{"gene":"CFI","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1973,"finding":"Immunochemical depletion of C3b inactivator (KAF/CFI) from serum leads to spontaneous activation of the alternative complement pathway, with conversion of C3 and depletion of cobra venom factor–C3 proactivator. This activation was prevented by co-depletion of C3, demonstrating that the alternative pathway is a C3b-feedback pathway normally controlled by CFI activity.","method":"Immunochemical depletion of CFI from serum using purified F(ab')2 antibody; in vitro complement activation assays","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional depletion experiment with defined readout, replicated in the KAF-deficient patient in vivo","pmids":["4632688"],"is_preprint":false},{"year":2007,"finding":"CFI is a two-chain serine protease whose light chain carries the catalytic domain; it downregulates the alternative and classical complement pathways by cleaving the alpha' chains of C3b and C4b in the presence of cofactor proteins (cofactor activity). aHUS-associated mutations I322T, D501N, and D506V in the serine protease domain abolish C3b and C4b cofactor activity despite producing secreted protein. The R299W heavy-chain mutant shows decreased cofactor activity, providing evidence that the heavy chain region around R299 is important for cofactor activity. The delTTCAC (1446-1450) mutant produces a protein that is not secreted.","method":"Recombinant expression of mutant CFI proteins; functional cofactor cleavage assays with C3b and C4b; secretion assays","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro functional assay of multiple mutants with defined catalytic and secretion readouts","pmids":["17597211"],"is_preprint":false},{"year":2013,"finding":"The rare missense CFI variant encoding p.Gly119Arg reduces CFI protein expression and secretion levels, and plasma/sera from carriers mediate degradation of C3b (both in fluid phase and on cell surface) to a lesser extent than controls. In zebrafish, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type Gly119 in regulating retinal vessel thickness and branching.","method":"Recombinant protein expression and secretion quantification; functional C3b degradation assays in plasma/sera; zebrafish in vivo vascular assay with human CFI mRNA injection","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (recombinant protein, serum functional assay, in vivo zebrafish model) in a single rigorous study","pmids":["23685748"],"is_preprint":false},{"year":2013,"finding":"A rare C3 allele encoding Gln155 (p.Lys155Gln) confers resistance to proteolytic inactivation by CFH and CFI, demonstrating that CFI's regulatory function requires proper C3 substrate recognition and that loss of this regulation leads to excessive alternative complement activation.","method":"Functional proteolytic inactivation assay of C3b variants with CFH and CFI","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional cleavage assay, single lab; relevant to CFI mechanism as it defines substrate requirements","pmids":["24036952"],"is_preprint":false},{"year":2017,"finding":"Systematic in vivo functional testing of 20 rare coding nonsynonymous CFI variants in zebrafish identified nine variants that alter CFI activity; six are specifically associated with hypoactive complement factor I, demonstrating that loss-of-function is the predominant direction of effect of disease-associated CFI alleles in AMD.","method":"Targeted sequencing of CFI; injection of variant human CFI mRNA into zebrafish embryos; in vivo retinal vascular assay as surrogate for CFI activity","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic in vivo assay for multiple alleles, single lab, zebrafish surrogate assay","pmids":["28282489"],"is_preprint":false},{"year":2017,"finding":"Complete CFI deficiency caused by a homozygous p.His380Arg mutation affecting the catalytic triad histidine residue (His380, part of the His380-Asp429-Ser525 catalytic triad) results in loss of protein function, identifying His380 as an essential catalytic residue of the CFI serine protease active site.","method":"CFI gene sequencing; serum complement functional testing in patients with homozygous CFI mutations; identification of catalytic triad residue","journal":"Journal of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — patient-derived loss-of-function with defined catalytic triad residue identified, single case report with complement functional testing","pmids":["28942469"],"is_preprint":false},{"year":2020,"finding":"Rare