{"gene":"FCN1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2017,"finding":"The collagen-like domain of FCN1 (M-ficolin) directly binds to IgG1 in vitro through portions of the CH1 and CH3 domains of IgG1, as demonstrated by Western blot binding assays; synthetic peptides corresponding to the CH1 and CH3 domains of IgG1 efficiently inhibited this association.","method":"Western blot binding assay (in vitro), synthetic peptide inhibition","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding with domain-mapping via inhibitory peptides, single lab, two orthogonal approaches (Wb binding + peptide inhibition)","pmids":["28900133"],"is_preprint":false},{"year":2012,"finding":"The Ser268Pro (rs150625869) non-synonymous mutation in FCN1 leads to complete loss of M-ficolin production. The Ala218Thr (rs148649884) and Asn289Ser (rs138055828) mutations cripple the ligand-binding capability of M-ficolin, as demonstrated by reduced binding to Group B Streptococcus in recombinant protein assays.","method":"Recombinant protein expression and ligand-binding assay (Group B Streptococcus binding), corroborated by clinical genotype-phenotype data","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — recombinant protein functional assay with mutagenesis validated by clinical observations, multiple orthogonal approaches in single study","pmids":["23209787"],"is_preprint":false},{"year":2012,"finding":"Promoter polymorphisms in FCN1 (positions -542 and -144) regulate both FCN1 mRNA expression and ficolin-1 protein secretion by monocytes; individuals homozygous for minor alleles at these positions have significantly higher FCN1 mRNA levels and higher ficolin-1 levels in monocyte culture supernatants.","method":"FCN1 mRNA expression in isolated monocytes/granulocytes (qRT-PCR implied), ELISA for ficolin-1 in monocyte culture supernatants, genotyping of FCN1 promoter SNPs","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter variant linked to mRNA and secreted protein levels in primary cells, single lab, two orthogonal readouts","pmids":["22673311"],"is_preprint":false},{"year":2023,"finding":"FCN1 overexpression in THP-1-derived macrophages promotes LPS-induced activation and maturation of the proinflammatory cytokine IL-1β via the NLRP3-caspase-1 axis.","method":"FCN1 overexpression in THP-1-derived macrophages, immunoblotting for IL-1β, NLRP3, and caspase-1","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function experiment with defined pathway readout (NLRP3-caspase-1-IL-1β), single lab, single method","pmids":["36932401"],"is_preprint":false}],"current_model":"FCN1-encoded M-ficolin is a collagen-like pattern-recognition molecule of the lectin complement pathway whose collagen-like domain directly binds IgG1 (via CH1/CH3 domains); specific non-synonymous mutations abolish its production or cripple its ligand-binding capacity; promoter variants regulate its transcription and secretion from monocytes; and within macrophages, FCN1 promotes IL-1β maturation via the NLRP3-caspase-1 axis."},"narrative":{"mechanistic_narrative":"FCN1 encodes M-ficolin (ficolin-1), a pattern-recognition molecule whose collagen-like domain directly binds the CH1 and CH3 domains of IgG1, an interaction mappable and competable with synthetic IgG1 domain peptides [PMID:28900133]. Non-synonymous coding variants define its functional output: Ser268Pro abolishes M-ficolin production entirely, while Ala218Thr and Asn289Ser cripple its ligand-binding capacity, evidenced by reduced binding to Group B Streptococcus [PMID:23209787]. Expression and secretion of ficolin-1 from monocytes are governed by FCN1 promoter polymorphisms at positions -542 and -144, which set both mRNA levels and secreted protein output [PMID:22673311]. Within macrophages, FCN1 acts as a proinflammatory amplifier, promoting LPS-induced IL-1β maturation through the NLRP3–caspase-1 axis [PMID:36932401]. Beyond these findings, the structural basis of complement activation by FCN1 has not been characterized in the available corpus.","teleology":[{"year":2012,"claim":"Establishing how FCN1 expression is set, promoter polymorphisms were shown to control transcript abundance and secreted ficolin-1, linking genetic variation to quantitative immune output.","evidence":"FCN1 promoter SNP genotyping with monocyte qRT-PCR and ELISA on culture supernatants","pmids":["22673311"],"confidence":"Medium","gaps":["Transcription factors binding the -542/-144 region not identified","Functional consequence of altered ficolin-1 levels on complement activation not tested"]},{"year":2012,"claim":"To connect coding variation with function, mutagenesis defined residues required for M-ficolin production versus ligand binding, distinguishing null from binding-deficient alleles.","evidence":"Recombinant protein expression