{"gene":"CFH","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1988,"finding":"CFH (complement factor H) is a 1213-amino-acid protein composed of 20 homologous ~60-amino-acid complement control protein (CCP/SCR) repeat units; cDNA sequencing revealed an 18-residue leader sequence and a tyrosine/histidine polymorphism in the seventh repeat unit, and evidence for alternative splicing producing at least two mRNA species.","method":"cDNA cloning and sequencing of three overlapping clones; protein sequence analysis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — complete primary structure determination by direct cDNA sequencing, foundational structural paper","pmids":["2963625"],"is_preprint":false},{"year":1998,"finding":"Mutations in the CFH gene (including a frameshift/premature stop causing half-normal serum factor H levels, and a point mutation in exon 20 causing an Arg-to-Gly change) are causally linked to familial and sporadic hemolytic uremic syndrome (HUS), implicating defective alternative pathway complement regulation in HUS pathogenesis.","method":"Genetic linkage analysis (microsatellite markers at 1q32) followed by direct mutation analysis of the CFH gene in HUS patients and families","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis/mutation analysis with functional implication; foundational disease-gene discovery replicated extensively","pmids":["9551389"],"is_preprint":false},{"year":2004,"finding":"CFH is an essential soluble complement regulatory protein that controls the alternative pathway in plasma and on cell surfaces by acting as a cofactor for factor I-mediated cleavage of C3b, by accelerating decay of the C3 convertase C3bBb, and by recognizing polyanion markers on host cells; distinct functional domains within the 20 CCP units mediate C3b binding, decay-acceleration, and surface recognition.","method":"Review synthesizing biochemical reconstitution, domain-deletion mutagenesis, and binding studies from multiple labs","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1-2 — synthesizes extensive in vitro reconstitution and mutagenesis data; widely replicated across labs","pmids":["15163532"],"is_preprint":false},{"year":2005,"finding":"A common Y402H polymorphism in CFH's seventh CCP domain (which binds heparin and C-reactive protein) is strongly associated with AMD risk (OR ~7.4 for homozygotes), identifying CFH's heparin/CRP-binding domain as functionally critical for macular protection.","method":"Genome-wide SNP association study (116,204 SNPs, 96 cases/50 controls) followed by resequencing to identify the coding variant; functional domain mapping","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 — GWAS with functional variant identification; independently replicated in multiple landmark papers","pmids":["15761122","15761121","15761120","15870199"],"is_preprint":false},{"year":2006,"finding":"CFH (factor H) accumulates within drusen of the retinal pigment epithelium and is synthesized by RPE cells; the Y402H risk variant is located in a region mediating heparin and C-reactive protein binding, and multiple CFH haplotypes confer elevated or reduced AMD risk through effects on alternative complement pathway regulation at Bruch's membrane.","method":"Immunohistochemical localization of CFH in drusen; genetic association with functional haplotype analysis in ~900 AMD cases and ~400 controls","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct protein localization plus functional haplotype analysis; replicated across cohorts","pmids":["15870199"],"is_preprint":false},{"year":2006,"finding":"Neisseria meningitidis outer-membrane lipoprotein GNA1870 (fHbp) binds human complement factor H (CFH) via direct protein-protein interaction; this binding recruits CFH to the bacterial surface, attenuates C3 deposition, and enhances serum resistance. Deletion of GNA1870 abolishes fH binding and increases C3 deposition and bacterial killing.","method":"GNA1870 deletion mutant generation; flow cytometry measuring fH binding; C3 deposition assays; serum bactericidal assays; anti-GNA1870 mAb blocking experiments; mass spectrometry identification","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal binding confirmed by genetic deletion and antibody blocking, with functional serum resistance assays","pmids":["16785547"],"is_preprint":false},{"year":2006,"finding":"Mutations in CFH (found in 15–30% of aHUS patients) impair complement regulation at host cell surfaces, predisposing to uncontrolled alternative pathway activation and endothelial damage; CFH mutations were identified in 30.1% of non-Shiga-toxin HUS patients, with mutations in the C-terminal SCR20 domain associated with poorest prognosis and highest disease recurrence after transplantation.","method":"Genetic screening of 156 non-Stx-HUS patients for CFH (and MCP, factor I) mutations; functional characterization of mutant proteins (C3b binding, expression levels); clinical outcome correlation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — large cohort mutation analysis with functional protein characterization; multiple orthogonal methods","pmids":["16621965"],"is_preprint":false},{"year":2007,"finding":"Candida albicans surface phosphoglycerate mutase (CaGpm1p) binds human CFH via CCP domains SCR6-7 and SCR19-20 (two distinct contact regions), and also binds FHL-1 via SCR6-7; surface-bound CFH retains cofactor activity for factor I-mediated C3b cleavage, enabling immune evasion.","method":"Protein array screening of 4088 S. cerevisiae proteins; recombinant CaGpm1p expression and pulldown; flow cytometry; C3b cleavage cofactor assays; gpm1(-/-) mutant generation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — binding domain mapping with functional cofactor assays, genetic null mutant confirmation","pmids":["17959597"],"is_preprint":false},{"year":2009,"finding":"The spectrum of diseases caused by CFH variants depends on differential effects on plasma-phase versus surface-bound CFH function: variants impairing systemic fluid-phase regulation predispose to MPGN/C3 glomerulopathy, while variants specifically disrupting C-terminal surface-recognition domains (SCR19-20) predispose to aHUS by preventing CFH from protecting host cell surfaces.","method":"Genotype-phenotype correlation across large patient cohorts; functional studies of CFH variants examining C3b binding, factor I cofactor activity, and surface-binding capacity","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 2 — functional characterization of multiple disease-associated variants with orthogonal assays; strong preponderance across labs","pmids":["19297022"],"is_preprint":false},{"year":2010,"finding":"CFH controls the alternative complement pathway by acting as a competitive inhibitor of the C3 convertase (C3bBb): it binds C3b on host cell surfaces decorated with polyanions (sialic acid, heparan sulfate), acts as cofactor for factor I to inactivate C3b, and accelerates decay of C3bBb; pathogenic mutations in CFH disrupt these activities through reduced protein expression or dysfunctional surface recognition.","method":"Review synthesizing genetic screening, functional protein assays (cofactor activity, decay acceleration, surface binding), and mutation analysis across multiple patient cohorts","journal":"Pediatric nephrology (Berlin, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 — established by reconstitution and mutagenesis across multiple independent labs","pmids":["20526633"],"is_preprint":false},{"year":2010,"finding":"IgG autoantibodies against CFH (targeting the C-terminal SCR19-20 domain) block CFH surface recognition function, mimicking gain-of-loss mutations at this domain and causing atypical HUS; these autoantibodies occur almost exclusively in patients with homozygous deletion of CFHR1/CFHR3 (the DEAP-HUS subgroup), suggesting CFHR1 normally competes with these autoantibodies or modulates immune tolerance.","method":"Autoantibody characterization by ELISA and epitope mapping; genetic deletion analysis by PCR/Southern blot; functional studies of CFH surface-binding inhibition","journal":"Pediatric nephrology (Berlin, Germany)","confidence":"High","confidence_rationale":"Tier 2 — epitope-mapped autoantibodies with functional blocking demonstrated, confirmed across multiple patient cohorts","pmids":["20157737","19190803"],"is_preprint":false},{"year":2011,"finding":"CFH is a major plasma binding protein for malondialdehyde (MDA), a common lipid peroxidation product; CFH binds MDA-modified proteins, blocks their uptake by macrophages, and suppresses MDA-induced proinflammatory effects in vivo. The AMD-associated H402 polymorphism markedly reduces CFH's ability to bind MDA, providing a mechanistic link between this variant and AMD pathogenesis via impaired oxidative stress responses.","method":"In vitro MDA-binding assays with recombinant CFH; macrophage uptake inhibition assays; in vivo mouse inflammation model; comparative binding assays of Y402 vs H402 CFH variants","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding reconstitution, in vivo validation, and functional comparison of disease variant; strong mechanistic study","pmids":["21979047"],"is_preprint":false},{"year":2012,"finding":"miR-125b and miR-146a, which are upregulated in Alzheimer's disease brain and in NF-κB-activated neuronal-glial cells, directly target CFH mRNA and significantly reduce CFH protein expression; combinatorial NF-κB signaling drives these miRNAs to downregulate CFH in the context of neuroinflammation.","method":"miRNA expression profiling in post-mortem AD brain tissue and primary HNG cell culture; miRNA target prediction and validation; NF-κB inhibitor experiments; ANOVA-based quantification of CFH expression","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 3 — target validation in cell culture with pathway inhibition; single lab, limited direct mechanistic follow-up","pmids":["22302353"],"is_preprint":false},{"year":2015,"finding":"CFH loss of function in liver tumor-initiating cells promotes cancer stemness: knockdown of CFH abolishes tumorsphere formation and induces differentiation, while overexpression stimulates stemness factor expression and in vivo tumor growth; mechanistically, CFH maintains stemness through regulation of LSF-1 transcription factor expression.","method":"Primary tumorsphere culture; NanoString CD antigen gene expression; CFH siRNA knockdown and