CFI genetic variants were categorized functionally into three types: Type 1 variants cause low serum FI protein levels with correspondingly reduced C3b cleavage activity; Type 2 variants show normal FI antigen levels but reduced C3b-to-iC3b degradation; Type 3 variants show normal antigen levels and C3b degradation but low iC3b generation per unit FI. This demonstrates that CFI pathogenic variants act through either quantitative (protein level) or qualitative (catalytic efficiency) mechanisms.","method":"Serum-based functional assay measuring FI-mediated proteolytic cleavage of C3b to iC3b with Factor H as cofactor; ELISA for FI antigen levels in patient and control sera","journal":"Translational vision science & technology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional cleavage assay in patient sera, systematic classification across multiple variants, single lab","pmids":["32908800"],"is_preprint":false},{"year":2022,"finding":"Using a fully processed recombinant CFI produced via an IRES-Furin-CFI expression vector, a surface plasmon resonance assay was developed to characterize the C3b:FH:FI complex in real time. An active-site mutant (S525A FI, inactivated serine protease domain) was used to show that patient-associated inactive CFI variants (e.g., I340T) competitively inhibit wild-type FI function, demonstrating a dominant negative mechanism for certain loss-of-function CFI variants.","method":"IRES-Furin-CFI expression for fully processed recombinant FI; active-site mutagenesis (S525A); real-time surface plasmon resonance assay of C3b:FH:FI complex; competition assays with wild-type and variant FI","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with recombinant protein, active-site mutagenesis, novel SPR assay, and dominant negative mechanism established in a single rigorous study","pmids":["36643920"],"is_preprint":false},{"year":2008,"finding":"The CFI polymorphism is controlled by two main alleles (CFI*A and CFI*B). CFI*A is composed of two suballeles: CFI*As (R201S substitution) and CFI*Ah (R406H substitution). A rare variant CFI*Aj arises from CFI*Ah with an additional R502L mutation. CFI*As is Japanese-specific, demonstrating that specific missense variants in CFI underlie the serologically defined polymorphism.","method":"DNA sequencing of CFI in 174 Japanese subjects and 2,471 individuals from 20 populations; isoelectric focusing; haplotype analysis","journal":"Journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — population genetics and sequencing, no direct functional assay of variant proteins","pmids":["18825487"],"is_preprint":false}],"current_model":"CFI (complement factor I) is a two-chain serine protease (catalytic triad His380-Asp429-Ser525 in the light chain) that regulates both the alternative and classical complement pathways by cleaving the α' chains of C3b and C4b in the presence of soluble cofactors such as factor H, thereby forming iC3b and preventing uncontrolled complement amplification; disease-associated variants cause CFI dysfunction through reduced protein secretion, loss of catalytic activity, or dominant negative inhibition of wild-type FI within the C3b:FH:FI ternary complex."},"narrative":{"mechanistic_narrative":"CFI (complement factor I) is the master proteolytic regulator of the complement system, acting as the negative-feedback brake on the C3b amplification loop that drives the alternative pathway [PMID:4632688]. It is a two-chain serine protease whose light chain carries the catalytic triad (His380-Asp429-Ser525); it downregulates both the alternative and classical pathways by cleaving the α' chains of C3b and C4b in the presence of soluble cofactor proteins such as factor H, converting C3b to iC3b and thereby preventing uncontrolled complement amplification [PMID:17597211, PMID:36643920]. Catalysis depends on integrity of the active site (His380 is an essential catalytic residue) and on correct substrate recognition, since a C3 variant resistant to cleavage escapes CFI/CFH regulation [PMID:28942469, PMID:24036952]. Disease-associated variants act through multiple mechanistic classes: reduced protein secretion (quantitative loss), loss of catalytic/cofactor activity (qualitative loss), and a dominant-negative mechanism in which catalytically inactive FI competitively inhibits wild-type FI within the C3b:FH:FI ternary complex [PMID:17597211, PMID:32908800, PMID:36643920]. Loss-of-function is the predominant direction of effect among disease-associated CFI alleles in age-related macular degeneration and aHUS, with reduced