{"gene":"F7","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1986,"finding":"Human factor VII (FVII) was characterized from cDNA: it is synthesized with a prepro-leader sequence, the mature plasma protein is a 406-amino-acid single-chain polypeptide activated by cleavage between Arg and Ile to form a light chain (152 aa, containing Gla and EGF-like domains) and a heavy chain (254 aa, containing the serine protease domain) linked by a disulfide bond. FVII activates factor X and/or factor IX in the presence of tissue factor and calcium.","method":"cDNA cloning from human liver and HepG2 libraries, amino acid sequencing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — original cDNA characterization with protein sequence validation, foundational paper (398 citations)","pmids":["3486420"],"is_preprint":false},{"year":1987,"finding":"The human F7 gene spans ~12.8 kb and contains 8 essential exons encoding domains conserved among vitamin K-dependent proteins (Gla, EGF-like, serine protease domains). Alternative splicing produces a transcript with an additional exon encoding a larger prepro-leader sequence. The intron positions relative to protein domains are shared with factor IX, factor X, protein C, and prothrombin, indicating a common evolutionary origin. The gene contains five regions of tandem oligonucleotide repeat elements.","method":"Genomic cloning, DNA sequencing of two overlapping genomic clones","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — complete gene sequence with functional domain mapping, foundational (287 citations)","pmids":["3037537"],"is_preprint":false},{"year":1988,"finding":"Human plasma factor VIIa contains 10 gamma-carboxyglutamic acid (Gla) residues at the N-terminus and 2 N-glycosylated asparagines (Asn145 and Asn322). No beta-hydroxyaspartic acid was detected. Recombinant FVIIa from BHK cells had identical protein backbone but partial gamma-carboxylation (9 full, 1 partial) and partial glycosylation at Asn145 (~66%), with nearly identical overall carbohydrate composition to plasma FVIIa.","method":"HPLC, amino acid analysis, peptide mapping, automated Edman degradation of plasma and recombinant FVIIa","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — direct protein characterization with multiple orthogonal methods, replicated in two protein sources (278 citations)","pmids":["3264725"],"is_preprint":false},{"year":1986,"finding":"Factor VII/VIIa binds tissue factor (TF) reconstituted into phospholipid vesicles with 1:1 stoichiometry (1 mol enzyme per mol available TF). The zymogen FVII binds TF with only slightly lower affinity than FVIIa (Kd ~13.2 nM vs ~4.54 nM with PC vesicles). Active-site modification with DFP increased binding affinity. Inclusion of phosphatidylserine (PS) in vesicles induced positive cooperativity in binding, consistent with a two-site cooperative binding model where TF acts as at least a dimer.","method":"Binding assays with purified bovine TF reconstituted into phospholipid vesicles of defined composition, protease digestion to assess TF orientation","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution assay with rigorous quantitative analysis, foundational (290 citations)","pmids":["3527261"],"is_preprint":false},{"year":1990,"finding":"Recombinant human factor VIIa activates both factor IX and factor X. In the presence of calcium alone, FVIIa preferentially activates factor IX over factor X (higher initial rates). Addition of phospholipids and tissue factor dramatically enhances activation of both substrates, with tissue factor increasing kcat/Km for factor X activation substantially. Calcium optimum for factor IX activation was ~1–2.5 mM and for factor X ~2.5 mM.","method":"Steady-state kinetics of recombinant FVIIa-catalyzed activation of purified factors IX and X under varying calcium, phospholipid, and tissue factor conditions","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro kinetic assay with rigorous parameter determination (176 citations)","pmids":["2248955"],"is_preprint":false},{"year":1996,"finding":"Crystal structure at 2.0 Å of active-site-inhibited FVIIa complexed with the cleaved extracellular domain of tissue factor (TF). FVIIa adopts an extended conformation in the complex. The structure reveals the molecular basis of TF-induced coagulation initiation, showing how TF positions FVIIa for substrate (FIX, FX) recognition and activation.","method":"X-ray crystallography at 2.0 Å resolution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure, foundational (670 citations)","pmids":["8598903"],"is_preprint":false},{"year":1999,"finding":"Crystal structure of Gla-domain-less human FVIIa at 2.8 Å resolution in the absence of tissue factor. Free FVIIa adopts a similar extended conformation to TF-bound FVIIa, but shows structural differences in the active site and a surface-exposed alpha-helix (residues 307–312) at the cofactor recognition site that is distorted in free FVIIa. The binding mode of the active-site inhibitor D-Phe-Phe-Arg methyl ketone differs between free and TF-bound FVIIa, indicating that TF binding influences substrate recognition in the active site.","method":"X-ray crystallography at 2.8 Å resolution","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with comparative analysis to TF-bound form (147 citations)","pmids":["10430872"],"is_preprint":false},{"year":2000,"finding":"Binding of activated FVII (FVIIa) to tissue factor (TF) on human keratinocytes induces gene expression of 24 mRNA species including transcription