overexpression; in vivo xenograft assays; LSF-1 expression analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 — KD/OE with defined phenotype and partial pathway placement; single lab, unconventional CFH function","pmids":["26723877"],"is_preprint":false},{"year":2018,"finding":"Rare structural variants (SVs) in the CFH-CFHR locus — including CFH::CFHR1 hybrid genes (caused by recurrent genomic rearrangements sharing a common 4.8-kbp ancestral CFHR promoter segment) — create fusion proteins with altered complement regulatory activity; bipolar clustering of rare nonsynonymous mutations in aHUS patients maps to C-terminal SCR domains (surface recognition) and in AMD patients maps to N-terminal domains (fluid-phase regulation), confirming domain-specific functional roles under positive selection.","method":"High-quality sequencing of ~360-kbp locus in six primate lineages; structural variant analysis in >2,400 individuals; burden testing in >5,000 AMD cases/controls; comparative genomics and selection analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — large-scale structural genomics with functional domain mapping; strong preponderance across cases and evolutionary data","pmids":["29686068"],"is_preprint":false},{"year":2020,"finding":"Factor H-like protein 1 (FHL-1), an alternative splice variant of CFH comprising the first 7 N-terminal CCP domains of CFH, has regulatory activity comparable to full-length CFH and is the predominant complement regulator on Bruch's membrane (a critical site for AMD). FHL-1 is specifically recruited by certain microorganisms for complement evasion, and some cancers upregulate FHL-1 for immune evasion, indicating tissue-specific roles distinct from CFH.","method":"Review synthesizing splice variant characterization, functional complement regulation assays, localization studies in Bruch's membrane, microbial binding studies, and cancer tissue analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — based on multiple experimental studies from different labs; FHL-1 functional equivalence to CFH shown by reconstitution","pmids":["33178228"],"is_preprint":false},{"year":2021,"finding":"Endogenous CFH expressed by RPE cells modulates complement regulation and inflammatory cytokine production independently of external complement sources; CFH silencing in hTERT-RPE1 cells increases IL-6, IL-8, GM-CSF, C3, and CFB while decreasing C5, and the NF-κB pathway is identified as the major pathway through which CFH loss drives these inflammatory and complement changes.","method":"CFH siRNA silencing in human hTERT-RPE1 cells; cytokine/complement protein quantification by ELISA and proteomics; NF-κB pathway inhibitor experiments; western blotting","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss-of-function with defined molecular phenotype and pathway identification; single lab with multiple readouts","pmids":["34445430"],"is_preprint":false},{"year":2010,"finding":"Complement factor H is a soluble regulator essential for controlling alternative pathway activation: it recognizes polyanion markers (e.g., sialic acid, heparan sulfate) on host cell surfaces via its C-terminal domains (SCR19-20) to provide surface-specific protection, while N-terminal domains (SCR1-4) mediate C3b binding, factor I cofactor activity, and C3 convertase decay acceleration in the fluid phase.","method":"Review synthesizing structural domain studies, binding assays, mutagenesis, and disease-variant functional analysis","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1-2 — established by extensive in vitro reconstitution, mutagenesis and structural studies across many independent labs","pmids":["20580090"],"is_preprint":false}],"current_model":"Complement factor H (CFH) is a soluble 20-CCP-domain plasma glycoprotein that restrains the alternative complement pathway by acting as a cofactor for factor I-mediated C3b inactivation and by accelerating C3 convertase (C3bBb) decay; it recognizes polyanion markers (heparin, sialic acid, heparan sulfate) on host cell surfaces via C-terminal SCR19-20 domains to provide surface-specific protection, while N-terminal SCR1-4 domains mediate fluid-phase regulation; the AMD-risk Y402H variant in SCR7 impairs binding to heparin, C-reactive protein, and malondialdehyde (a lipid peroxidation product), reducing oxidative stress protection at Bruch's membrane; C-terminal domain mutations predispose to aHUS by abrogating host-surface recognition, whereas N-terminal mutations affect systemic C3b regulation; an alternatively spliced variant FHL-1 (SCR1-7) is the predominant regulator at Bruch's membrane; pathogens recruit CFH/FHL-1 to their surfaces via specific CCP-domain interactions to evade complement killing; and CFH expression in RPE cells is regulated by NF-κB and by miRNAs (miR-125b, miR-146a) in neuroinflammatory contexts."},"narrative":{"teleology":[{"year":1988,"claim":"Determining the complete primary structure of CFH revealed a modular 20-CCP-repeat architecture and evidence for alternative splicing, establishing the structural framework for all subsequent domain-function studies.","evidence":"cDNA cloning and sequencing of overlapping clones covering the full-length 1213-amino-acid protein","pmids":["2963625"],"confidence":"High","gaps":["Three-dimensional structure of individual CCP domains and full-length CFH not yet resolved","Functional roles of individual CCP domains not mapped"]},{"year":2004,"claim":"Biochemical reconstitution and domain-deletion mutagenesis established that CFH controls the alternative pathway through three distinct activities—factor I cofactor activity, C3 convertase decay acceleration, and polyanion-dependent host-surface recognition—mapped to separable CCP domains.","evidence":"Synthesis of in vitro reconstitution, binding assays, and domain-deletion mutagenesis from multiple laboratories","pmids":["15163532"],"confidence":"High","gaps":["Precise stoichiometry and kinetics of CFH–C3b interaction on physiological surfaces not fully defined","Relative contributions of each activity in vivo not resolved"]},{"year":1998,"claim":"Identification of CFH mutations in familial and sporadic HUS provided the first causal genetic link between defective alternative pathway regulation and thrombotic microangiopathy, showing that both loss-of-expression (frameshift) and C-terminal missense variants drive disease.","evidence":"Linkage analysis at 1q32 followed by direct CFH gene mutation screening in HUS families","pmids":["9551389"],"confidence":"High","gaps":["Spectrum of causative mutations incomplete","Mechanism by which C-terminal mutations specifically predispose to endothelial damage not elucidated"]},{"year":2005,"claim":"Genome-wide association identified Y402H in SCR7 as a major AMD risk variant, implicating complement dysregulation in macular degeneration and pinpointing the heparin/CRP-binding region as functionally critical for retinal protection.","evidence":"GWAS (116,204 SNPs) with resequencing in AMD case-control cohorts; independently replicated across four studies","pmids":["15761122","15761121","15761120","15870199"],"confidence":"High","gaps":["Molecular mechanism by which Y402H alters local complement regulation at Bruch's membrane not defined","Whether the variant acts through altered CRP binding, heparin binding, or both remained unclear"]},{"year":2006,"claim":"Combined pathogen-interaction and genotype-phenotype studies demonstrated that CFH domain specificity determines both disease type and microbial exploitation: C-terminal SCR19–20 mutations cause aHUS via loss of surface protection, and bacteria such as N. meningitidis hijack CFH to their surfaces via specific protein–protein interactions to evade complement killing.","evidence":"Genetic screening of 156 HUS patients with functional characterization of mutant proteins; GNA1870 deletion mutant, flow cytometry, and serum bactericidal assays for meningococcal fH binding","pmids":["16621965","16785547"],"confidence":"High","gaps":["Full repertoire of microbial CFH-binding proteins not catalogued","Structural basis of CFH recruitment to bacterial surfaces not resolved at atomic level"]},{"year":2009,"claim":"Systematic genotype-phenotype correlation resolved the paradox of how CFH variants cause different diseases: N-terminal dysfunction impairs fluid-phase C3b regulation causing MPGN/C3 glomerulopathy, while C-terminal dysfunction abrogates host-surface recognition causing aHUS.","evidence":"Functional studies of disease-associated CFH variants measuring C3b binding, cofactor activity, and surface binding across large patient cohorts","pmids":["19297022"],"confidence":"High","gaps":["Incomplete penetrance and environmental modifiers not explained","Role of CFH-related proteins (CFHRs) in modifying disease phenotype only partially understood"]},{"year":2010,"claim":"Anti-CFH autoantibodies targeting SCR19–20 were shown to functionally mimic C-terminal loss-of-function mutations, causing aHUS almost exclusively in patients with homozygous CFHR1/CFHR3 deletion, revealing a genetic susceptibility to autoimmune complement dysregulation.","evidence":"Autoantibody epitope mapping by ELISA, functional surface-binding inhibition assays, and genetic deletion analysis in patient cohorts","pmids":["20157737","19190803"],"confidence":"High","gaps":["Mechanism by which CFHR1 deletion breaks immune tolerance to CFH not established","Whether autoantibodies also impair fluid-phase CFH activity not fully tested"]},{"year":2011,"claim":"Discovery that CFH is a major plasma MDA-binding protein that blocks MDA-induced macrophage uptake and inflammation provided a complement-independent protective function and mechanistically explained the AMD-risk Y402H variant, which has markedly reduced MDA binding.","evidence":"In vitro MDA-binding and macrophage uptake assays with recombinant CFH; in vivo mouse inflammation model; comparative binding of Y402 versus H402 variants","pmids":["21979047"],"confidence":"High","gaps":["In vivo relevance of MDA-binding in human retina not directly demonstrated","Whether MDA-binding operates independently of or synergistically with complement regulation in AMD not resolved"]},{"year":2018,"claim":"Large-scale structural genomic analysis of the CFH-CFHR locus identified recurrent hybrid gene formation and confirmed bipolar clustering of rare disease mutations—N-terminal for AMD, C-terminal for aHUS—under positive selection, revealing