C3b regulatory activity tracking with pathogenicity [PMID:23685748, PMID:28282489, PMID:32908800].","teleology":[{"year":1973,"claim":"Established that CFI is the physiological brake on complement by showing its removal triggers spontaneous, C3-dependent activation of the alternative pathway, defining the C3b-feedback loop it controls.","evidence":"Immunochemical depletion of CFI from serum with F(ab')2 antibody and in vitro complement activation assays","pmids":["4632688"],"confidence":"High","gaps":["Did not resolve the molecular nature of CFI as a protease","No identification of cofactor requirements","No structural or substrate-level mechanism"]},{"year":2007,"claim":"Defined CFI as a two-chain serine protease cleaving C3b and C4b with cofactor proteins, and showed disease mutations separate catalytic loss from secretion defects.","evidence":"Recombinant expression of CFI mutants with C3b/C4b cofactor cleavage and secretion assays","pmids":["17597211"],"confidence":"High","gaps":["Catalytic triad residues not directly mapped functionally here","Mechanism by which heavy-chain R299 contributes to cofactor activity unresolved","No real-time kinetics of the cofactor complex"]},{"year":2013,"claim":"Linked rare CFI loss-of-function variants to disease by showing reduced secretion and impaired C3b degradation, with in vivo confirmation in zebrafish.","evidence":"Recombinant protein/secretion quantification, serum C3b-degradation assays, and zebrafish retinal vascular assay with human CFI mRNA","pmids":["23685748"],"confidence":"High","gaps":["Zebrafish retinal assay is a surrogate for human CFI activity","Does not distinguish secretion from catalytic contributions to the deficit"]},{"year":2013,"claim":"Demonstrated CFI regulation requires proper substrate recognition, since a cleavage-resistant C3 variant escapes CFI/CFH-mediated inactivation.","evidence":"Functional proteolytic inactivation assay of C3b variants with CFH and CFI","pmids":["24036952"],"confidence":"Medium","gaps":["Single-lab functional assay","Structural basis of the substrate determinant not defined","Effect studied from the substrate side, not CFI mutations"]},{"year":2017,"claim":"Systematically established loss-of-function as the predominant direction of effect for disease-associated CFI alleles by screening many variants in vivo.","evidence":"Targeted CFI sequencing and injection of variant human CFI mRNA into zebrafish with a retinal vascular surrogate assay","pmids":["28282489"],"confidence":"Medium","gaps":["Zebrafish surrogate may not capture human-specific cofactor interactions","Mechanism (secretion vs catalysis) per variant not resolved","Single-lab assay"]},{"year":2017,"claim":"Identified His380 as an essential catalytic-triad residue by linking a homozygous His380Arg mutation to complete CFI deficiency.","evidence":"CFI sequencing and serum complement functional testing in patients with homozygous mutations","pmids":["28942469"],"confidence":"Medium","gaps":["Single case report","No recombinant kinetic confirmation of the catalytic role","Other triad residues not tested in this study"]},{"year":2020,"claim":"Resolved that CFI pathogenic variants act through three distinct mechanistic classes spanning quantitative (protein level) and qualitative (catalytic efficiency) defects.","evidence":"Serum FI-mediated C3b-to-iC3b cleavage assays with factor H cofactor plus ELISA for FI antigen in patient and control sera","pmids":["32908800"],"confidence":"Medium","gaps":["Single-lab serum-based classification","Molecular basis of the Type 3 iC3b-generation defect unresolved","No structural correlates for each class"]},{"year":2022,"claim":"Established a dominant-negative mechanism whereby catalytically inactive CFI competitively inhibits wild-type FI within the C3b:FH:FI complex.","evidence":"Fully processed recombinant FI (IRES-Furin-CFI), S525A active-site mutagenesis, and real-time SPR competition assays of the C3b:FH:FI complex","pmids":["36643920"],"confidence":"High","gaps":["Tested for specific variants (e.g., I340T); generality across all loss-of-function alleles not established","In vivo relevance of competition not demonstrated","Stoichiometry of inhibition in plasma not defined"]},{"year":null,"claim":"How CFI is recruited to and oriented within the C3b:cofactor complex at atomic resolution, and which variants act by secretion loss versus catalytic loss versus dominant-negative competition, remains incompletely mapped.