regulators (c-fos, egr-1, c-myc), growth factors (amphiregulin, hbEGF, CTGF), proinflammatory cytokines (IL-1β, IL-8), and proteins involved in cellular reorganization (RhoE, uPAR, collagenases). This response was abrogated by anti-TF antibodies and unaffected by hirudin, indicating it is TF-dependent and thrombin-independent.","method":"cDNA arrays on human keratinocyte cell line treated with FVIIa; antibody blocking experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — defined cellular response with specific blocking controls confirming TF-dependence (157 citations)","pmids":["10692465"],"is_preprint":false},{"year":2001,"finding":"A homozygous 15-bp in-frame insertion in F7 (duplicating residues Leu213–Asp217) caused FVII:c <1% and FVII:Ag 10%. Molecular modeling showed the insertion is located at a surface loop of the catalytic domain at the calcium-binding site, disrupting calcium binding and protein folding. In vitro expression in transfected cells showed equivalent intracellular FVII antigen levels for wild-type and mutant, but secreted mutant FVII was only 5–10% of wild-type. Pulse-chase studies demonstrated mutant FVII did not accumulate intracellularly; protease inhibitor studies showed partial degradation in the pre-Golgi compartment.","method":"DNA analysis, molecular graphics modeling, in vitro transfection/expression, Western blotting, ELISA, pulse-chase studies, inhibitor studies","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (expression, pulse-chase, structural modeling) in a single study","pmids":["11159523"],"is_preprint":false},{"year":2002,"finding":"A novel E25K mutation in the F7 gene (located in the propeptide/signal region) produces a dysfunctional FVII molecule: in transiently transfected HEK293 cells, FVII-E25K showed significantly lower coagulant activity in culture media compared to wild-type, while antigen levels were similar, indicating a functional rather than secretion defect. A second mutation, -96C>T in the F7 promoter (double heterozygous with IVS4+1), was shown by EMSA to disrupt binding of the transcription factor Sp1.","method":"F7 gene sequencing, transient transfection of HEK293 cells, functional/antigen assays, electrophoretic mobility shift assay (EMSA)","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 — expression assay plus EMSA, single study","pmids":["12472587"],"is_preprint":false},{"year":2005,"finding":"In vitro transfection studies in HepG2 cells with 15 F7 promoter constructs carrying different polymorphism combinations showed that the -323ins10 (A2) allele and -122C allele strongly reduced F7 promoter activity, the -402A allele significantly increased promoter activity, and a novel -2989A variant also increased F7 expression. The A2 (decanucleotide insertion) allele had a dominant effect masking the -2989A variant in Spanish populations.","method":"In vitro transfection of HepG2 cells with 15 F7 promoter-reporter constructs; functional reporter assays","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 1 — systematic in vitro functional dissection of promoter variants with 15 constructs","pmids":["17292373"],"is_preprint":false},{"year":2009,"finding":"A nonsense mutation (p.Arg462X) in F7, causing loss of the five C-terminal amino acids of FVII, resulted in undetectable secretion (by Western blot and ELISA) into culture medium. In vitro expression of truncated FVIIs deleted of limited numbers of C-terminal amino acids showed secretion decreased proportionally with deletion length. Arg462X FVII did not co-localize with the Golgi apparatus on immunofluorescence, suggesting ER retention and intracellular degradation.","method":"Expression of truncated FVII variants in CHO-K1 cells, Western blot, ELISA, immunofluorescence colocalization with Golgi marker","journal":"Thrombosis research","confidence":"High","confidence_rationale":"Tier 1–2 — systematic deletion series plus localization studies establishing C-terminal role in secretion","pmids":["19822353"],"is_preprint":false},{"year":2009,"finding":"A splice site mutation IVS1a+5g>a in F7 causes two novel aberrant splicing patterns: (1) predominant transcript skipping exon 2 but retaining intron 3, causing frameshift and premature stop; (2) minor transcript skipping both exon 2 and exon 3 (FVII Δ2,3), causing in-frame deletion of propeptide and Gla domains. In vitro expression of the FVII Δ2,3 transcript in HEK293 cells showed that the protein could be secreted but had no procoagulant activity.","method":"Ectopic transcript analysis in patient leukocytes, F7 minigene construction spanning intron 4 to intron 7 transfected into HEK293T cells, RT-PCR sequencing, in vitro expression","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1–2 — minigene functional splicing assay plus in vitro expression confirming functional consequences","pmids":["15968391"],"is_preprint":false},{"year":2009,"finding":"A splice site mutation c.572-1G>A in F7 was shown by minigene analysis to cause exon 6 skipping, producing erroneously spliced mRNA, while normal splicing occurred in wild-type transfectant. Ectopic transcription in patient leukocytes did not detect the aberrant transcript, demonstrating the minigene approach is required for genes with poor expression in blood cells.","method":"F7 minigene (intron 4 to intron 7) transfected into HEK293T cells, RT-PCR analysis; ectopic transcript analysis in leukocytes","journal":"Haemophilia","confidence":"Medium","confidence_rationale":"Tier 2 — minigene splicing assay, single