ongoing evolutionary pressures shaping domain-specific regulation.","evidence":"High-quality sequencing of ~360-kbp locus across six primate species; structural variant analysis in >2,400 individuals; burden testing in >5,000 AMD cases/controls","pmids":["29686068"],"confidence":"High","gaps":["Functional consequences of most hybrid CFH-CFHR proteins not tested biochemically","Selective pressures driving CFHR copy-number variation not identified"]},{"year":2020,"claim":"Characterization of the alternative splice variant FHL-1 (SCR1–7) as the predominant complement regulator at Bruch's membrane established tissue-specific division of labor between CFH and FHL-1 and showed that pathogens and tumors can selectively exploit FHL-1 for immune evasion.","evidence":"Synthesis of splice variant functional assays, Bruch's membrane localization studies, and microbial/tumor binding analyses","pmids":["33178228"],"confidence":"Medium","gaps":["Mechanisms controlling relative CFH versus FHL-1 expression in specific tissues not fully defined","Whether FHL-1 loss alone is sufficient for AMD pathology not tested"]},{"year":2021,"claim":"Endogenous CFH in RPE cells was shown to modulate local complement and cytokine expression through NF-κB signaling, demonstrating that CFH has cell-autonomous anti-inflammatory functions beyond its classical role as a plasma complement regulator.","evidence":"CFH siRNA silencing in hTERT-RPE1 cells; cytokine and complement protein quantification; NF-κB pathway inhibition experiments","pmids":["34445430"],"confidence":"Medium","gaps":["Whether intracellular CFH directly engages NF-κB pathway components or acts indirectly through autocrine complement signaling unknown","Relevance of RPE-derived CFH versus liver-derived plasma CFH in AMD pathogenesis not resolved in vivo"]},{"year":null,"claim":"The structural basis for how full-length CFH simultaneously engages C3b and host-surface polyanions in a physiological membrane context, and how intracellular CFH functions are integrated with canonical plasma complement regulation, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full-length CFH bound to C3b on a membrane surface","Intracellular signaling mechanisms of CFH in RPE and other cells not defined","Therapeutic strategies to selectively restore surface-specific CFH function in aHUS or AMD not clinically validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8,9,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,4,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,9,17]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,9,17]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[4,15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,6,8,9,10,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,6,8,14]}],"complexes":[],"partners":["C3B","CFI","CRP","CFB","FHBP"],"other_free_text":[]},"mechanistic_narrative":"Complement factor H (CFH) is a soluble 20-CCP-domain plasma glycoprotein that serves as the principal negative regulator of the alternative complement pathway, restraining amplification both in the fluid phase and on host cell surfaces. Its N-terminal domains (SCR1–4) mediate C3b binding, cofactor activity for factor I–mediated C3b inactivation, and decay-acceleration of the C3 convertase C3bBb, while C-terminal domains (SCR19–20) discriminate self from non-self by recognizing polyanion markers such as sialic acid and heparan sulfate on host surfaces [PMID:15163532, PMID:20580090]. Loss-of-function mutations in the C-terminal surface-recognition domains cause atypical hemolytic uremic syndrome (aHUS), whereas variants impairing fluid-phase regulation predispose to C3 glomerulopathy, and the common Y402H polymorphism in SCR7 impairs binding to heparin, C-reactive protein, and the lipid peroxidation product malondialdehyde, conferring strong risk for age-related macular degeneration [PMID:9551389, PMID:15761122, PMID:21979047, PMID:19297022]. Pathogens including Neisseria meningitidis and Candida albicans recruit CFH to their surfaces via specific CCP-domain interactions to evade complement-mediated killing, and an alternatively spliced variant FHL-1 (SCR1–7) functions as the predominant complement regulator at Bruch's membrane [PMID:16785547, PMID:17959597, PMID:33178228]."},"prefetch_data":{"uniprot":{"accession":"P08603","full_name":"Complement factor H","aliases":["H factor 1"],"length_aa":1231,"mass_kda":139.1,"function":"Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation. Acts as a soluble inhibitor of complement, where its binding to self markers such as glycan structures prevents complement activation and amplification on cell surfaces (PubMed:21285368, PubMed:21317894, PubMed:25402769). Accelerates the decay of the complement alternative pathway (AP) C3 convertase C3bBb, thus preventing local formation of more C3b, the central player of the complement amplification loop (PubMed:19503104, PubMed:21317894, PubMed:26700768). As a cofactor of the serine protease factor I, CFH also regulates proteolytic degradation of already-deposited C3b (PubMed:18252712, PubMed:23332154, PubMed:28671664). In addition, mediates several cellular responses through interaction with specific receptors. For example, interacts with CR3/ITGAM receptor and thereby mediates the adhesion of human neutrophils to different pathogens. In turn, these pathogens are phagocytosed and destroyed (PubMed:20008295, PubMed:9558116) (Microbial infection) In the mosquito midgut, binds to the surface of parasite P.falciparum gametocytes and protects the parasite from alternative complement pathway-mediated elimination","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P08603/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFH","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"AKAP12","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CFH","total_profiled":1310},"omim":[{"mim_id":"616842","title":"DNase1 HYPERSENSITIVITY, CHROMOSOME 6, SITE 1; DHS6S1","url":"https://www.omim.org/entry/616842"},{"mim_id":"615489","title":"MACULAR DEGENERATION, AGE-RELATED, 14; ARMD14","url":"https://www.omim.org/entry/615489"},{"mim_id":"615439","title":"MACULAR DEGENERATION, AGE-RELATED, 13; ARMD13","url":"https://www.omim.org/entry/615439"},{"mim_id":"615008","title":"NEPHROTIC SYNDROME, TYPE 7; NPHS7","url":"https://www.omim.org/entry/615008"},{"mim_id":"614809","title":"C3 GLOMERULOPATHY 3; C3G3","url":"https://www.omim.org/entry/614809"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":1585.8}],"url":"https://www.proteinatlas.org/search/CFH"},"hgnc":{"alias_symbol":["HUS","FHL1","ARMS1","ARMD4"],"prev_symbol":["HF","HF1","HF2"]},"alphafold":{"accession":"P08603","domains":[{"cath_id":"2.10.70.10","chopping":"32-83","consensus_level":"high","plddt":81.7173,"start":32,"end":83},{"cath_id":"2.10.70.10","chopping":"95-144","consensus_level":"medium","plddt":84.6094,"start":95,"end":144},{"cath_id":"2.10.70.10","chopping":"146-208","consensus_level":"medium","plddt":78.439,"start":146,"end":208},{"cath_id":"2.10.70.10","chopping":"211-265","consensus_level":"high","plddt":81.7731,"start":211,"end":265},{"cath_id":"2.10.70.10","chopping":"269-323","consensus_level":"high","plddt":77.7084,"start":269,"end":323},{"cath_id":"2.10.70.10","chopping":"334-385","consensus_level":"medium","plddt":84.341,"start":334,"end":385},{"cath_id":"2.10.70.10","chopping":"448-511","consensus_level":"medium","plddt":78.5845,"start":448,"end":511},{"cath_id":"2.10.70.10","chopping":"512-567","consensus_level":"medium","plddt":76.2857,"start":512,"end":567},{"cath_id":"2.10.70.10","chopping":"689-802","consensus_level":"medium","plddt":77.093,"start":689,"end":802},{"cath_id":"2.10.70.10","chopping":"880-929","consensus_level":"medium","plddt":71.1844,"start":880,"end":929},{"cath_id":"2.10.70.10","chopping":"941-986","consensus_level":"medium","plddt":73.7207,"start":941,"end":986},{"cath_id":"2.10.70.10","chopping":"990-1046","consensus_level":"medium","plddt":75.0611,"start":990,"end":1046},{"cath_id":"2.10.70.10","chopping":"1058-1105","consensus_level":"medium","plddt":77.9788,"start":1058,"end":1105},{"cath_id":"2.10.70.10","chopping":"1119-1165","consensus_level":"medium","plddt":83.4168,"start":1119,"end":1165},{"cath_id":"2.10.70.10","chopping":"1168-1231","consensus_level":"high","plddt":83.0159,"start":1168,"end":1231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08603","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08603-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08603-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFH","jax_strain_url":"https://www.jax.org/strain/search?query=CFH"},"sequence":{"accession":"P08603","fasta_url":"https://rest.uniprot.org/uniprotkb/P08603.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08603/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08603"}},"corpus_meta":[{"pmid":"22986360","id":"PMC_22986360","title":"STEC-HUS, atypical HUS and TTP are all diseases of complement activation.","date":"2012","source":"Nature reviews. 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23455636","citation_count":649,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16174643","id":"PMC_16174643","title":"Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16174643","citation_count":640,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16621965","id":"PMC_16621965","title":"Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16621965","citation_count":555,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21399633","id":"PMC_21399633","title":"Genome-wide association study identifies susceptibility loci for IgA nephropathy.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21399633","citation_count":522,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23702979","id":"PMC_23702979","title":"Immunology of age-related macular degeneration.","date":"2013","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23702979","citation_count":514,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8125298","id":"PMC_8125298","title":"Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8125298","citation_count":492,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16936732","id":"PMC_16936732","title":"Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16936732","citation_count":489,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15163532","id":"PMC_15163532","title":"The human complement factor H: functional roles, genetic variations and disease associations.","date":"2004","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15163532","citation_count":447,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21979047","id":"PMC_21979047","title":"Complement factor H binds malondialdehyde epitopes and protects from oxidative stress.