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking heavy-chain residues (e.g., R299) to cofactor binding in the timeline","Per-variant mechanistic assignment incomplete","Cofactor-dependent allosteric activation mechanism not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,5,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]}],"complexes":["C3b:FH:FI ternary complex"],"partners":["C3","CFH","C4B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05156","full_name":"Complement factor I","aliases":["C3B/C4B inactivator"],"length_aa":583,"mass_kda":65.8,"function":"Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways. Inhibits these pathways by cleaving three peptide bonds in the alpha-chain of C3b and two bonds in the alpha-chain of C4b thereby inactivating these proteins (PubMed:17320177, PubMed:7360115). Essential cofactors for these reactions include factor H and C4BP in the fluid phase and membrane cofactor protein/CD46 and CR1 on cell surfaces (PubMed:12055245, PubMed:2141838, PubMed:9605165). The presence of these cofactors on healthy cells allows degradation of deposited C3b by CFI in order to prevent undesired complement activation, while in apoptotic cells or microbes, the absence of such cofactors leads to C3b-mediated complement activation and subsequent opsonization (PubMed:28671664)","subcellular_location":"Secreted, extracellular space; Secreted","url":"https://www.uniprot.org/uniprotkb/P05156/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFI","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFI","total_profiled":1310},"omim":[{"mim_id":"615591","title":"MACULAR DEGENERATION, AGE-RELATED, 15; ARMD15","url":"https://www.omim.org/entry/615591"},{"mim_id":"615439","title":"MACULAR DEGENERATION, AGE-RELATED, 13; ARMD13","url":"https://www.omim.org/entry/615439"},{"mim_id":"614809","title":"C3 GLOMERULOPATHY 3; C3G3","url":"https://www.omim.org/entry/614809"},{"mim_id":"612925","title":"HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 5; AHUS5","url":"https://www.omim.org/entry/612925"},{"mim_id":"612923","title":"HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3; AHUS3","url":"https://www.omim.org/entry/612923"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":917.6}],"url":"https://www.proteinatlas.org/search/CFI"},"hgnc":{"alias_symbol":["FI","C3b-INA","C3bINA","KAF"],"prev_symbol":["IF"]},"alphafold":{"accession":"P05156","domains":[{"cath_id":"3.10.250.10","chopping":"109-322","consensus_level":"medium","plddt":87.3659,"start":109,"end":322},{"cath_id":"2.40.10.10","chopping":"325-332_342-583","consensus_level":"medium","plddt":86.1738,"start":325,"end":583}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05156","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05156-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05156-F1-predicted_aligned_error_v6.png","plddt_mean":84.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFI","jax_strain_url":"https://www.jax.org/strain/search?query=CFI"},"sequence":{"accession":"P05156","fasta_url":"https://rest.uniprot.org/uniprotkb/P05156.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05156/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05156"}},"corpus_meta":[{"pmid":"24036952","id":"PMC_24036952","title":"Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24036952","citation_count":293,"is_preprint":false},{"pmid":"16642048","id":"PMC_16642048","title":"Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP).","date":"2006","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/16642048","citation_count":172,"is_preprint":false},{"pmid":"25043604","id":"PMC_25043604","title":"Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent.","date":"2014","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/25043604","citation_count":164,"is_preprint":false},{"pmid":"23685748","id":"PMC_23685748","title":"A functional variant in the CFI gene confers a high risk of age-related macular degeneration.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23685748","citation_count":162,"is_preprint":false},{"pmid":"4632688","id":"PMC_4632688","title":"The alternate pathway of complement activation. The role of C3 and its inactivator (KAF).","date":"1973","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/4632688","citation_count":160,"is_preprint":false},{"pmid":"21295486","id":"PMC_21295486","title":"Crystal structure of a human cleavage factor CFI(m)25/CFI(m)68/RNA complex provides an insight into poly(A) site recognition and RNA looping.","date":"2011","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/21295486","citation_count":134,"is_preprint":false},{"pmid":"20479262","id":"PMC_20479262","title":"Structural basis of UGUA recognition by the Nudix protein CFI(m)25 and implications for a regulatory role in mRNA 3' processing.