of variant M-ficolin with Group B Streptococcus binding assay, corroborated by clinical genotype-phenotype data","pmids":["23209787"],"confidence":"High","gaps":["Structural basis of how Ala218Thr/Asn289Ser impair binding not resolved","Effect on downstream complement activation not measured"]},{"year":2017,"claim":"Addressing what M-ficolin recognizes beyond microbial ligands, its collagen-like domain was shown to directly bind IgG1, implicating it in antibody-associated recognition.","evidence":"In vitro Western blot binding assay with synthetic CH1/CH3 peptide inhibition","pmids":["28900133"],"confidence":"Medium","gaps":["Physiological/in vivo relevance of the IgG1 interaction not established","Single lab, no reciprocal or structural validation"]},{"year":2023,"claim":"Probing an intracellular/inflammatory role, FCN1 overexpression was found to enhance IL-1β maturation via NLRP3-caspase-1, positioning it as a proinflammatory amplifier in macrophages.","evidence":"FCN1 overexpression in THP-1-derived macrophages with immunoblotting for IL-1β, NLRP3, caspase-1","pmids":["36932401"],"confidence":"Medium","gaps":["Gain-of-function only; loss-of-function not tested","Mechanism linking FCN1 to NLRP3 activation unknown","Single lab, single method"]},{"year":null,"claim":"How FCN1's pattern recognition couples mechanistically to lectin-pathway complement activation and to intracellular inflammasome signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FCN1 ligand complexes","Link between extracellular recognition and macrophage NLRP3 activation not established","MASP partners and complement readouts not characterized in this corpus"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["IGHG1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00602","full_name":"Ficolin-1","aliases":["Collagen/fibrinogen domain-containing protein 1","Ficolin-A","Ficolin-alpha","M-ficolin"],"length_aa":326,"mass_kda":35.1,"function":"Extracellular lectin, which acts as a pattern recognition receptor that initiates the lectin pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:16116205, PubMed:17897951, PubMed:20032467). Specifically recognizes and binds carbohydrates on the pathogen surface, activating the MASP1 serine protease and initiating the proteolytic cascade of the lectin complement pathway (PubMed:16116205, PubMed:20032467). Binds preferentially to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in a 2-3 linkage (PubMed:20032467, PubMed:20400674). May also activate monocytes through a G protein-coupled receptor, FFAR2, inducing the secretion of interleukin-8/IL-8 (PubMed:21037097)","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/O00602/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FCN1","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/FCN1","total_profiled":1310},"omim":[{"mim_id":"613357","title":"FIBRINOGEN C DOMAIN-CONTAINING PROTEIN 1; FIBCD1","url":"https://www.omim.org/entry/613357"},{"mim_id":"604973","title":"FICOLIN 3; FCN3","url":"https://www.omim.org/entry/604973"},{"mim_id":"601624","title":"FICOLIN 2; FCN2","url":"https://www.omim.org/entry/601624"},{"mim_id":"601252","title":"FICOLIN 1; FCN1","url":"https://www.omim.org/entry/601252"},{"mim_id":"301110","title":"HEMOLYTIC UREMIC SYNDROME, ATYPICAL, 8, WITH RHIZOMELIC SHORT STATURE; AHUS8","url":"https://www.omim.org/entry/301110"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":150.0},{"tissue":"lymphoid tissue","ntpm":45.0}],"url":"https://www.proteinatlas.org/search/FCN1"},"hgnc":{"alias_symbol":["FCNM"],"prev_symbol":[]},"alphafold":{"accession":"O00602","domains":[{"cath_id":"3.90.215.10","chopping":"119-261_317-326","consensus_level":"high","plddt":98.2256,"start":119,"end":326}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00602","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00602-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00602-F1-predicted_aligned_error_v6.png","plddt_mean":84.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FCN1","jax_strain_url":"https://www.jax.org/strain/search?query=FCN1"},"sequence":{"accession":"O00602","fasta_url":"https://rest.uniprot.org/uniprotkb/O00602.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00602/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00602"}},"corpus_meta":[{"pmid":"19501910","id":"PMC_19501910","title":"MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement.","date":"2009","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19501910","citation_count":122,"is_preprint":false},{"pmid":"22673311","id":"PMC_22673311","title":"Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation.","date":"2012","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/22673311","citation_count":64,"is_preprint":false},{"pmid":"18032536","id":"PMC_18032536","title":"Polymorphisms in the ficolin 1 gene (FCN1) are associated with susceptibility to the development of rheumatoid arthritis.","date":"2007","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18032536","citation_count":52,"is_preprint":false},{"pmid":"36932401","id":"PMC_36932401","title":"Identification of FCN1 as a novel macrophage infiltration-associated biomarker for diagnosis of pediatric inflammatory bowel diseases.