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21979047","citation_count":445,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20385819","id":"PMC_20385819","title":"Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20385819","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9551389","id":"PMC_9551389","title":"Genetic studies into inherited and sporadic hemolytic uremic syndrome.","date":"1998","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/9551389","citation_count":390,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20385826","id":"PMC_20385826","title":"Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC).","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20385826","citation_count":376,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16335952","id":"PMC_16335952","title":"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.","date":"2005","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/16335952","citation_count":350,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17767156","id":"PMC_17767156","title":"Variation in complement factor 3 is associated with risk of age-related macular degeneration.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17767156","citation_count":344,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16785547","id":"PMC_16785547","title":"The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16785547","citation_count":330,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20580090","id":"PMC_20580090","title":"Complement control protein factor H: the good, the bad, and the inadequate.","date":"2010","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20580090","citation_count":319,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18596911","id":"PMC_18596911","title":"Systemic complement activation in age-related macular degeneration.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18596911","citation_count":310,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2963625","id":"PMC_2963625","title":"The complete amino acid sequence of human complement factor H.","date":"1988","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/2963625","citation_count":309,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50534,"output_tokens":3589,"usd":0.102719},"stage2":{"model":"claude-opus-4-6","input_tokens":6730,"output_tokens":2515,"usd":0.144788},"total_usd":0.556982,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62567,"output_tokens":5360,"usd":0.13405},"round2_rules_fired":"R2,R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8390,"output_tokens":3000,"usd":0.175425}},"stage1_raw":"Looking at the corpus, I need to identify papers about CFH (Complement Factor H), the human gene encoding a key regulator of the alternative complement pathway. Many papers in this corpus are about FHL1 (Four and a Half LIM domains 1), which shares the symbol in some contexts but is a completely different gene. I need to carefully distinguish CFH (complement factor H) from FHL1 (the LIM domain muscle protein).\n\nLet me identify the relevant CFH papers:\n\n- Papers about CFH as complement regulator: [1], [3], [6], [7], [8], [10], [14], [22], [23], [28], [31], [36], [39], [42], [49], [54], [62], [63], [76], [79]\n\nPapers [4], [15], [18], [20], [24], [25], [29], [33], etc. are about FHL1 (the LIM domain protein) — NOT CFH complement factor H. Skip these.\n\nNow let me extract mechanistic findings from the CFH-relevant papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Candida albicans surface protein Gpm1p (phosphoglycerate mutase) binds Factor H and FHL-1 via distinct domains: FHL-1 contacts SCRs 6-7, while Factor H uses two contact regions in SCRs 6-7 and SCRs 19-20. Bound Factor H and FHL-1 retain cofactor activity for C3b cleavage, demonstrating that microbial surface recruitment of CFH preserves its regulatory function.\",\n      \"method\": \"Protein array screening, recombinant protein pulldown, flow cytometry, cofactor activity assay, C. albicans null mutant generation\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including binding domain mapping, functional cofactor assay, and null mutant confirmation in a single study\",\n      \"pmids\": [\"17959597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CFH functions as a soluble and cell surface-bound complement inhibitor that suppresses excessive activation of the alternative complement pathway by inactivating C3b. The functional impact of CFH variants depends on whether they affect plasma-phase or surface-bound CFH activity, explaining distinct genotype-phenotype correlations for renal (aHUS, MPGN) versus ocular (AMD, basal laminar drusen) diseases.\",\n      \"method\": \"Functional characterization of CFH variants in patient cohorts combined with mechanistic analysis of complement regulatory activity\",\n      \"journal\": \"Molecular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — review synthesizing functional variant data; mechanistic framework supported by patient mutation studies but not primary experimental reconstitution in this paper\",\n      \"pmids\": [\"19297022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mutations in CFH associated with aHUS fall into two mechanistic categories: (1) loss-of-function mutations causing CFH protein deficiency, leading to uncontrolled alternative pathway activation systemically; and (2) missense mutations producing dysfunctional but normally expressed CFH protein with impaired surface recognition (C-terminal SCR 19-20 domain), selectively disrupting complement regulation on host cell surfaces while leaving fluid-phase regulation intact.\",\n      \"method\": \"Genetic screening of aHUS patient cohorts, functional complement assays, protein quantification\",\n      \"journal\": \"Pediatric Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional mechanistic classification from multi-patient genetic and biochemical data, replicated across multiple studies referenced\",\n      \"pmids\": [\"20526633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IgG autoantibodies against CFH in aHUS patients bind the C-terminus of CFH (SCR 19-20), blocking CFH surface recognition and mimicking the functional defect caused by genetic CFH mutations in this domain. This autoimmune mechanism occurs almost exclusively in patients with genetic deletion of CFHR1 and CFHR3 (DEAP-HUS), suggesting CFHR1/CFHR3 normally compete with CFH autoantibody binding or that their absence permits autoantibody development.\",\n      \"method\": \"Autoantibody characterization, epitope mapping to CFH C-terminus, genetic background analysis of CFHR1/CFHR3 deletion in patient cohorts\",\n      \"journal\": \"Thrombosis and Haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epitope localization combined with genetic background analysis in patient cohorts; replicated across multiple aHUS centers\",\n      \"pmids\": [\"19190803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DEAP-HUS is mechanistically defined by CFH autoantibodies that block CFH-mediated surface complement regulation, combined with homozygous deletion of CFHR1 and CFHR3. Clinical reduction of autoantibody titers by plasma therapy, steroids, or immunosuppression restores complement regulation and controls the disease, directly linking CFH autoantibody titer to disease activity.\",\n      \"method\": \"Clinical intervention studies, serial autoantibody titer measurement, plasma therapy and immunosuppression response monitoring\",\n      \"journal\": \"Pediatric Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic link between autoantibody levels and disease confirmed by therapeutic response, but no in vitro reconstitution\",\n      \"pmids\": [\"20157737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CFH (complement factor H) regulates the alternative pathway C3 convertase (C3bBb) by acting as a cofactor for Factor I-mediated cleavage of C3b and by accelerating decay of C3bBb. Mutations in aHUS patients map to CFH's C-terminal SCR 19-20 domain (surface recognition) or reduce overall CFH expression, with distinct functional consequences: surface-specific loss vs. global complement dysregulation.\",\n      \"method\": \"Functional complement assays, mutant protein analysis, patient mutation screening with AP activation quantification\",\n      \"journal\": \"Journal of Immunological Methods\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays characterizing mechanism of aHUS-associated CFH variants, synthesizing data from multiple patient studies\",\n      \"pmids\": [\"21215749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In human brain (Alzheimer's disease), NF-κB-activated miRNAs miR-125b and miR-146a directly target CFH mRNA and significantly downregulate CFH protein expression in neuronal-glial cells. This was demonstrated experimentally using IL-1β and Aβ42-peptide-stressed human neuronal-glial cells in primary culture, with validated effects on CFH protein levels.\",\n      \"method\": \"miRNA target validation in primary human neuronal-glial cell culture, cytokine stress model, ANOVA quantification of CFH expression changes\",\n      \"journal\": \"Molecular Neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct experimental validation in primary cell culture with multiple miRNAs and stressors, single lab\",\n      \"pmids\": [\"22302353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CFH loss-of-function in liver cancer tumor-initiating cells (tumorspheres) is required for stemness maintenance. CFH knockdown abrogated tumorsphere formation and induced differentiation, while CFH overexpression stimulated stemness factor expression and in vivo tumor growth. Mechanistically, CFH-dependent effects on stemness were mediated through LSF-1 (Late SV40 Factor 1) transcription factor expression.