-6","input_tokens":4367,"output_tokens":1325,"usd":0.08244},"total_usd":0.394646,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58561,"output_tokens":2855,"usd":0.109254},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5679,"output_tokens":2101,"usd":0.12138}},"stage1_raw":"Looking through the corpus, I need to identify papers about human/mammalian complement component C6 (the terminal complement protein) and extract mechanistic findings. I'll carefully distinguish these from papers about C6 glioma cell line (a rat tumor cell model, not the gene), cytochrome c6 (photosynthetic protein), HOXC6 (homeobox transcription factor), TRPC6 (ion channel), brassinosteroid C-6 oxidases, and other symbol collisions.\n\nThe relevant papers about complement C6 protein are: PMID:8512929 (C6 gene structure), PMID:7535801 (subtotal C6 deficiency - truncated but active C6), PMID:9276537 (C6 deficiency in PVG/c rats), PMID:885533 (linkage study - not mechanistic), PMID:7625764 (DNA polymorphisms), PMID:7625765 (C6 deficiency haplotypes), PMID:11378347 (C6 mRNA reduction in cancer - expression only), PMID:32444389 (C6 KO mice - innate immunity), PMID:32325082 (C6 in endometriosis - biomarker).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The human C6 gene contains 18 exons encoding a mosaic protein composed of modules homologous to parts of other proteins. Analysis of 17 of 18 exon boundaries revealed that only one protein module follows the conventional intron phase pattern, indicating a more complex evolutionary history than anticipated for terminal complement component genes (C6–C9).\",\n      \"method\": \"Gene structure determination by exon boundary sequencing and intron phase analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct gene structural analysis; single study but defines the primary gene architecture\",\n      \"pmids\": [\"8512929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A subtotal C6 deficiency is caused by an abnormal 5′ splice donor site in intron 15 of the C6 gene, preventing splicing and introducing an in-frame stop codon 17 codons downstream, producing a carboxy-terminally truncated C6 protein that is ~14% smaller than normal C6. Critically, this truncated C6 retains bactericidal activity, demonstrating that the carboxy-terminal region (previously thought to contain the C5b binding site or an enzymatic region) is dispensable for membrane attack complex function.\",\n      \"method\": \"PCR sequencing of C6 gene region, expression of C6 cDNA fragments as fusion proteins (pUEX system) for epitope mapping, bactericidal activity assays\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutation identified by sequencing, functional activity confirmed by bactericidal assay, epitope mapped by recombinant fragment expression\",\n      \"pmids\": [\"7535801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"C6 deficiency in the PVG/c rat strain is not caused by a large gene deletion (Southern blot normal) but is associated with approximately 100-fold reduced C6 mRNA in liver, suggesting the defect arises from a point mutation causing mRNA instability or aberrant transcription, or a trans-acting mutation affecting C6 biosynthesis.\",\n      \"method\": \"Northern blot for C6 mRNA quantification, Southern blot for genomic deletion analysis, RT-PCR for tissue expression, cloning of rat C6 cDNA\",\n      \"journal\": \"Clinical and Experimental Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Northern, Southern, RT-PCR); single lab study defining mechanism of deficiency\",\n      \"pmids\": [\"9276537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Genetic knockout of complement C6 in mice results in defective neutrophil (PMN) innate immune responses including impaired surface adhesion molecule expression, reduced superoxide/ROS generation, defective phagocytosis, and histone release after activation. C6 deficiency also impairs NLRP3 inflammasome activation in both PMNs and macrophages, demonstrating that MAC formation (C6-dependent) is required for proper NLRP3 inflammasome function and downstream innate immune responses.\",\n      \"method\": \"C6 knockout mouse model (C6−/−); functional assays for PMN adhesion molecules, superoxide anion generation, ROS, phagocytosis, histone release; NLRP3 inflammasome activity assays in PMNs and macrophages; polymicrobial sepsis and LPS-induced acute lung injury models\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined cellular phenotypic readouts across multiple cell types and in vivo models\",\n      \"pmids\": [\"32444389\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Complement C6 is a mosaic terminal complement protein encoded by an 18-exon gene on chromosome 5p; it assembles into the membrane attack complex (MAC) downstream of C5b, with its carboxy-terminal region dispensable for bactericidal activity, and MAC formation mediated by C6 is required for normal neutrophil effector functions (adhesion, ROS generation, phagocytosis) and NLRP3 inflammasome activation, while C6 deficiency in humans and rats arises from splice-site mutations causing mRNA instability rather than gross gene deletions.