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20479262","citation_count":131,"is_preprint":false},{"pmid":"17597211","id":"PMC_17597211","title":"Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome.","date":"2007","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17597211","citation_count":128,"is_preprint":false},{"pmid":"31475020","id":"PMC_31475020","title":"siRNA-Finder (si-Fi) Software for RNAi-Target Design and Off-Target Prediction.","date":"2019","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/31475020","citation_count":124,"is_preprint":false},{"pmid":"22112647","id":"PMC_22112647","title":"Use of laptop computers connected to internet through Wi-Fi decreases human sperm motility and increases sperm DNA fragmentation.","date":"2011","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/22112647","citation_count":110,"is_preprint":false},{"pmid":"25788521","id":"PMC_25788521","title":"Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25788521","citation_count":108,"is_preprint":false},{"pmid":"28270606","id":"PMC_28270606","title":"Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28270606","citation_count":101,"is_preprint":false},{"pmid":"29573716","id":"PMC_29573716","title":"Wi-Fi is an important threat to human health.","date":"2018","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/29573716","citation_count":79,"is_preprint":false},{"pmid":"10024596","id":"PMC_10024596","title":"Safety and immunogenicity of a Pseudomonas aeruginosa hybrid outer membrane protein F-I vaccine in human volunteers.","date":"1999","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10024596","citation_count":66,"is_preprint":false},{"pmid":"16562138","id":"PMC_16562138","title":"Episome-mediated Transfer of Drug Resistance in Enterobacteriaceae X. Restriction and Modification of Phages by fi R Factors.","date":"1966","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/16562138","citation_count":64,"is_preprint":false},{"pmid":"26775760","id":"PMC_26775760","title":"Does prolonged radiofrequency radiation emitted from Wi-Fi devices induce DNA damage in various tissues of rats?","date":"2016","source":"Journal of chemical neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/26775760","citation_count":59,"is_preprint":false},{"pmid":"25703814","id":"PMC_25703814","title":"Investigation of the effects of distance from sources on apoptosis, oxidative stress and cytosolic calcium accumulation via TRPV1 channels induced by mobile phones and Wi-Fi in breast cancer cells.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25703814","citation_count":57,"is_preprint":false},{"pmid":"25723005","id":"PMC_25723005","title":"The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent.","date":"2015","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25723005","citation_count":57,"is_preprint":false},{"pmid":"2435059","id":"PMC_2435059","title":"An equine rotavirus (FI-14 strain) which bears both subgroup I and subgroup II specificities on its VP6.","date":"1987","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/2435059","citation_count":56,"is_preprint":false},{"pmid":"25775055","id":"PMC_25775055","title":"Effects of 2.4 GHz radiofrequency radiation emitted from Wi-Fi equipment on microRNA expression in brain tissue.","date":"2015","source":"International journal of radiation 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inactivator (KAF/CFI) from serum leads to spontaneous activation of the alternative complement pathway, with conversion of C3 and depletion of cobra venom factor–C3 proactivator. This activation was prevented by co-depletion of C3, demonstrating that the alternative pathway is a C3b-feedback pathway normally controlled by CFI activity.\",\n      \"method\": \"Immunochemical depletion of CFI from serum using purified F(ab')2 antibody; in vitro complement activation assays\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional depletion experiment with defined readout, replicated in the KAF-deficient patient in vivo\",\n      \"pmids\": [\"4632688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CFI is a two-chain serine protease whose light chain carries the catalytic domain; it downregulates the alternative and classical complement pathways by cleaving the alpha' chains of C3b and C4b in the presence of cofactor proteins (cofactor activity). aHUS-associated mutations I322T, D501N, and D506V in the serine protease domain abolish C3b and C4b cofactor activity despite producing secreted protein. The R299W heavy-chain mutant shows decreased cofactor activity, providing evidence that the heavy chain region around R299 is important for cofactor activity. The delTTCAC (1446-1450) mutant produces a protein that is not secreted.