\",\n      \"method\": \"Primary tumorsphere culture, NanoString gene expression, siRNA knockdown, overexpression, in vivo xenograft, LSF-1 mechanistic analysis\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple functional assays with mechanistic pathway identification (LSF-1), but non-canonical role for complement protein CFH\",\n      \"pmids\": [\"26723877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Structural variation analysis of the CFH gene family revealed that rare missense mutations clustering at the N-terminus of CFH (P < 5.81×10⁻⁸) are significantly associated with AMD risk, while a bipolar clustering pattern of rare nonsynonymous mutations maps AMD-associated variants to functional domains under positive selection during primate evolution, distinct from AHUS-associated variants. This maps disease-relevant functional domains of CFH to specific structural regions.\",\n      \"method\": \"High-quality sequencing of CFH locus in six primate lineages, structural variation analysis in >2,400 individuals, case-control study >5,000 AMD cases\",\n      \"journal\": \"Proceedings of the National Academy of Sciences USA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale genomic structural analysis with functional domain mapping; identifies disease-relevant domains but is primarily genetic/structural rather than biochemical reconstitution\",\n      \"pmids\": [\"29686068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endogenous CFH expressed by retinal pigment epithelium (RPE) cells modulates inflammatory cytokine production and complement regulation in a cell-autonomous manner, independent of external complement sources. CFH silencing in hTERT-RPE1 cells increased IL-6, IL-8, GM-CSF, upregulated C3 and CFB, and downregulated C5. The NF-κB pathway was identified as the major pathway through which FH and complement balance are co-regulated in RPE cells.\",\n      \"method\": \"CFH siRNA silencing in human hTERT-RPE1 cells, cytokine measurement (IL-6, IL-8, GM-CSF), complement protein quantification (C3, CFB, C5), NF-κB pathway analysis\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype and pathway identification (NF-κB), single lab with multiple readouts\",\n      \"pmids\": [\"34445430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FHL-1, the alternatively spliced isoform of CFH comprising the first 7 N-terminal complement control protein domains of Factor H, was shown to have regulatory activity comparable to full-length FH, not weaker as previously thought. FHL-1 is the predominant complement regulator on Bruch's membrane, making it an indispensable, tissue-specific regulator at a critical site for AMD onset and progression.\",\n      \"method\": \"Review synthesizing functional complement regulatory assays, tissue localization studies, and splice variant analysis\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — synthesis of published functional assay data showing FHL-1 regulatory equivalence, localization experiments; review paper citing primary studies\",\n      \"pmids\": [\"33178228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A missense variant N1050Y in CFH (in complete linkage disequilibrium with a variant in CFHR4) is significantly associated with protection against phenytoin-induced maculopapular exanthema in Europeans, implicating CFH's complement regulatory function in drug hypersensitivity through the alternative pathway.\",\n      \"method\": \"Case-control genome-wide association study, meta-analysis across epilepsy cohorts, linkage disequilibrium analysis\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — GWAS association; no direct mechanistic experiment performed\",\n      \"pmids\": [\"29288229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CFH-CFHR structural variants (SVs) including CFH::CFHR1 hybrid genes cause primary aHUS through loss of normal CFH complement regulatory function, with 12/13 acute episodes not treated with eculizumab resulting in chronic ESRD. Anti-complement therapy with eculizumab induced remission in 4/4 acute episodes in patients with CFH-involving SVs, mechanistically confirming that complement dysregulation is the driver of pathology in CFH structural variant-associated aHUS.\",\n      \"method\": \"MLPA copy number variation analysis, long-read SMRT sequencing of breakpoints, clinical outcome analysis with eculizumab treatment\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genomic characterization combined with therapeutic intervention confirming mechanism; large patient cohort\",\n      \"pmids\": [\"36793547\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Complement Factor H (CFH) is a soluble and cell surface-associated inhibitor of the alternative complement pathway that acts by serving as a cofactor for Factor I-mediated cleavage of C3b and by accelerating decay of the alternative pathway C3 convertase (C3bBb); disease-associated mutations cluster in either the N-terminal regulatory domains (causing global complement dysregulation) or the C-terminal SCR 19-20 surface-recognition domain (causing selective loss of host cell surface protection), autoantibodies against the C-terminal domain mimic this loss-of-function, its alternatively spliced form FHL-1 (comprising SCRs 1-7) functions as an indispensable tissue-specific regulator particularly on Bruch's membrane, and endogenous CFH in retinal pigment epithelium cells maintains inflammatory and complement balance via the NF-κB pathway.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe target gene is **CFH** (Complement Factor H), a complement regulatory protein.\n\nMany papers in this corpus are about **FHL1** (Four and a Half LIM domains 1) — a completely different gene (Xq27) involved in muscle biology. These are SYMBOL COLLISION / ALIAS COLLISION papers and must be EXCLUDED.\n\nPaper [39] describes **circ-CFH** (circular RNA from the CFH locus) — this is an alt-locus product (case B) → EXCLUDE.\n\nPaper [61] describes **cfH** = ciprofloxacin (a drug abbreviation) → EXCLUDE (symbol collision with a chemical).\n\nPapers [2], [9], [30], [47], [80] are about heart failure drugs (PARADIGM-HF, sacubitril/valsartan) → EXCLUDE (unrelated).\n\nPapers [13] is about hemophilia B/Factor IX gene therapy → EXCLUDE.\n\nPapers [51] is about mass spectrometry methods → EXCLUDE.\n\nPapers [95] is about CRISPR in yeast → EXCLUDE.\n\nPapers [96] is about yeast Fhl1 (forkhead transcription factor in yeast, FHA domain) — completely different from CFH → EXCLUDE (symbol collision).\n\nPaper [4], [15], [18], [20], [24], [25], [29], [32], [33], [35], [36 — wait, [36] is about MCP/CD46 and HUS, which relates to CFH context], [41], [43], [44 — wait these are FHL1 papers], [53], [56], [58], [59], [60], [65], [66], [69], [71], [73], [74], [75], [78], [81], [84], [85], [87], [88], [91], [92], [94], [97], [98], [99] — all FHL1 muscle/cancer papers → EXCLUDE.\n\nLet me now identify all KEEP papers (about canonical CFH complement factor H):\n\nKEEP: [1], [3], [6], [7], [8], [10], [11], [12], [14], [16], [17], [19 — wait, spironolactone proteomics, not CFH mechanistic], [21], [22], [23], [27], [28], [31], [36 — MCP/CD46 in HUS context, mentions CFH briefly], [37], [38], [40], [42], [46], [48], [49], [50], [54], [55], [62], [63], [64], [70], [72], [76], [77], [79], [89], [90], [100], and all gene2pubmed papers [g1]-[g30] about CFH.\n\nNow extracting mechanistic discoveries only from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"CFH (complement factor H) is a 1213-amino-acid protein composed of 20 homologous ~60-amino-acid complement control protein (CCP/SCR) repeat units; cDNA sequencing revealed an 18-residue leader sequence and a tyrosine/histidine polymorphism in the seventh repeat unit, and evidence for alternative splicing producing at least two mRNA species.\",\n      \"method\": \"cDNA cloning and sequencing of three overlapping clones; protein sequence analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete primary structure determination by direct cDNA sequencing, foundational structural paper\",\n      \"pmids\": [\"2963625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mutations in the CFH gene (including a frameshift/premature stop causing half-normal serum factor H levels, and a point mutation in exon 20 causing an Arg-to-Gly change) are causally linked to familial and sporadic hemolytic uremic syndrome (HUS), implicating defective alternative pathway complement regulation in HUS pathogenesis.\",\n      \"method\": \"Genetic linkage analysis (microsatellite markers at 1q32) followed by direct mutation analysis of the CFH gene in HUS patients and families\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis/mutation analysis with functional implication; foundational disease-gene discovery replicated extensively\",\n      \"pmids\": [\"9551389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CFH is an essential soluble complement regulatory protein that controls the alternative pathway in plasma and on cell surfaces by acting as a cofactor for factor I-mediated cleavage of C3b, by accelerating decay of the C3 convertase C3bBb, and by recognizing polyanion markers on host cells; distinct functional domains within the 20 CCP units mediate C3b binding, decay-acceleration, and surface recognition.\",\n      \"method\": \"Review synthesizing biochemical reconstitution, domain-deletion mutagenesis, and binding studies from multiple labs\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — synthesizes extensive in vitro reconstitution and mutagenesis data; widely replicated across labs\",\n      \"pmids\": [\"15163532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A common Y402H polymorphism in CFH's seventh CCP domain (which binds heparin and C-reactive protein) is strongly associated with AMD risk (OR ~7.4 for homozygotes), identifying CFH's heparin/CRP-binding domain as functionally critical for macular protection.\",\n      \"method\": \"Genome-wide SNP association study (116,204 SNPs, 96 cases/50 controls) followed by resequencing to identify the coding variant; functional domain mapping\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — GWAS with functional variant identification; independently replicated in multiple landmark papers\",\n      \"pmids\": [\"15761122\", \"15761121\", \"15761120\", \"15870199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CFH (factor H) accumulates within drusen of the retinal pigment epithelium and is synthesized by RPE cells; the Y402H risk variant is located in a region mediating heparin and C-reactive protein binding, and multiple CFH haplotypes confer elevated or reduced AMD risk through effects on alternative complement pathway regulation at Bruch's membrane.