study","pmids":["19601987"],"is_preprint":false},{"year":2012,"finding":"F7 promoter methylation inversely regulates plasma FVII concentrations in subjects with the A1A1 genotype (absence of the -323ins10 insertion). Higher methylation at the F7 promoter is associated with lower plasma FVII levels and was more prevalent in the coronary-artery-disease-free group compared to CAD subjects, suggesting epigenetic regulation of F7 via promoter CpG methylation modulates cardiovascular risk.","method":"Methyl-specific PCR and bisulfite sequencing of F7 promoter in 253 subjects; correlation with plasma FVII activity and CAD status","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct methylation quantification correlated with functional FVII levels, single study","pmids":["22315437"],"is_preprint":false},{"year":2012,"finding":"Novel F7 promoter mutations (-65G>C single nucleotide substitution and -60_-59delTT 2-bp deletion) causing lethal FVII deficiency were shown to disrupt HNF4 (hepatocyte nuclear factor 4) binding. Computer-assisted analysis predicted disrupted binding of both HNF4 and COUP-TF. Experimental reporter assays confirmed altered HNF4-induced transactivation with each promoter variant.","method":"Sequencing of F7 promoter, in silico binding site analysis, functional transactivation reporter assays","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 — functional transactivation assay confirming HNF4 regulatory role, single study","pmids":["22628013"],"is_preprint":false},{"year":2022,"finding":"A novel F7 promoter mutation (-58G>C) in the HNF4 binding region caused FVII deficiency (compound heterozygous with p.Leu13Pro). EMSA demonstrated that the -58G>C promoter mutation reduced HNF4 binding, establishing that HNF4 binding to the F7 promoter is required for normal F7 transcription and FVII protein synthesis.","method":"F7 gene sequencing, EMSA for transcription factor binding","journal":"The Kurume medical journal","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA directly demonstrates HNF4 binding disruption, replicates prior finding from PMID 22628013","pmids":["36123027"],"is_preprint":false},{"year":2023,"finding":"Functional and structural analysis of eight novel F7 mutations identified in Chinese patients: three type I missense mutations (p.Cys238Phe, p.Gly420Asp, p.Ala252Val) reduced FVII secretion/antigen; four type II missense mutations (p.Val336Met, p.Ser342Gly, p.Gly432Ser, p.Ile213Asn) affected FVII coagulant activity with relatively preserved antigen. Molecular dynamic simulations and binding energy calculations for p.Gly432Ser revealed that Gly432 is critical for the binding interface between activated FVIIa and tissue factor. Structural analysis confirmed that p.Ile213Asn impacts the cleavage/activation site.","method":"In vitro expression, functional coagulant and antigen assays, molecular dynamic simulations, binding energy calculations, structural analysis","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro expression plus computational structural analysis, single study","pmids":["36951360"],"is_preprint":false},{"year":2024,"finding":"A synonymous variant at the terminal nucleotide of exon 3 (c.291G>A) in F7, which does not alter the amino acid sequence, was shown by minigene analysis to cause exon 3 skipping, thereby disrupting the protein sequence and function and causing FVII deficiency when compound heterozygous with a splice donor mutation (c.681+1G>T).","method":"Whole exome sequencing, Sanger sequencing validation, minigene splicing assay","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 — minigene directly demonstrates aberrant splicing from synonymous terminal exonic variant","pmids":["39007454"],"is_preprint":false}],"current_model":"Human coagulation Factor VII (FVII) is a vitamin K-dependent plasma glycoprotein synthesized in the liver as a single-chain zymogen with a prepro-leader sequence; it contains a Gla domain (with 10 gamma-carboxylated glutamic acids), two EGF-like domains, and a serine protease domain, and is activated by cleavage between Arg152 and Ile153 to form a two-chain enzyme (FVIIa) held by a disulfide bond. FVIIa binds its obligate allosteric cofactor tissue factor (TF) with ~1:1 stoichiometry, with phosphatidylserine-containing membranes inducing cooperative binding; TF binding causes conformational changes in the FVIIa active site (including an alpha-helix at residues 307–312) that enhance substrate recognition, enabling FVIIa/TF to activate factors IX and X and initiate coagulation. The FVIIa/TF complex also induces TF-dependent, thrombin-independent gene expression (including c-fos, IL-1β, uPAR, collagenases) in keratinocytes, implicating it in wound repair signaling. F7 transcription is regulated by HNF4 binding to the promoter and by epigenetic promoter methylation; promoter polymorphisms (-323ins10, -402G>A, -122C) and missense/splicing mutations throughout the gene modulate plasma FVII levels, secretion efficiency, and procoagulant activity, with the C-terminal residues and calcium-binding loop of the catalytic domain being critical for proper folding and secretion."