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nThe gene query is **C6** = human complement component 6 (the terminal complement protein that forms part of the membrane attack complex).\n\nGoing through the corpus:\n\n- Papers about C6 glioma cell line (rat glioma model): These use \"C6\" as a cell line name, NOT the complement C6 gene → EXCLUDE (alias collision with cell line name)\n- Papers about HOXC6 (homeobox C6): Different gene → EXCLUDE\n- Papers about cytochrome c6 (plant/algal photosynthesis protein): Different protein, plant/algal context → EXCLUDE (symbol collision)\n- Papers about TRPC6 (transient receptor potential C6): Different gene → EXCLUDE\n- Papers about C6/36 mosquito cells: Cell line, not complement C6 → EXCLUDE\n- Papers about complement C6 protein: KEEP\n- BioPlex/interactome papers: General proteomics, not specific to complement C6 → EXCLUDE\n- APOBEC3G/CEM15 papers: Different gene → EXCLUDE\n- Proteasome papers: Different gene → EXCLUDE\n- PER.C6 cell line papers: Cell line, not complement C6 → EXCLUDE\n- C6 ceramide papers: Chemical, not gene → EXCLUDE\n- NPC6 (plant phospholipase): Different organism/gene → EXCLUDE\n- Lyme C6 peptide EIA: Diagnostic assay using C6 peptide of Borrelia — not human complement C6 → EXCLUDE\n\n**KEEP papers (complement C6):**\n- PMID:8512929 — Structure of human C6 gene\n- PMID:7535801 — Subtotal C6 deficiency, carboxy-terminally truncated C6\n- PMID:9276537 — C6 deficiency in PVG/c rat strain\n- PMID:7625765 — C6 and C7 haplotypes associated with C6 deficiencies\n- PMID:7625764 — DNA polymorphisms of C6 and C7 genes\n- PMID:885533 — Nonlinkage between C6 and chromosome 6 markers\n- PMID:11378347 — Reduction of C6 and C7 mRNAs in esophageal carcinoma\n- PMID:32444389 — Requirement of complement C6 for innate immune responses in mice\n- PMID:32325082 — C6 in endometriosis (serum levels, largely biomarker) → EXCLUDE (expression/biomarker only)\n- PMID:37558876 — TRIM5α restricted by vaccinia C6 protein — this is vaccinia virus protein C6, not human complement C6 → EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The human C6 gene spans 18 exons; analysis of 17 exon boundaries revealed that the intron/exon organization of C6 (and related terminal complement components C7 and C9) does not follow the conventional pattern where recognized protein modules are bounded by class 1 introns, suggesting a more complex evolutionary history for terminal complement component genes than anticipated.\",\n      \"method\": \"Genomic DNA sequencing, exon boundary mapping, comparison with published C7 and C9 gene structures\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct sequencing of 17/18 exons with boundary classification; single study\",\n      \"pmids\": [\"8512929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A naturally occurring carboxy-terminally truncated C6 molecule (14% shorter than normal C6), arising from an abnormal 5' splice donor site in intron 15 that creates an in-frame stop codon 17 codons downstream, retains bactericidal activity, demonstrating that the carboxy-terminal region of C6 is dispensable for membrane attack complex function.\",\n      \"method\": \"PCR amplification and sequencing of C6 genomic region; expression of C6 cDNA fragments as fusion proteins in pUEX system to map epitopes; hemolytic/bactericidal assays of patient serum\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — combined sequencing, epitope mapping by expressed fusion proteins, and functional bactericidal assay; replicated in three individuals from two families\",\n      \"pmids\": [\"7535801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Haplotype analysis using seven DNA markers across the linked C6 and C7 loci revealed that complete C6 deficiency (C6*Q0) is associated with at least four haplotypes, with one common defective haplotype predominating in South African patients; subtotal C6 deficiency (C6*SD) shares a haplotype with combined C6/C7 deficiency, indicating the C6 gene defect alone does not explain the associated C7 deficiency.\",\n      \"method\": \"DNA marker haplotyping (7 markers spanning ~300 kbp of chromosome 5p12-14) in patients and family members; comparison with protein phenotyping\",\n      \"journal\": \"Annals of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-marker haplotyping in defined patient cohorts; single study but comprehensive marker coverage\",\n      \"pmids\": [\"7625765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Three C6 DNA polymorphisms were localized precisely within the C6 gene: one in exon 3, one in intron 3, and one adjacent to exon 17; together with four C7 markers, these define 128 possible haplotypes across ~300 kbp of chromosome 5p12-14, and allelic associations between C6 and C7 markers are surprisingly weak.\",\n      \"method\": \"RFLP analysis, DNA sequencing, gene frequency estimation in North European Caucasian and Japanese populations\",\n      \"journal\": \"Annals of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization of polymorphisms within gene structure; population-level replication\",\n      \"pmids\": [\"7625764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1977,\n      \"finding\": \"Genetic linkage analysis excludes linkage between the C6 locus and HLA region marker loci on chromosome 6, and also excludes linkage to PGM3; C6 electrophoretic variants (C6A and C6B) were identified with allele frequencies of 0.61 and 0.39 respectively in a Norwegian population, establishing C6 as a genetically polymorphic protein.