\",\n      \"method\": \"Recombinant expression of mutant CFI proteins; functional cofactor cleavage assays with C3b and C4b; secretion assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro functional assay of multiple mutants with defined catalytic and secretion readouts\",\n      \"pmids\": [\"17597211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The rare missense CFI variant encoding p.Gly119Arg reduces CFI protein expression and secretion levels, and plasma/sera from carriers mediate degradation of C3b (both in fluid phase and on cell surface) to a lesser extent than controls. In zebrafish, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type Gly119 in regulating retinal vessel thickness and branching.\",\n      \"method\": \"Recombinant protein expression and secretion quantification; functional C3b degradation assays in plasma/sera; zebrafish in vivo vascular assay with human CFI mRNA injection\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (recombinant protein, serum functional assay, in vivo zebrafish model) in a single rigorous study\",\n      \"pmids\": [\"23685748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A rare C3 allele encoding Gln155 (p.Lys155Gln) confers resistance to proteolytic inactivation by CFH and CFI, demonstrating that CFI's regulatory function requires proper C3 substrate recognition and that loss of this regulation leads to excessive alternative complement activation.\",\n      \"method\": \"Functional proteolytic inactivation assay of C3b variants with CFH and CFI\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional cleavage assay, single lab; relevant to CFI mechanism as it defines substrate requirements\",\n      \"pmids\": [\"24036952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Systematic in vivo functional testing of 20 rare coding nonsynonymous CFI variants in zebrafish identified nine variants that alter CFI activity; six are specifically associated with hypoactive complement factor I, demonstrating that loss-of-function is the predominant direction of effect of disease-associated CFI alleles in AMD.\",\n      \"method\": \"Targeted sequencing of CFI; injection of variant human CFI mRNA into zebrafish embryos; in vivo retinal vascular assay as surrogate for CFI activity\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic in vivo assay for multiple alleles, single lab, zebrafish surrogate assay\",\n      \"pmids\": [\"28282489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Complete CFI deficiency caused by a homozygous p.His380Arg mutation affecting the catalytic triad histidine residue (His380, part of the His380-Asp429-Ser525 catalytic triad) results in loss of protein function, identifying His380 as an essential catalytic residue of the CFI serine protease active site.\",\n      \"method\": \"CFI gene sequencing; serum complement functional testing in patients with homozygous CFI mutations; identification of catalytic triad residue\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — patient-derived loss-of-function with defined catalytic triad residue identified, single case report with complement functional testing\",\n      \"pmids\": [\"28942469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rare CFI genetic variants were categorized functionally into three types: Type 1 variants cause low serum FI protein levels with correspondingly reduced C3b cleavage activity; Type 2 variants show normal FI antigen levels but reduced C3b-to-iC3b degradation; Type 3 variants show normal antigen levels and C3b degradation but low iC3b generation per unit FI. This demonstrates that CFI pathogenic variants act through either quantitative (protein level) or qualitative (catalytic efficiency) mechanisms.