},"narrative":{"teleology":[{"year":1986,"claim":"Cloning of F7 cDNA and characterization of TF binding established FVII as a modular vitamin K-dependent serine protease zymogen that requires tissue factor as an obligate cofactor on phospholipid surfaces for coagulation initiation.","evidence":"cDNA cloning from liver/HepG2 libraries with protein sequencing; reconstituted TF-phospholipid binding assays with stoichiometric and affinity measurements","pmids":["3486420","3527261"],"confidence":"High","gaps":["Three-dimensional structure of the FVIIa–TF complex not yet determined","Mechanism by which TF enhances catalytic activity unknown","Relative preference for FIX vs FX activation not quantified"]},{"year":1987,"claim":"Determination of the complete F7 gene structure revealed conserved intron-exon organization shared with other vitamin K-dependent coagulation factors, establishing a common evolutionary origin for this protease family.","evidence":"Genomic cloning and DNA sequencing of overlapping clones spanning 12.8 kb","pmids":["3037537"],"confidence":"High","gaps":["Regulatory elements controlling liver-specific expression not defined","Functional significance of alternative splicing of prepro-leader not established"]},{"year":1988,"claim":"Complete post-translational modification mapping of plasma and recombinant FVIIa confirmed 10 Gla residues essential for calcium/membrane binding and identified glycosylation sites, validating recombinant FVIIa as a faithful therapeutic surrogate.","evidence":"HPLC, amino acid analysis, Edman degradation of plasma-derived and BHK-expressed FVIIa","pmids":["3264725"],"confidence":"High","gaps":["Functional impact of partial gamma-carboxylation at position 10 in recombinant protein not tested","Role of individual glycosylation sites in activity or clearance unknown"]},{"year":1990,"claim":"Quantitative kinetic analysis demonstrated that FVIIa activates both FIX and FX, with TF and phospholipid dramatically increasing catalytic efficiency, resolving uncertainty about substrate specificity and cofactor requirements.","evidence":"Steady-state kinetics with purified recombinant FVIIa, FIX, and FX under defined calcium/TF/phospholipid conditions","pmids":["2248955"],"confidence":"High","gaps":["Structural basis of substrate discrimination between FIX and FX unresolved","In vivo relative contributions of FIX vs FX activation not addressed"]},{"year":1996,"claim":"The 2.0-Å crystal structure of the FVIIa–TF complex revealed how TF positions FVIIa in an extended conformation for macromolecular substrate recognition, providing the first atomic-level view of extrinsic pathway initiation.","evidence":"X-ray crystallography of active-site-inhibited FVIIa bound to soluble TF ectodomain","pmids":["8598903"],"confidence":"High","gaps":["Conformation of free FVIIa unknown at atomic resolution","How TF allosterically remodels the active site not delineated"]},{"year":1999,"claim":"Comparison of free FVIIa structure with the TF-bound form revealed that TF binding remodels the 307–312 alpha-helix and active-site geometry, providing the structural explanation for TF-dependent allosteric activation.","evidence":"X-ray crystallography of Gla-domainless FVIIa at 2.8 Å in the absence of TF","pmids":["10430872"],"confidence":"High","gaps":["Full-length FVIIa with Gla domain not crystallized in the free state","Dynamic conformational transitions upon TF binding not captured"]},{"year":2000,"claim":"Discovery that the FVIIa–TF complex induces TF-dependent, thrombin-independent gene expression of wound-repair mediators in keratinocytes expanded FVII function beyond coagulation to cell signaling.","evidence":"cDNA array profiling of FVIIa-treated keratinocytes with anti-TF blocking and hirudin controls","pmids":["10692465"],"confidence":"High","gaps":["Intracellular signaling pathway linking TF engagement to transcription not identified","Whether PAR cleavage mediates this response not determined","In vivo relevance to wound healing not tested"]},{"year":2001,"claim":"Demonstration that disruption of the catalytic domain calcium-binding loop causes ER retention and pre-Golgi degradation established that proper folding of the protease domain is a checkpoint for FVII secretion.","evidence":"In vitro expression, pulse-chase, protease inhibitor studies, and molecular modeling of a 15-bp insertion mutant in transfected cells","pmids":["11159523"],"confidence":"High","gaps":["Identity of the ER quality-control machinery responsible for mutant FVII degradation unknown","Whether similar retention mechanisms apply to other vitamin K-dependent factors not tested"]},{"year":2005,"claim":"Systematic dissection of F7 promoter polymorphisms showed that -323ins10 dominantly suppresses transcription while -402A increases it, defining the cis-regulatory architecture controlling plasma FVII levels.","evidence":"Reporter assays with 15 promoter-haplotype constructs in HepG2 cells","pmids":["17292373"],"confidence":"High","gaps":["Trans-acting factors mediating the -323ins10 effect not identified","Chromatin context effects not captured by episomal reporter assays"]},{"year":2009,"claim":"Studies of C-terminal truncations and splice-site mutations collectively established that both the C-terminal residues of the catalytic domain and correct exon inclusion (particularly exons encoding the Gla domain and propeptide) are indispensable for FVII secretion and procoagulant function.","evidence":"Systematic C-terminal deletion series with immunofluorescence in CHO-K1 cells; minigene splicing assays in HEK293T cells for splice-site mutations","pmids":["19822353","15968391","19601987"],"confidence":"High","gaps":["Structural basis of C-terminal requirement for ER export not resolved","Whether truncated FVII forms are targeted by ERAD specifically not shown"]},{"year":2012,"claim":"Identification of HNF4 as an essential transactivator of F7 and demonstration that