\",\n      \"method\": \"High-voltage agarose gel electrophoresis and isoelectric focusing with hemolytic assay; LOD score linkage analysis in families\",\n      \"journal\": \"Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein typing plus formal linkage analysis; foundational mapping study\",\n      \"pmids\": [\"885533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"C6 deficiency in the PVG/c rat strain is not caused by a large gene deletion (Southern blot normal) but is associated with ~100-fold reduced C6 mRNA in liver; C6 mRNA of normal size (~3.3 kb) is present at low levels and C6 mRNA is also detectable in kidney by RT-PCR, indicating the defect likely involves a point mutation causing mRNA instability or aberrant transcription rather than a structural gene deletion.\",\n      \"method\": \"Northern blot analysis, RT-PCR with rat C6-specific primers cloned from liver cDNA library using human C6 as probe, Southern blot of genomic DNA, immunization to generate anti-rat C6 antibodies for antigen detection\",\n      \"journal\": \"Clinical and Experimental Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Northern, Southern, RT-PCR, immunological); single laboratory\",\n      \"pmids\": [\"9276537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"C6 mRNA expression is significantly reduced in esophageal carcinoma tissues compared to paired normal esophageal epithelium, and similar reductions occur in colon and kidney cancers; Southern blot analysis showed no gene deletion in cancer cell lines, suggesting transcriptional downregulation rather than genomic loss underlies reduced C6 expression in tumors.\",\n      \"method\": \"Differential display of tumor/normal pairs, in situ hybridization, semi-quantitative RT-PCR in 10 tumor/normal pairs, Southern blot, tumor/normal expression array analysis\",\n      \"journal\": \"European Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (differential display, ISH, RT-PCR, Southern) in paired human specimens; single study\",\n      \"pmids\": [\"11378347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"C6 knockout mice exhibit defective innate immune responses including impaired PMN surface adhesion molecule expression, superoxide generation, reactive oxygen species production, histone release, and phagocytosis; C6-deficient PMNs and macrophages have defective NLRP3 inflammasome activation. C6-/- mice subjected to polymicrobial sepsis show improved survival with reduced proinflammatory cytokines/chemokines, attenuated cardiac dysfunction, and reduced lung injury in LPS-induced acute lung injury, indicating C6-dependent MAC formation drives organ damage during sepsis.\",\n      \"method\": \"C6 knockout mouse model; flow cytometry for surface molecules; superoxide/ROS assays; phagocytosis assays; NLRP3 inflammasome activation assays in PMNs and macrophages; cecal ligation puncture polymicrobial sepsis model; LPS-induced acute lung injury model; ELISA for cytokines/chemokines/histones\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple orthogonal cellular and in vivo phenotypic readouts across two disease models; single laboratory but comprehensive\",\n      \"pmids\": [\"32444389\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Complement C6 is a terminal complement component encoded on chromosome 5p12-14 whose 18-exon gene produces a mosaic protein that, when incorporated into the membrane attack complex, drives cell lysis and innate immune activation; a carboxy-terminally truncated C6 retains bactericidal activity, liver is the primary site of C6 mRNA expression, C6 mRNA is transcriptionally downregulated in several carcinomas without genomic deletion, and genetic ablation of C6 in mice establishes that MAC-dependent C6 activity is required for normal PMN/macrophage innate immune functions (adhesion, ROS, phagocytosis, NLRP3 inflammasome) and drives organ injury in sepsis and acute lung injury.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Complement C6 is a terminal complement component that assembles into the membrane attack complex (MAC) downstream of C5b; its 18-exon gene encodes a mosaic protein composed of modules with a complex evolutionary origin [PMID:8512929]. A naturally occurring splice-site mutation in intron 15 produces a carboxy-terminally truncated C6 that retains bactericidal activity, demonstrating that the C-terminal region is dispensable for MAC-mediated lysis [PMID:7535801]. Beyond its classical pore-forming role, C6-dependent MAC formation is required for neutrophil effector functions—including adhesion molecule expression, superoxide generation, and phagocytosis—and for NLRP3 inflammasome activation in both neutrophils and macrophages [PMID:32444389].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Defining the gene architecture of C6 revealed an 18-exon mosaic structure with atypical intron phasing, establishing that terminal complement components evolved by mechanisms more complex than simple module duplication.