\",\n      \"method\": \"Immunohistochemical localization of CFH in drusen; genetic association with functional haplotype analysis in ~900 AMD cases and ~400 controls\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization plus functional haplotype analysis; replicated across cohorts\",\n      \"pmids\": [\"15870199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Neisseria meningitidis outer-membrane lipoprotein GNA1870 (fHbp) binds human complement factor H (CFH) via direct protein-protein interaction; this binding recruits CFH to the bacterial surface, attenuates C3 deposition, and enhances serum resistance. Deletion of GNA1870 abolishes fH binding and increases C3 deposition and bacterial killing.\",\n      \"method\": \"GNA1870 deletion mutant generation; flow cytometry measuring fH binding; C3 deposition assays; serum bactericidal assays; anti-GNA1870 mAb blocking experiments; mass spectrometry identification\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal binding confirmed by genetic deletion and antibody blocking, with functional serum resistance assays\",\n      \"pmids\": [\"16785547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutations in CFH (found in 15–30% of aHUS patients) impair complement regulation at host cell surfaces, predisposing to uncontrolled alternative pathway activation and endothelial damage; CFH mutations were identified in 30.1% of non-Shiga-toxin HUS patients, with mutations in the C-terminal SCR20 domain associated with poorest prognosis and highest disease recurrence after transplantation.\",\n      \"method\": \"Genetic screening of 156 non-Stx-HUS patients for CFH (and MCP, factor I) mutations; functional characterization of mutant proteins (C3b binding, expression levels); clinical outcome correlation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large cohort mutation analysis with functional protein characterization; multiple orthogonal methods\",\n      \"pmids\": [\"16621965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Candida albicans surface phosphoglycerate mutase (CaGpm1p) binds human CFH via CCP domains SCR6-7 and SCR19-20 (two distinct contact regions), and also binds FHL-1 via SCR6-7; surface-bound CFH retains cofactor activity for factor I-mediated C3b cleavage, enabling immune evasion.\",\n      \"method\": \"Protein array screening of 4088 S. cerevisiae proteins; recombinant CaGpm1p expression and pulldown; flow cytometry; C3b cleavage cofactor assays; gpm1(-/-) mutant generation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — binding domain mapping with functional cofactor assays, genetic null mutant confirmation\",\n      \"pmids\": [\"17959597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The spectrum of diseases caused by CFH variants depends on differential effects on plasma-phase versus surface-bound CFH function: variants impairing systemic fluid-phase regulation predispose to MPGN/C3 glomerulopathy, while variants specifically disrupting C-terminal surface-recognition domains (SCR19-20) predispose to aHUS by preventing CFH from protecting host cell surfaces.\",\n      \"method\": \"Genotype-phenotype correlation across large patient cohorts; functional studies of CFH variants examining C3b binding, factor I cofactor activity, and surface-binding capacity\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization of multiple disease-associated variants with orthogonal assays; strong preponderance across labs\",\n      \"pmids\": [\"19297022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CFH controls the alternative complement pathway by acting as a competitive inhibitor of the C3 convertase (C3bBb): it binds C3b on host cell surfaces decorated with polyanions (sialic acid, heparan sulfate), acts as cofactor for factor I to inactivate C3b, and accelerates decay of C3bBb; pathogenic mutations in CFH disrupt these activities through reduced protein expression or dysfunctional surface recognition.\",\n      \"method\": \"Review synthesizing genetic screening, functional protein assays (cofactor activity, decay acceleration, surface binding), and mutation analysis across multiple patient cohorts\",\n      \"journal\": \"Pediatric nephrology (Berlin, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — established by reconstitution and mutagenesis across multiple independent labs\",\n      \"pmids\": [\"20526633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IgG autoantibodies against CFH (targeting the C-terminal SCR19-20 domain) block CFH surface recognition function, mimicking gain-of-loss mutations at this domain and causing atypical HUS; these autoantibodies occur almost exclusively in patients with homozygous deletion of CFHR1/CFHR3 (the DEAP-HUS subgroup), suggesting CFHR1 normally competes with these autoantibodies or modulates immune tolerance.\",\n      \"method\": \"Autoantibody characterization by ELISA and epitope mapping; genetic deletion analysis by PCR/Southern blot; functional studies of CFH surface-binding inhibition\",\n      \"journal\": \"Pediatric nephrology (Berlin, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epitope-mapped autoantibodies with functional blocking demonstrated, confirmed across multiple patient cohorts\",\n      \"pmids\": [\"20157737\", \"19190803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CFH is a major plasma binding protein for malondialdehyde (MDA), a common lipid peroxidation product; CFH binds MDA-modified proteins, blocks their uptake by macrophages, and suppresses MDA-induced proinflammatory effects in vivo. The AMD-associated H402 polymorphism markedly reduces CFH's ability to bind MDA, providing a mechanistic link between this variant and AMD pathogenesis via impaired oxidative stress responses.\",\n      \"method\": \"In vitro MDA-binding assays with recombinant CFH; macrophage uptake inhibition assays; in vivo mouse inflammation model; comparative binding assays of Y402 vs H402 CFH variants\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding reconstitution, in vivo validation, and functional comparison of disease variant; strong mechanistic study\",\n      \"pmids\": [\"21979047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-125b and miR-146a, which are upregulated in Alzheimer's disease brain and in NF-κB-activated neuronal-glial cells, directly target CFH mRNA and significantly reduce CFH protein expression; combinatorial NF-κB signaling drives these miRNAs to downregulate CFH in the context of neuroinflammation.\",\n      \"method\": \"miRNA expression profiling in post-mortem AD brain tissue and primary HNG cell culture; miRNA target prediction and validation; NF-κB inhibitor experiments; ANOVA-based quantification of CFH expression\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — target validation in cell culture with pathway inhibition; single lab, limited direct mechanistic follow-up\",\n      \"pmids\": [\"22302353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CFH loss of function in liver tumor-initiating cells promotes cancer stemness: knockdown of CFH abolishes tumorsphere formation and induces differentiation, while overexpression stimulates stemness factor expression and in vivo tumor growth; mechanistically, CFH maintains stemness through regulation of LSF-1 transcription factor expression.\",\n      \"method\": \"Primary tumorsphere culture; NanoString CD antigen gene expression; CFH siRNA knockdown and overexpression; in vivo xenograft assays; LSF-1 expression analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD/OE with defined phenotype and partial pathway placement; single lab, unconventional CFH function\",\n      \"pmids\": [\"26723877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rare structural variants (SVs) in the CFH-CFHR locus — including CFH::CFHR1 hybrid genes (caused by recurrent genomic rearrangements sharing a common 4.8-kbp ancestral CFHR promoter segment) — create fusion proteins with altered complement regulatory activity; bipolar clustering of rare nonsynonymous mutations in aHUS patients maps to C-terminal SCR domains (surface recognition) and in AMD patients maps to N-terminal domains (fluid-phase regulation), confirming domain-specific functional roles under positive selection.\",\n      \"method\": \"High-quality sequencing of ~360-kbp locus in six primate lineages; structural variant analysis in >2,400 individuals; burden testing in >5,000 AMD cases/controls; comparative genomics and selection analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large-scale structural genomics with functional domain mapping; strong preponderance across cases and evolutionary data\",\n      \"pmids\": [\"29686068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Factor H-like protein 1 (FHL-1), an alternative splice variant of CFH comprising the first 7 N-terminal CCP domains of CFH, has regulatory activity comparable to full-length CFH and is the predominant complement regulator on Bruch's membrane (a critical site for AMD). FHL-1 is specifically recruited by certain microorganisms for complement evasion, and some cancers upregulate FHL-1 for immune evasion, indicating tissue-specific roles distinct from CFH.\",\n      \"method\": \"Review synthesizing splice variant characterization, functional complement regulation assays, localization studies in Bruch's membrane, microbial binding studies, and cancer tissue analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — based on multiple experimental studies from different labs; FHL-1 functional equivalence to CFH shown by reconstitution\",\n      \"pmids\": [\"33178228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endogenous CFH expressed by RPE cells modulates complement regulation and inflammatory cytokine production independently of external complement sources; CFH silencing in hTERT-RPE1 cells increases IL-6, IL-8, GM-CSF, C3, and CFB while decreasing C5, and the NF-κB pathway is identified as the major pathway through which CFH loss drives these inflammatory and complement changes.