promoter CpG methylation inversely regulates plasma FVII levels established dual transcriptional and epigenetic control of F7 expression in the liver.","evidence":"EMSA/reporter assays showing HNF4-binding mutations cause lethal FVII deficiency; bisulfite sequencing correlating methylation with FVII levels in 253 subjects","pmids":["22628013","22315437"],"confidence":"Medium","gaps":["Causal role of methylation not proven by intervention experiments","Other hepatic transcription factors contributing to F7 regulation not systematically mapped","Methylation findings from a single cohort study"]},{"year":2023,"claim":"Functional and molecular-dynamics analysis of novel missense mutations distinguished type I (secretion-defective) from type II (activity-defective) FVII deficiency and identified Gly432 as critical for the FVIIa–TF binding interface.","evidence":"In vitro expression with antigen/activity assays and molecular dynamics simulations of eight F7 missense mutations","pmids":["36951360"],"confidence":"Medium","gaps":["Computational binding energy predictions not validated by direct binding measurements","Structural predictions based on modeling, not experimental structures of mutant proteins"]},{"year":2024,"claim":"A synonymous exonic variant at the terminal nucleotide of exon 3 was shown to cause exon skipping, demonstrating that silent mutations in F7 can be pathogenic through disruption of splicing regulatory elements.","evidence":"Minigene splicing assay confirming exon 3 skipping caused by c.291G>A","pmids":["39007454"],"confidence":"Medium","gaps":["Exonic splicing enhancer element disrupted by this variant not precisely mapped","Quantitative effect on FVII protein levels in patient hepatocytes not measured"]},{"year":null,"claim":"The intracellular signaling pathway by which FVIIa–TF engagement drives gene expression (e.g., whether PAR2 cleavage is involved), the ER quality-control machinery responsible for misfolded FVII degradation, and the full chromatin-level regulatory landscape of F7 transcription in hepatocytes remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["Signal transduction pathway downstream of FVIIa–TF in non-coagulant signaling not defined","ERAD components targeting misfolded FVII not identified","No genome-wide chromatin accessibility or enhancer mapping for F7 locus in primary hepatocytes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[8,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,3,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10,15,16]}],"complexes":["FVIIa–tissue factor complex"],"partners":["F3","F9","F10","HNF4A","SP1"],"other_free_text":[]},"mechanistic_narrative":"Coagulation factor VII (FVII) is a vitamin K-dependent serine protease zymogen synthesized in the liver that initiates the extrinsic coagulation cascade upon binding its obligate cofactor tissue factor (TF). The single-chain zymogen contains a Gla domain with 10 gamma-carboxylated glutamic acid residues, two EGF-like domains, and a C-terminal serine protease domain; activation occurs by cleavage at Arg152–Ile153 to yield a disulfide-linked two-chain enzyme (FVIIa) that, in complex with TF on phosphatidylserine-containing membranes, activates factors IX and X with dramatically enhanced catalytic efficiency [PMID:3486420, PMID:2248955, PMID:8598903]. Crystal structures of free and TF-bound FVIIa reveal that TF binding remodels an alpha-helix at residues 307–312 and the active-site cleft, explaining allosteric enhancement of substrate recognition [PMID:8598903, PMID:10430872]. Beyond hemostasis, FVIIa/TF signaling on keratinocytes induces TF-dependent, thrombin-independent transcription of wound-repair genes including c-fos, IL-1β, and uPAR [PMID:10692465]. F7 transcription requires HNF4 binding to a proximal promoter element and is modulated by promoter polymorphisms (-323ins10, -402G>A) and CpG methylation, while mutations disrupting the catalytic domain calcium-binding loop or C-terminal residues cause ER retention and secretion failure, collectively accounting for hereditary FVII deficiency [PMID:22628013, PMID:17292373, PMID:22315437, PMID:11159523, PMID:19822353]."},"prefetch_data":{"uniprot":{"accession":"P08709","full_name":"Coagulation factor VII","aliases":["Proconvertin","Serum prothrombin conversion accelerator","SPCA"],"length_aa":466,"mass_kda":51.6,"function":"Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. 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C1286T) associated with congenital factor VII deficiency: A case report and literature review.","date":"2022","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/35349734","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33480651","id":"PMC_33480651","title":"Compound Heterozygous Mutations in the F7 Gene in 2 Unrelated Families With Congenital Factor VII Deficiency.","date":"2021","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33480651","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23358202","id":"PMC_23358202","title":"Double heterozygous mutations Gln100Leu and His348Gln of the F7 gene in a patient with factor VII deficiency.","date":"2013","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/23358202","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22232927","id":"PMC_22232927","title":"[Polymorphic markers Ala455Val of the THBD gene and Arg353Gln of the F7 gene and association with unfavorable outcomes of coronary atherosclerosis in patients with a history of acute ischemic heart disease].","date":"2011","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/22232927","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35802509","id":"PMC_35802509","title":"Clinical phenotype and F7 gene genotype in 40 Tunisian patients with congenital factor VII deficiency.","date":"2022","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/35802509","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19596910","id":"PMC_19596910","title":"N-terminally LRMK-linked HER-2 peptides, AE-37 [p776(774-788)] and AE-47 [Ava-F7(776-788)], aid differentiation of E75-TCR+CD8+ cells to perforin-positive cells.