\",\n      \"evidence\": \"Exon boundary sequencing and intron phase analysis of the human C6 gene\",\n      \"pmids\": [\"8512929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only 17 of 18 exon boundaries were characterized\",\n        \"No functional significance assigned to individual modules\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of a splice-site mutation producing a truncated but bactericidally active C6 overturned the assumption that the C-terminal region was essential for MAC function, redefining the minimal functional domain of C6.\",\n      \"evidence\": \"PCR sequencing of a C6-deficient patient, recombinant fragment epitope mapping, and serum bactericidal assays\",\n      \"pmids\": [\"7535801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The precise C5b-binding interface on C6 was not mapped\",\n        \"No structural model of the truncated C6 within the MAC pore\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Analysis of the C6-deficient PVG/c rat showed that deficiency arises from drastically reduced mRNA rather than a gross gene deletion, pointing to mRNA instability or a regulatory mutation as the molecular basis.\",\n      \"evidence\": \"Southern blot (intact gene), Northern blot (~100-fold reduced mRNA), and RT-PCR in liver of PVG/c rats\",\n      \"pmids\": [\"9276537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The causative point mutation was not identified\",\n        \"Trans-acting versus cis-acting mechanism was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"C6 knockout mice revealed that MAC formation is not only lytic but is required for neutrophil adhesion, ROS generation, phagocytosis, and NLRP3 inflammasome activation, establishing C6 as a regulator of innate immune cell effector programs.\",\n      \"evidence\": \"C6−/− mouse model with functional assays across PMNs and macrophages, validated in polymicrobial sepsis and LPS-induced lung injury models\",\n      \"pmids\": [\"32444389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The signaling pathway connecting sublytic MAC to NLRP3 activation is undefined\",\n        \"Whether C6-dependent effects on neutrophils are cell-autonomous or require paracrine MAC deposition is unresolved\",\n        \"Relevance of these findings to human C6 deficiency patients has not been tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of C6 incorporation into the MAC pore, the signaling intermediates linking sublytic MAC to NLRP3 inflammasome assembly, and the identity of the causative mutation in the rat C6 deficiency model.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of C6 within the assembled MAC\",\n        \"Mechanism linking sublytic MAC to intracellular inflammasome signaling is unknown\",\n        \"Rat C6 deficiency-causing mutation remains unidentified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005576\",\n        \"supporting_discovery_ids\": [1, 3]\n      },\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [1, 3]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [1, 3]\n      }\n    ],\n    \"complexes\": [\n      \"Membrane attack complex (MAC)\"\n    ],\n    \"partners\": [\n      \"C5b\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Complement component C6 is a terminal complement protein that assembles into the membrane attack complex (MAC) to mediate cell lysis and shape innate immune responses. The C6 gene spans 18 exons on chromosome 5p12-14 with a mosaic domain architecture whose intron/exon boundaries do not conform to the conventional module-class 1 intron paradigm, suggesting a complex evolutionary origin for terminal complement components [PMID:8512929]. A naturally occurring carboxy-terminal truncation (loss of ~14% of the protein) retains bactericidal activity, demonstrating that the C-terminal region is dispensable for MAC-dependent killing [PMID:7535801]. Genetic ablation of C6 in mice reveals that MAC-dependent C6 activity is required for normal PMN and macrophage innate immune functions—including adhesion molecule expression, superoxide generation, phagocytosis, and NLRP3 inflammasome activation—and drives organ injury in sepsis and acute lung injury models [PMID:32444389].\",\n  \"teleology\": [\n    {\n      \"year\": 1977,\n      \"claim\": \"Establishing that C6 is a genetically polymorphic serum protein whose locus is unlinked to the MHC region addressed the fundamental question of where C6 maps and whether it co-segregates with other immune loci.\",\n      \"evidence\": \"High-voltage agarose electrophoresis, isoelectric focusing with hemolytic overlay, and LOD score linkage analysis in Norwegian families\",\n      \"pmids\": [\"885533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Chromosomal assignment was not determined in this study\",\n        \"Functional consequences of C6 allelic variants (C6A vs C6B) not characterized\"\n      ]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Determination that the C6 gene spans 18 exons whose boundaries do not follow the expected class 1 intron/module pattern resolved the structural genomic organization and challenged assumptions about how terminal complement component genes evolved.