\",\n      \"method\": \"CFH siRNA silencing in human hTERT-RPE1 cells; cytokine/complement protein quantification by ELISA and proteomics; NF-κB pathway inhibitor experiments; western blotting\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with defined molecular phenotype and pathway identification; single lab with multiple readouts\",\n      \"pmids\": [\"34445430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Complement factor H is a soluble regulator essential for controlling alternative pathway activation: it recognizes polyanion markers (e.g., sialic acid, heparan sulfate) on host cell surfaces via its C-terminal domains (SCR19-20) to provide surface-specific protection, while N-terminal domains (SCR1-4) mediate C3b binding, factor I cofactor activity, and C3 convertase decay acceleration in the fluid phase.\",\n      \"method\": \"Review synthesizing structural domain studies, binding assays, mutagenesis, and disease-variant functional analysis\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — established by extensive in vitro reconstitution, mutagenesis and structural studies across many independent labs\",\n      \"pmids\": [\"20580090\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Complement factor H (CFH) is a soluble 20-CCP-domain plasma glycoprotein that restrains the alternative complement pathway by acting as a cofactor for factor I-mediated C3b inactivation and by accelerating C3 convertase (C3bBb) decay; it recognizes polyanion markers (heparin, sialic acid, heparan sulfate) on host cell surfaces via C-terminal SCR19-20 domains to provide surface-specific protection, while N-terminal SCR1-4 domains mediate fluid-phase regulation; the AMD-risk Y402H variant in SCR7 impairs binding to heparin, C-reactive protein, and malondialdehyde (a lipid peroxidation product), reducing oxidative stress protection at Bruch's membrane; C-terminal domain mutations predispose to aHUS by abrogating host-surface recognition, whereas N-terminal mutations affect systemic C3b regulation; an alternatively spliced variant FHL-1 (SCR1-7) is the predominant regulator at Bruch's membrane; pathogens recruit CFH/FHL-1 to their surfaces via specific CCP-domain interactions to evade complement killing; and CFH expression in RPE cells is regulated by NF-κB and by miRNAs (miR-125b, miR-146a) in neuroinflammatory contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Complement Factor H (CFH) is the principal soluble inhibitor of the alternative complement pathway, acting both as a cofactor for Factor I-mediated proteolytic inactivation of C3b and as an accelerator of C3bBb convertase decay [PMID:21215749]. Disease-associated mutations define two functional classes: N-terminal or quantitative loss-of-function variants cause global complement dysregulation (linked to AMD), whereas C-terminal SCR 19–20 missense mutations selectively abolish host cell-surface recognition while preserving fluid-phase regulation, causing atypical hemolytic uremic syndrome (aHUS); autoantibodies targeting this same C-terminal domain phenocopy the surface-specific defect [PMID:20526633, PMID:19190803]. The alternatively spliced isoform FHL-1 (SCRs 1–7) is the predominant complement regulator on Bruch's membrane and functions with regulatory potency comparable to full-length Factor H, establishing it as a tissue-specific mediator at a critical site for AMD pathogenesis [PMID:33178228]. Endogenous CFH in retinal pigment epithelium cells additionally maintains inflammatory and complement homeostasis through the NF-κB pathway, with its loss upregulating C3, CFB, IL-6, and IL-8 in a cell-autonomous manner [PMID:34445430].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that microbial surface proteins recruit CFH/FHL-1 via distinct SCR domains and that surface-bound CFH retains cofactor activity for C3b cleavage established how pathogens exploit complement evasion through CFH hijacking.\",\n      \"evidence\": \"Recombinant protein pulldown, cofactor assay, and C. albicans Gpm1p null mutant analysis\",\n      \"pmids\": [\"17959597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether all microbial CFH-binding proteins use the same SCR contact sites\",\n        \"In vivo significance of Gpm1p-mediated CFH recruitment for Candida virulence\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of anti-CFH autoantibodies targeting the C-terminal SCR 19–20 domain in DEAP-HUS patients, occurring on a background of CFHR1/CFHR3 deletion, revealed an autoimmune mechanism that mimics the functional defect of genetic CFH C-terminal mutations.\",\n      \"evidence\": \"Epitope mapping of patient autoantibodies to CFH C-terminus, CFHR1/CFHR3 deletion genotyping in aHUS cohorts\",\n      \"pmids\": [\"19190803\", \"20157737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which CFHR1/CFHR3 absence permits autoantibody development\",\n        \"No in vitro reconstitution of autoantibody-mediated surface complement dysregulation\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Functional classification of aHUS-associated CFH mutations into quantitative deficiency (global dysregulation) versus dysfunctional surface recognition (SCR 19–20 missense) explained the genotype–phenotype divergence between systemic and surface-specific complement disorders.\",\n      \"evidence\": \"Genetic screening, complement functional assays, and protein quantification in aHUS patient cohorts\",\n      \"pmids\": [\"20526633\", \"19297022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for how individual SCR 19–20 missense mutations disrupt surface binding\",\n        \"Whether modifier genes beyond CFH modulate penetrance\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Biochemical confirmation that CFH performs dual inhibitory functions—Factor I cofactor activity and C3bBb decay acceleration—and that aHUS mutations differentially impair these activities solidified the mechanistic model of CFH as a bifunctional complement regulator.\",\n      \"evidence\": \"Functional complement assays on mutant CFH proteins from aHUS patients\",\n      \"pmids\": [\"21215749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relative contribution of cofactor versus decay-accelerating activity to in vivo protection\",\n        \"Whether different tissues rely preferentially on one function\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that NF-κB-induced miR-125b and miR-146a directly target CFH mRNA and reduce CFH protein in stressed neuronal-glial cells provided a transcriptional regulatory mechanism linking neuroinflammation to local complement dysregulation in Alzheimer's disease brain.\",\n      \"evidence\": \"miRNA target validation in IL-1β/Aβ42-stressed primary human neuronal-glial cell culture\",\n      \"pmids\": [\"22302353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo validation of miRNA-mediated CFH reduction in AD brain tissue\",\n        \"Whether miRNA-driven CFH loss is sufficient to cause local complement activation\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Large-scale genomic analysis mapped AMD-associated rare CFH missense mutations to the N-terminus, distinct from the C-terminal aHUS cluster, and showed these domains are under distinct evolutionary selection pressures—clarifying that different disease mechanisms operate through separable functional regions of CFH.\",\n      \"evidence\": \"High-quality sequencing across six primate lineages, case–control study of >5,000 AMD cases\",\n      \"pmids\": [\"29686068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Biochemical characterization of individual AMD-associated N-terminal missense variants\",\n        \"No structural explanation for why N-terminal mutations predispose to ocular rather than renal disease\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing that FHL-1 (the alternatively spliced SCR 1–7 isoform) has full regulatory potency and is the predominant complement regulator on Bruch's membrane redefined the tissue-specific complement landscape relevant to AMD pathogenesis.\",\n      \"evidence\": \"Synthesis of functional regulatory assays and tissue localization studies of FHL-1 versus full-length FH\",\n      \"pmids\": [\"33178228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct comparison of FHL-1 and full-length FH in an AMD animal model\",\n        \"Whether FHL-1 has unique binding partners at Bruch's membrane\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Endogenous CFH in RPE cells was shown to regulate inflammatory cytokines (IL-6, IL-8, GM-CSF) and complement components (C3, CFB) cell-autonomously via NF-κB, establishing an intracellular signaling role beyond its classical extracellular complement inhibitory function.\",\n      \"evidence\": \"siRNA knockdown of CFH in hTERT-RPE1 cells with cytokine and complement protein quantification and NF-κB pathway analysis\",\n      \"pmids\": [\"34445430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the NF-κB–CFH axis operates in RPE in vivo\",\n        \"Molecular mechanism by which intracellular CFH modulates NF-κB signaling\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural variants producing CFH::CFHR1 hybrid genes were confirmed as causative for aHUS through complement dysregulation, validated by eculizumab-induced remission, linking genomic rearrangement directly to pathogenic complement overactivation.\",\n      \"evidence\": \"MLPA and long-read SMRT sequencing of breakpoints, clinical eculizumab response in CFH-SV patients\",\n      \"pmids\": [\"36793547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Precise functional defect of each hybrid gene product\",\n        \"Whether all CFH::CFHR hybrid configurations are equally pathogenic\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which intracellular or cell-surface CFH modulates NF-κB in non-immune cells (e.g., RPE, tumor cells) remains undefined, as does the structural basis for domain-specific disease variant effects and the relative in vivo contributions of FHL-1 versus full-length FH in specific tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of CFH–NF-κB interaction in RPE or tumor cells\",\n        \"No animal model directly comparing FHL-1 and full-length FH rescue at Bruch's membrane\",\n        \"Role of CFHR protein family members in modulating CFH function in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 5, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 5, 10, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"C3b\",\n      \"CFI\",\n      \"CFB\",\n      \"CFHR1\",\n      \"CFHR3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Complement factor H (CFH) is a soluble 20-CCP-domain plasma glycoprotein that serves as the principal negative regulator of the alternative complement pathway, restraining amplification both in the fluid phase and on host cell surfaces. Its N-terminal domains (SCR1–4) mediate C3b binding, cofactor activity for factor I–mediated C3b inactivation, and decay-acceleration of the C3 convertase C3bBb, while C-terminal domains (SCR19–20) discriminate self from non-self by recognizing polyanion markers such as sialic acid and heparan sulfate on host surfaces [PMID:15163532, PMID:20580090]. Loss-of-function mutations in the C-terminal surface-recognition domains cause atypical hemolytic uremic syndrome (aHUS), whereas variants impairing fluid-phase regulation predispose to C3 glomerulopathy, and the common Y402H polymorphism in SCR7 impairs binding to heparin, C-reactive protein, and the lipid peroxidation product malondialdehyde, conferring strong risk for age-related macular degeneration [PMID:9551389, PMID:15761122, PMID:21979047, PMID:19297022]. Pathogens including Neisseria meningitidis and Candida albicans recruit CFH to their surfaces via specific CCP-domain interactions to evade complement-mediated killing, and an alternatively spliced variant FHL-1 (SCR1–7) functions as the predominant complement regulator at Bruch's membrane [PMID:16785547, PMID:17959597, PMID:33178228].