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19596910","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40306427","id":"PMC_40306427","title":"Nutrient consumption patterns of Streptococcus thermophilus F7 under acid stress and their application in enhancing biomass production.","date":"2025","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/40306427","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25177734","id":"PMC_25177734","title":"Quorum sensing activity of Mesorhizobium sp. 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Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/24301286","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24818391","id":"PMC_24818391","title":"[Cloning, expression and identification of Der f7 gene from Dermatophagoides farinae and its immunological characteristics].","date":"2013","source":"Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24818391","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29665924","id":"PMC_29665924","title":"[Analysis of Phenotype and L12R Mutation in Signal Peptide and 3' Non-translation Region c11814-insAA Mutation of F7 Gene in a Family with Hereditary Coagulation Factor VII Deficiency].","date":"2018","source":"Zhongguo shi yan xue ye xue za 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Epidemiology) Consortium.","date":"2010","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/20231535","citation_count":295,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3527261","id":"PMC_3527261","title":"Factor VII binding to tissue factor in reconstituted phospholipid vesicles: induction of cooperativity by phosphatidylserine.","date":"1986","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3527261","citation_count":290,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3037537","id":"PMC_3037537","title":"Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation.","date":"1987","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/3037537","citation_count":287,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28611215","id":"PMC_28611215","title":"Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28611215","citation_count":282,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3264725","id":"PMC_3264725","title":"Amino acid sequence and posttranslational modifications of human factor VIIa from plasma and transfected baby hamster kidney cells.","date":"1988","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3264725","citation_count":278,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15174051","id":"PMC_15174051","title":"An investigation into the human serum \"interactome\".","date":"2004","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/15174051","citation_count":247,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7598447","id":"PMC_7598447","title":"Tissue factor pathway inhibitor and the revised theory of coagulation.","date":"1995","source":"Annual review of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7598447","citation_count":233,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16580898","id":"PMC_16580898","title":"Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements.","date":"2006","source":"Clinical pharmacology and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/16580898","citation_count":219,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25037231","id":"PMC_25037231","title":"Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25037231","citation_count":203,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10984565","id":"PMC_10984565","title":"Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease.","date":"2000","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10984565","citation_count":185,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15735798","id":"PMC_15735798","title":"Clinical phenotypes and factor VII genotype in congenital factor VII deficiency.","date":"2005","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/15735798","citation_count":183,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12615788","id":"PMC_12615788","title":"No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age.","date":"2003","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/12615788","citation_count":177,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2248955","id":"PMC_2248955","title":"Proteolytic activation of human factors IX and X by recombinant human factor VIIa: effects of calcium, phospholipids, and tissue factor.","date":"1990","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2248955","citation_count":176,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19913121","id":"PMC_19913121","title":"Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19913121","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10692465","id":"PMC_10692465","title":"Binding of factor VIIa to tissue factor on keratinocytes induces gene expression.