\",\n      \"evidence\": \"Genomic DNA sequencing and exon boundary classification across 17 of 18 exon junctions\",\n      \"pmids\": [\"8512929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"One exon boundary was not characterized\",\n        \"Promoter and regulatory elements upstream of the gene were not defined\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery that a naturally occurring C-terminally truncated C6 retains bactericidal function demonstrated that the distal ~14% of the protein is dispensable for MAC assembly and lytic activity, redefining the minimal functional unit of C6.\",\n      \"evidence\": \"PCR/sequencing of a splice-site mutation in intron 15 creating premature stop codon; hemolytic and bactericidal assays of patient serum; replicated across three individuals from two families\",\n      \"pmids\": [\"7535801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the truncated C6 has altered kinetics of MAC insertion or assembly was not assessed\",\n        \"Structural basis for dispensability of the C-terminal region is unknown\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Multi-marker haplotyping across the C6/C7 locus revealed that complete C6 deficiency arises from multiple independent mutations, with subtotal C6 deficiency sharing a haplotype with combined C6/C7 deficiency, clarifying the genetic heterogeneity underlying C6 deficiency states.\",\n      \"evidence\": \"DNA marker haplotyping using 7 markers spanning ~300 kbp of chromosome 5p12-14 in South African and other patient cohorts\",\n      \"pmids\": [\"7625765\", \"7625764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causative mutations for each deficiency haplotype were not identified\",\n        \"Mechanism linking the C6 defect haplotype to associated C7 deficiency was not resolved\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Finding that C6 deficiency in the PVG/c rat arises from ~100-fold reduced mRNA rather than gene deletion established that regulatory or mRNA stability defects can abolish C6 protein without structural gene loss, and identified liver as the primary expression site.\",\n      \"evidence\": \"Northern blot, RT-PCR, and Southern blot in PVG/c rat liver and kidney; comparison with wild-type\",\n      \"pmids\": [\"9276537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The causative point mutation or regulatory lesion was not identified\",\n        \"Contribution of extrahepatic C6 expression (e.g. kidney) to circulating levels was not quantified\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that C6 mRNA is transcriptionally downregulated in esophageal, colon, and kidney carcinomas without genomic deletion raised the possibility that tumors evade complement-mediated surveillance by silencing terminal complement components.\",\n      \"evidence\": \"Differential display, in situ hybridization, semi-quantitative RT-PCR in 10 paired human tumor/normal specimens, and Southern blot in cancer cell lines\",\n      \"pmids\": [\"11378347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of transcriptional downregulation (promoter methylation, transcription factor loss) was not identified\",\n        \"Functional consequence of C6 loss for tumor immune evasion was not tested experimentally\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic ablation of C6 in mice revealed that MAC-dependent C6 activity is required for multiple innate immune effector functions and is a major driver of organ damage in sepsis and acute lung injury, establishing C6/MAC as a double-edged sword in innate immunity.\",\n      \"evidence\": \"C6 knockout mice assessed by flow cytometry, ROS/superoxide assays, phagocytosis assays, NLRP3 inflammasome activation in PMNs and macrophages, cecal ligation puncture sepsis model, and LPS-induced acute lung injury model\",\n      \"pmids\": [\"32444389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether C6/MAC effects on innate cells are direct (sublytic MAC signaling) or indirect (via downstream mediators) was not resolved\",\n        \"Findings from a single laboratory; independent replication in other KO or inhibitor models pending\",\n        \"Relevance of mouse C6 KO phenotypes to human C6 deficiency states not formally demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the precise mechanism by which MAC/sublytic MAC activates NLRP3 inflammasome in innate immune cells, the structural basis for the dispensability of the C6 C-terminal domain, and the epigenetic mechanism responsible for C6 silencing in carcinomas.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of C6 within the assembled MAC pore at atomic resolution\",\n        \"Sublytic vs lytic MAC signaling pathways downstream of C6 incorporation not delineated\",\n        \"Therapeutic potential of C6 inhibition in sepsis not tested in clinical settings\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 4, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\n      \"Membrane attack complex (MAC, C5b-9)\"\n    ],\n    \"partners\": [\n      \"C5b\",\n      \"C7\",\n      \"C8\",\n      \"C9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}