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Determining the complete primary structure of CFH revealed a modular 20-CCP-repeat architecture and evidence for alternative splicing, establishing the structural framework for all subsequent domain-function studies.\",\n      \"evidence\": \"cDNA cloning and sequencing of overlapping clones covering the full-length 1213-amino-acid protein\",\n      \"pmids\": [\"2963625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional structure of individual CCP domains and full-length CFH not yet resolved\", \"Functional roles of individual CCP domains not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Biochemical reconstitution and domain-deletion mutagenesis established that CFH controls the alternative pathway through three distinct activities—factor I cofactor activity, C3 convertase decay acceleration, and polyanion-dependent host-surface recognition—mapped to separable CCP domains.\",\n      \"evidence\": \"Synthesis of in vitro reconstitution, binding assays, and domain-deletion mutagenesis from multiple laboratories\",\n      \"pmids\": [\"15163532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise stoichiometry and kinetics of CFH–C3b interaction on physiological surfaces not fully defined\", \"Relative contributions of each activity in vivo not resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of CFH mutations in familial and sporadic HUS provided the first causal genetic link between defective alternative pathway regulation and thrombotic microangiopathy, showing that both loss-of-expression (frameshift) and C-terminal missense variants drive disease.\",\n      \"evidence\": \"Linkage analysis at 1q32 followed by direct CFH gene mutation screening in HUS families\",\n      \"pmids\": [\"9551389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spectrum of causative mutations incomplete\", \"Mechanism by which C-terminal mutations specifically predispose to endothelial damage not elucidated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Genome-wide association identified Y402H in SCR7 as a major AMD risk variant, implicating complement dysregulation in macular degeneration and pinpointing the heparin/CRP-binding region as functionally critical for retinal protection.\",\n      \"evidence\": \"GWAS (116,204 SNPs) with resequencing in AMD case-control cohorts; independently replicated across four studies\",\n      \"pmids\": [\"15761122\", \"15761121\", \"15761120\", \"15870199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which Y402H alters local complement regulation at Bruch's membrane not defined\", \"Whether the variant acts through altered CRP binding, heparin binding, or both remained unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Combined pathogen-interaction and genotype-phenotype studies demonstrated that CFH domain specificity determines both disease type and microbial exploitation: C-terminal SCR19–20 mutations cause aHUS via loss of surface protection, and bacteria such as N. meningitidis hijack CFH to their surfaces via specific protein–protein interactions to evade complement killing.\",\n      \"evidence\": \"Genetic screening of 156 HUS patients with functional characterization of mutant proteins; GNA1870 deletion mutant, flow cytometry, and serum bactericidal assays for meningococcal fH binding\",\n      \"pmids\": [\"16621965\", \"16785547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of microbial CFH-binding proteins not catalogued\", \"Structural basis of CFH recruitment to bacterial surfaces not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Systematic genotype-phenotype correlation resolved the paradox of how CFH variants cause different diseases: N-terminal dysfunction impairs fluid-phase C3b regulation causing MPGN/C3 glomerulopathy, while C-terminal dysfunction abrogates host-surface recognition causing aHUS.\",\n      \"evidence\": \"Functional studies of disease-associated CFH variants measuring C3b binding, cofactor activity, and surface binding across large patient cohorts\",\n      \"pmids\": [\"19297022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Incomplete penetrance and environmental modifiers not explained\", \"Role of CFH-related proteins (CFHRs) in modifying disease phenotype only partially understood\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Anti-CFH autoantibodies targeting SCR19–20 were shown to functionally mimic C-terminal loss-of-function mutations, causing aHUS almost exclusively in patients with homozygous CFHR1/CFHR3 deletion, revealing a genetic susceptibility to autoimmune complement dysregulation.\",\n      \"evidence\": \"Autoantibody epitope mapping by ELISA, functional surface-binding inhibition assays, and genetic deletion analysis in patient cohorts\",\n      \"pmids\": [\"20157737\", \"19190803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CFHR1 deletion breaks immune tolerance to CFH not established\", \"Whether autoantibodies also impair fluid-phase CFH activity not fully tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that CFH is a major plasma MDA-binding protein that blocks MDA-induced macrophage uptake and inflammation provided a complement-independent protective function and mechanistically explained the AMD-risk Y402H variant, which has markedly reduced MDA binding.\",\n      \"evidence\": \"In vitro MDA-binding and macrophage uptake assays with recombinant CFH; in vivo mouse inflammation model; comparative binding of Y402 versus H402 variants\",\n      \"pmids\": [\"21979047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of MDA-binding in human retina not directly demonstrated\", \"Whether MDA-binding operates independently of or synergistically with complement regulation in AMD not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Large-scale structural genomic analysis of the CFH-CFHR locus identified recurrent hybrid gene formation and confirmed bipolar clustering of rare disease mutations—N-terminal for AMD, C-terminal for aHUS—under positive selection, revealing ongoing evolutionary pressures shaping domain-specific regulation.\",\n      \"evidence\": \"High-quality sequencing of ~360-kbp locus across six primate species; structural variant analysis in >2,400 individuals; burden testing in >5,000 AMD cases/controls\",\n      \"pmids\": [\"29686068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of most hybrid CFH-CFHR proteins not tested biochemically\", \"Selective pressures driving CFHR copy-number variation not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Characterization of the alternative splice variant FHL-1 (SCR1–7) as the predominant complement regulator at Bruch's membrane established tissue-specific division of labor between CFH and FHL-1 and showed that pathogens and tumors can selectively exploit FHL-1 for immune evasion.\",\n      \"evidence\": \"Synthesis of splice variant functional assays, Bruch's membrane localization studies, and microbial/tumor binding analyses\",\n      \"pmids\": [\"33178228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanisms controlling relative CFH versus FHL-1 expression in specific tissues not fully defined\", \"Whether FHL-1 loss alone is sufficient for AMD pathology not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Endogenous CFH in RPE cells was shown to modulate local complement and cytokine expression through NF-κB signaling, demonstrating that CFH has cell-autonomous anti-inflammatory functions beyond its classical role as a plasma complement regulator.\",\n      \"evidence\": \"CFH siRNA silencing in hTERT-RPE1 cells; cytokine and complement protein quantification; NF-κB pathway inhibition experiments\",\n      \"pmids\": [\"34445430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether intracellular CFH directly engages NF-κB pathway components or acts indirectly through autocrine complement signaling unknown\", \"Relevance of RPE-derived CFH versus liver-derived plasma CFH in AMD pathogenesis not resolved in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how full-length CFH simultaneously engages C3b and host-surface polyanions in a physiological membrane context, and how intracellular CFH functions are integrated with canonical plasma complement regulation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of full-length CFH bound to C3b on a membrane surface\", \"Intracellular signaling mechanisms of CFH in RPE and other cells not defined\", \"Therapeutic strategies to selectively restore surface-specific CFH function in aHUS or AMD not clinically validated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8, 9, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 4, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 9, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 9, 17]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [4, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 6, 8, 9, 10, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 6, 8, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"C3b\",\n      \"CFI\",\n      \"CRP\",\n      \"CFB\",\n      \"fHbp\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}