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10692465","citation_count":157,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10430872","id":"PMC_10430872","title":"Structure of human factor VIIa and its implications for the triggering of blood coagulation.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10430872","citation_count":147,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44947,"output_tokens":2945,"usd":0.089508},"stage2":{"model":"claude-opus-4-6","input_tokens":6197,"output_tokens":2067,"usd":0.12399},"total_usd":0.543621,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":59322,"output_tokens":5836,"usd":0.132753},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":9101,"output_tokens":3443,"usd":0.19737}},"stage1_raw":"Looking through these abstracts, I need to identify papers about the human coagulation Factor VII gene (F7/FVII). Many papers in this corpus are about unrelated genes or organisms that happen to use \"F7\" as a label (E. coli fimbriae, bacterial strains, cell lines named F7, etc.). I'll focus on papers about human coagulation Factor VII (F7 gene, FVII protein).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"A 15-bp in-frame insertion in F7 at the calcium-binding site of the catalytic domain causes impaired FVII secretion: in vitro expression showed equivalent intracellular FVII protein levels between wild-type and mutant, but secreted mutant was only 5–10% of wild-type. Pulse-chase and protease-inhibitor studies demonstrated partial pre-Golgi degradation of mutant FVII, with undetectable procoagulant activity in conditioned media, indicating the calcium-binding site is essential for proper folding and secretion.\",\n      \"method\": \"In vitro expression in transfected cells, pulse-chase studies, inhibitors of protein degradation, molecular graphic analysis of calcium-binding site\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (expression, pulse-chase, degradation inhibitors, structural modeling) in a single rigorous study\",\n      \"pmids\": [\"11159523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A nonsense mutation (p.Arg462X) in F7 truncating the last five C-terminal amino acids causes FVII deficiency by blocking secretion: recombinant Arg462X FVII was expressed intracellularly at normal levels but failed to co-localize with the Golgi and was not secreted, indicating the C-terminal residues of FVII are required for ER-to-Golgi trafficking and secretion.\",\n      \"method\": \"Expression in CHO-K1 cells, Western blot, ELISA, immunofluorescence co-localization with Golgi marker, serial C-terminal deletion constructs\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Western, ELISA, immunofluorescence, deletion series) establishing secretion defect mechanism\",\n      \"pmids\": [\"19822353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A splice-site mutation in F7 (IVS1a+5g>a) produces two aberrant transcripts: a predominant one with exon 2 skipping plus intron 3 retention (frameshift, premature stop) and a minor one with exon 2 and 3 skipping (in-frame deletion of propeptide and Gla domains). In vitro expression of the minor transcript (FVII Δ2,3) showed the protein was secreted but had no procoagulant activity, demonstrating that the Gla domain is required for FVII function.\",\n      \"method\": \"Ectopic transcript analysis in patient leukocytes, minigene transfection in HEK293 cells, RT-PCR, in vitro expression of aberrant transcript\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — minigene functional validation plus in vitro expression demonstrating loss of procoagulant activity\",\n      \"pmids\": [\"15968391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A splice-site mutation (c.572-1G>A) in F7 causes exon 6 skipping as demonstrated by minigene analysis in HEK293T cells, while the compound heterozygous missense mutation (p.Cys389Gly) disrupts a conserved disulfide bond in FVII, together explaining the patient's FVII deficiency.\",\n      \"method\": \"Ectopic transcript analysis, minigene construction and transfection in HEK293T cells, RT-PCR sequencing\",\n      \"journal\": \"Haemophilia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — minigene functional splicing assay with direct sequencing validation\",\n      \"pmids\": [\"19601987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The F7 mutation E25K results in a dysfunctional secreted FVII protein: transient transfection in HEK293 cells showed FVII-E25K antigen levels comparable to wild-type in culture media, but coagulant activity was significantly reduced, indicating E25K impairs FVII catalytic function rather than secretion.\",\n      \"method\": \"Transient transfection of HEK293 cells, FVII activity and antigen measurement in conditioned media\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based expression assay with paired activity/antigen readout\",\n      \"pmids\": [\"12472587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The F7 promoter mutation -96C>T disrupts binding of the transcription factor Sp1 to the F7 promoter, as demonstrated by electrophoretic mobility shift assay, reducing F7 transcriptional activity and contributing to FVII deficiency.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA directly demonstrating loss of Sp1 binding at F7 promoter\",\n      \"pmids\": [\"12472587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In vitro transfection of HepG2 hepatocytes with F7 promoter constructs carrying different polymorphic combinations showed that the -323ins10 (decanucleotide insertion, A2 allele) and -122C allelic variants strongly reduced F7 promoter activity, while the -402A variant significantly increased promoter activity, and a novel -2989A variant increased expression but was masked by -323ins10 in linkage disequilibrium.