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36932401","citation_count":33,"is_preprint":false},{"pmid":"23209787","id":"PMC_23209787","title":"Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23209787","citation_count":23,"is_preprint":false},{"pmid":"28900133","id":"PMC_28900133","title":"FCN1 (M-ficolin), which directly associates with immunoglobulin G1, is a molecular target of intravenous immunoglobulin therapy for Kawasaki disease.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28900133","citation_count":16,"is_preprint":false},{"pmid":"39402337","id":"PMC_39402337","title":"FPR1 signaling aberrantly regulates S100A8/A9 production by CD14+FCN1hi macrophages and aggravates pulmonary pathology in severe COVID-19.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/39402337","citation_count":15,"is_preprint":false},{"pmid":"32142211","id":"PMC_32142211","title":"Ficolin-1 gene (FCN1) -144 C/A polymorphism is associated with adverse outcome of severe pneumonia in the under-five Egyptian children: A multicenter study.","date":"2020","source":"Pediatric pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/32142211","citation_count":8,"is_preprint":false},{"pmid":"38262391","id":"PMC_38262391","title":"Sputum Transcriptomics Reveals FCN1+ Macrophage Activation in Mild Eosinophilic Asthma Compared to Non-Asthmatic Eosinophilic Bronchitis.","date":"2024","source":"Allergy, asthma & immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/38262391","citation_count":7,"is_preprint":false},{"pmid":"36569030","id":"PMC_36569030","title":"Effect of Polymorphisms in the FCN1, FCN2, and FCN3 Genes on the Susceptibility to Develop Rheumatoid Arthritis: A Systematic Review.","date":"2022","source":"International journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/36569030","citation_count":5,"is_preprint":false},{"pmid":"33600013","id":"PMC_33600013","title":"FCN1 polymorphisms are not the markers of dental caries susceptibility in Polish children: A case-control study.","date":"2021","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33600013","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8220,"output_tokens":1073,"usd":0.020377,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7599,"output_tokens":1618,"usd":0.039223,"stage2_stop_reason":"end_turn"},"total_usd":0.0596,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"The collagen-like domain of FCN1 (M-ficolin) directly binds to IgG1 in vitro through portions of the CH1 and CH3 domains of IgG1, as demonstrated by Western blot binding assays; synthetic peptides corresponding to the CH1 and CH3 domains of IgG1 efficiently inhibited this association.\",\n      \"method\": \"Western blot binding assay (in vitro), synthetic peptide inhibition\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding with domain-mapping via inhibitory peptides, single lab, two orthogonal approaches (Wb binding + peptide inhibition)\",\n      \"pmids\": [\"28900133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The Ser268Pro (rs150625869) non-synonymous mutation in FCN1 leads to complete loss of M-ficolin production. The Ala218Thr (rs148649884) and Asn289Ser (rs138055828) mutations cripple the ligand-binding capability of M-ficolin, as demonstrated by reduced binding to Group B Streptococcus in recombinant protein assays.\",\n      \"method\": \"Recombinant protein expression and ligand-binding assay (Group B Streptococcus binding), corroborated by clinical genotype-phenotype data\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — recombinant protein functional assay with mutagenesis validated by clinical observations, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"23209787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Promoter polymorphisms in FCN1 (positions -542 and -144) regulate both FCN1 mRNA expression and ficolin-1 protein secretion by monocytes; individuals homozygous for minor alleles at these positions have significantly higher FCN1 mRNA levels and higher ficolin-1 levels in monocyte culture supernatants.\",\n      \"method\": \"FCN1 mRNA expression in isolated monocytes/granulocytes (qRT-PCR implied), ELISA for ficolin-1 in monocyte culture supernatants, genotyping of FCN1 promoter SNPs\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter variant linked to mRNA and secreted protein levels in primary cells, single lab, two orthogonal readouts\",\n      \"pmids\": [\"22673311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FCN1 overexpression in THP-1-derived macrophages promotes LPS-induced activation and maturation of the proinflammatory cytokine IL-1β via the NLRP3-caspase-1 axis.