\",\n      \"method\": \"Serum-based functional assay measuring FI-mediated proteolytic cleavage of C3b to iC3b with Factor H as cofactor; ELISA for FI antigen levels in patient and control sera\",\n      \"journal\": \"Translational vision science & technology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional cleavage assay in patient sera, systematic classification across multiple variants, single lab\",\n      \"pmids\": [\"32908800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Using a fully processed recombinant CFI produced via an IRES-Furin-CFI expression vector, a surface plasmon resonance assay was developed to characterize the C3b:FH:FI complex in real time. An active-site mutant (S525A FI, inactivated serine protease domain) was used to show that patient-associated inactive CFI variants (e.g., I340T) competitively inhibit wild-type FI function, demonstrating a dominant negative mechanism for certain loss-of-function CFI variants.\",\n      \"method\": \"IRES-Furin-CFI expression for fully processed recombinant FI; active-site mutagenesis (S525A); real-time surface plasmon resonance assay of C3b:FH:FI complex; competition assays with wild-type and variant FI\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with recombinant protein, active-site mutagenesis, novel SPR assay, and dominant negative mechanism established in a single rigorous study\",\n      \"pmids\": [\"36643920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The CFI polymorphism is controlled by two main alleles (CFI*A and CFI*B). CFI*A is composed of two suballeles: CFI*As (R201S substitution) and CFI*Ah (R406H substitution). A rare variant CFI*Aj arises from CFI*Ah with an additional R502L mutation. CFI*As is Japanese-specific, demonstrating that specific missense variants in CFI underlie the serologically defined polymorphism.\",\n      \"method\": \"DNA sequencing of CFI in 174 Japanese subjects and 2,471 individuals from 20 populations; isoelectric focusing; haplotype analysis\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — population genetics and sequencing, no direct functional assay of variant proteins\",\n      \"pmids\": [\"18825487\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFI (complement factor I) is a two-chain serine protease (catalytic triad His380-Asp429-Ser525 in the light chain) that regulates both the alternative and classical complement pathways by cleaving the α' chains of C3b and C4b in the presence of soluble cofactors such as factor H, thereby forming iC3b and preventing uncontrolled complement amplification; disease-associated variants cause CFI dysfunction through reduced protein secretion, loss of catalytic activity, or dominant negative inhibition of wild-type FI within the C3b:FH:FI ternary complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CFI (complement factor I) is the master proteolytic regulator of the complement system, acting as the negative-feedback brake on the C3b amplification loop that drives the alternative pathway [#0]. It is a two-chain serine protease whose light chain carries the catalytic triad (His380-Asp429-Ser525); it downregulates both the alternative and classical pathways by cleaving the \\u03b1' chains of C3b and C4b in the presence of soluble cofactor proteins such as factor H, converting C3b to iC3b and thereby preventing uncontrolled complement amplification [#1, #7]. Catalysis depends on integrity of the active site (His380 is an essential catalytic residue) and on correct substrate recognition, since a C3 variant resistant to cleavage escapes CFI/CFH regulation [#5, #3]. Disease-associated variants act through multiple mechanistic classes: reduced protein secretion (quantitative loss), loss of catalytic/cofactor activity (qualitative loss), and a dominant-negative mechanism in which catalytically inactive FI competitively inhibits wild-type FI within the C3b:FH:FI ternary complex [#1, #6, #7]. Loss-of-function is the predominant direction of effect among disease-associated CFI alleles in age-related macular degeneration and aHUS, with reduced C3b regulatory activity tracking with pathogenicity [#2, #4, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 1973,\n      \"claim\": \"Established that CFI is the physiological brake on complement by showing its removal triggers spontaneous, C3-dependent activation of the alternative pathway, defining the C3b-feedback loop it controls.\",\n      \"evidence\": \"Immunochemical depletion of CFI from serum with F(ab')2 antibody and in vitro complement activation assays\",\n      \"pmids\": [\"4632688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular nature of CFI as a protease\", \"No identification of cofactor requirements\", \"No structural or substrate-level mechanism\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined CFI as a two-chain serine protease cleaving C3b and C4b with cofactor proteins, and showed disease mutations separate catalytic loss from secretion defects.\",\n      \"evidence\": \"Recombinant expression of CFI mutants with C3b/C4b cofactor cleavage and secretion assays\",\n      \"pmids\": [\"17597211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic triad residues not directly mapped functionally here\", \"Mechanism by which heavy-chain R299 contributes to cofactor activity unresolved\", \"No real-time kinetics of the cofactor complex\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked rare CFI loss-of-function variants to disease by showing reduced secretion and impaired C3b degradation, with in vivo confirmation in zebrafish.\",\n      \"evidence\": \"Recombinant protein/secretion quantification, serum C3b-degradation assays, and zebrafish retinal vascular assay with human CFI mRNA\",\n      \"pmids\": [\"23685748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Zebrafish retinal assay is a surrogate for human CFI activity\", \"Does not distinguish secretion from catalytic contributions to the deficit\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated CFI regulation requires proper substrate recognition, since a cleavage-resistant C3 variant escapes CFI/CFH-mediated inactivation.\",\n      \"evidence\": \"Functional proteolytic inactivation assay of C3b variants with CFH and CFI\",\n      \"pmids\": [\"24036952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional assay\", \"Structural basis of the substrate determinant not defined\", \"Effect studied from the substrate side, not CFI mutations\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Systematically established loss-of-function as the predominant direction of effect for disease-associated CFI alleles by screening many variants in vivo.\",\n      \"evidence\": \"Targeted CFI sequencing and injection of variant human CFI mRNA into zebrafish with a retinal vascular surrogate assay\",\n      \"pmids\": [\"28282489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Zebrafish surrogate may not capture human-specific cofactor interactions\", \"Mechanism (secretion vs catalysis) per variant not resolved\", \"Single-lab assay\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified His380 as an essential catalytic-triad residue by linking a homozygous His380Arg mutation to complete CFI deficiency.\",\n      \"evidence\": \"CFI sequencing and serum complement functional testing in patients with homozygous mutations\",\n      \"pmids\": [\"28942469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case report\", \"No recombinant kinetic confirmation of the catalytic role\", \"Other triad residues not tested in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved that CFI pathogenic variants act through three distinct mechanistic classes spanning quantitative (protein level) and qualitative (catalytic efficiency) defects.\",\n      \"evidence\": \"Serum FI-mediated C3b-to-iC3b cleavage assays with factor H cofactor plus ELISA for FI antigen in patient and control sera\",\n      \"pmids\": [\"32908800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab serum-based classification\", \"Molecular basis of the Type 3 iC3b-generation defect unresolved\", \"No structural correlates for each class\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a dominant-negative mechanism whereby catalytically inactive CFI competitively inhibits wild-type FI within the C3b:FH:FI complex.\",\n      \"evidence\": \"Fully processed recombinant FI (IRES-Furin-CFI), S525A active-site mutagenesis, and real-time SPR competition assays of the C3b:FH:FI complex\",\n      \"pmids\": [\"36643920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tested for specific variants (e.g., I340T); generality across all loss-of-function alleles not established\", \"In vivo relevance of competition not demonstrated\", \"Stoichiometry of inhibition in plasma not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CFI is recruited to and oriented within the C3b:cofactor complex at atomic resolution, and which variants act by secretion loss versus catalytic loss versus dominant-negative competition, remains incompletely mapped.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking heavy-chain residues (e.g., R299) to cofactor binding in the timeline\", \"Per-variant mechanistic assignment incomplete\", \"Cofactor-dependent allosteric activation mechanism not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 5, 7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"C3b:FH:FI ternary complex\"],\n    \"partners\": [\"C3\", \"CFH\", \"C4B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}