\",\n      \"method\": \"FCN1 overexpression in THP-1-derived macrophages, immunoblotting for IL-1β, NLRP3, and caspase-1\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function experiment with defined pathway readout (NLRP3-caspase-1-IL-1β), single lab, single method\",\n      \"pmids\": [\"36932401\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FCN1-encoded M-ficolin is a collagen-like pattern-recognition molecule of the lectin complement pathway whose collagen-like domain directly binds IgG1 (via CH1/CH3 domains); specific non-synonymous mutations abolish its production or cripple its ligand-binding capacity; promoter variants regulate its transcription and secretion from monocytes; and within macrophages, FCN1 promotes IL-1β maturation via the NLRP3-caspase-1 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FCN1 encodes M-ficolin (ficolin-1), a pattern-recognition molecule whose collagen-like domain directly binds the CH1 and CH3 domains of IgG1, an interaction mappable and competable with synthetic IgG1 domain peptides [#0]. Non-synonymous coding variants define its functional output: Ser268Pro abolishes M-ficolin production entirely, while Ala218Thr and Asn289Ser cripple its ligand-binding capacity, evidenced by reduced binding to Group B Streptococcus [#1]. Expression and secretion of ficolin-1 from monocytes are governed by FCN1 promoter polymorphisms at positions -542 and -144, which set both mRNA levels and secreted protein output [#2]. Within macrophages, FCN1 acts as a proinflammatory amplifier, promoting LPS-induced IL-1\\u03b2 maturation through the NLRP3\\u2013caspase-1 axis [#3]. Beyond these findings, the structural basis of complement activation by FCN1 has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing how FCN1 expression is set, promoter polymorphisms were shown to control transcript abundance and secreted ficolin-1, linking genetic variation to quantitative immune output.\",\n      \"evidence\": \"FCN1 promoter SNP genotyping with monocyte qRT-PCR and ELISA on culture supernatants\",\n      \"pmids\": [\"22673311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors binding the -542/-144 region not identified\", \"Functional consequence of altered ficolin-1 levels on complement activation not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"To connect coding variation with function, mutagenesis defined residues required for M-ficolin production versus ligand binding, distinguishing null from binding-deficient alleles.\",\n      \"evidence\": \"Recombinant protein expression of variant M-ficolin with Group B Streptococcus binding assay, corroborated by clinical genotype-phenotype data\",\n      \"pmids\": [\"23209787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how Ala218Thr/Asn289Ser impair binding not resolved\", \"Effect on downstream complement activation not measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Addressing what M-ficolin recognizes beyond microbial ligands, its collagen-like domain was shown to directly bind IgG1, implicating it in antibody-associated recognition.\",\n      \"evidence\": \"In vitro Western blot binding assay with synthetic CH1/CH3 peptide inhibition\",\n      \"pmids\": [\"28900133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological/in vivo relevance of the IgG1 interaction not established\", \"Single lab, no reciprocal or structural validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Probing an intracellular/inflammatory role, FCN1 overexpression was found to enhance IL-1\\u03b2 maturation via NLRP3-caspase-1, positioning it as a proinflammatory amplifier in macrophages.\",\n      \"evidence\": \"FCN1 overexpression in THP-1-derived macrophages with immunoblotting for IL-1\\u03b2, NLRP3, caspase-1\",\n      \"pmids\": [\"36932401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gain-of-function only; loss-of-function not tested\", \"Mechanism linking FCN1 to NLRP3 activation unknown\", \"Single lab, single method\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FCN1's pattern recognition couples mechanistically to lectin-pathway complement activation and to intracellular inflammasome signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FCN1 ligand complexes\", \"Link between extracellular recognition and macrophage NLRP3 activation not established\", \"MASP partners and complement readouts not characterized in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IGHG1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":4,"faith_pct":75.0}}