\",\n      \"method\": \"In vitro transfection/luciferase reporter assay in HepG2 cells with 15 promoter variant constructs\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic in vitro functional dissection of promoter variants with multiple constructs in relevant cell line\",\n      \"pmids\": [\"17292373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Lethal FVII deficiency was caused by F7 promoter mutations (-65G>C and -60_-59delTT) that disrupt HNF4 binding: electrophoretic mobility shift assay and transactivation reporter assays demonstrated reduced HNF4-induced transactivation from both mutant promoters, establishing HNF4 as a critical transcriptional activator of F7.\",\n      \"method\": \"Computer-assisted sequence analysis, EMSA, transactivation reporter assay\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — EMSA plus functional transactivation assay with two independent mutations converging on same mechanism\",\n      \"pmids\": [\"22628013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel F7 promoter mutation (-58G>C) reduces HNF-4 binding to the F7 promoter as shown by EMSA, establishing that HNF-4 binding at this site is required for normal FVII expression.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), PCR sequencing of F7 exons and promoter\",\n      \"journal\": \"The Kurume medical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA demonstrating direct loss of HNF-4 binding from a single paper\",\n      \"pmids\": [\"36123027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"F7 promoter methylation inversely regulates plasma FVII concentrations in individuals with the A1A1 (no decanucleotide insertion) genotype, as determined by methyl-specific PCR and bisulfite sequencing, demonstrating epigenetic control of F7 gene expression.\",\n      \"method\": \"Methyl-specific PCR, bisulfite sequencing, correlation with plasma FVII antigen levels\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — association between methylation and expression levels in human subjects, single study\",\n      \"pmids\": [\"22315437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Structural and functional analysis of novel F7 missense mutations revealed: (1) p.Ile213Asn disrupts FVII cleavage/activation site function as confirmed by in vitro expression; (2) molecular dynamics simulations and binding energy calculations showed p.Gly432Ser disrupts the critical interaction between activated FVII and tissue factor at residue Gly432.\",\n      \"method\": \"In vitro expression, functional studies, molecular dynamic simulations, binding energy calculations, structural analysis\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro expression plus computational structural validation for two mutations\",\n      \"pmids\": [\"36951360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A synonymous variant at the terminal nucleotide of F7 exon 3 (c.291G>A) causes exon 3 skipping, as demonstrated by minigene analysis, showing that synonymous terminal-exon nucleotide substitutions can disrupt splicing and impair FVII production.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, minigene splicing assay\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — minigene functional splicing assay directly demonstrating exon skipping from synonymous mutation\",\n      \"pmids\": [\"39007454\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Coagulation Factor VII (F7 gene product) is a vitamin K-dependent serine protease secreted by hepatocytes whose expression is transcriptionally regulated by HNF4 and Sp1 binding to its promoter (with promoter methylation and sequence polymorphisms modulating transcriptional activity), and whose protein requires an intact C-terminus and calcium-binding site in the catalytic domain for proper ER-to-Golgi trafficking and secretion, intact Gla and propeptide domains for procoagulant activity, and a functional active-site cleavage region and Gly432 residue for interaction with tissue factor and activation of the extrinsic coagulation cascade.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**Classification summary:**\n- Papers about coagulation Factor VII (F7/FVII, human clotting protein): KEEP\n- Papers about E. coli F7 fimbriae, CB-F7 cell lines, SLAMF7, myoglobin serine92, microbial strains named F7, HDAC6 inhibitor named F7, CDK inhibitor named F7, anti-CRISPR AcrIE4-F7, botulinum F7, Der f7, etc.: EXCLUDE (alias/symbol collision)\n\n**KEEP papers:** [4],[5] (gene2pubmed), [9] (corpus - promoter methylation/F7 gene), [10] (corpus - repeat polymorphism F7 gene), [15] (corpus - F7 QTL), [17] (corpus - F7 genotype-phenotype), [18] (corpus - F7 promoter functional analysis), [25] (corpus - F7 haplotypes), [26] (corpus - nonsense mutation secretion), [31] (corpus - splice site mutation minigene), [32] (corpus - 15bp insertion calcium binding), [34] (corpus - F7 haplotypes/FVII levels), [38] (corpus - double heterozygous mutations), [51] (corpus - splice site mutation), [54] (corpus - promoter HNF4), [55] (corpus - novel F7 mutations structural/functional), [57] (corpus - elephant FVII), [71] (corpus), [72] (corpus), [73] (corpus), [80] (corpus), [82] (corpus), [83] (corpus), [84] (corpus), [85] (corpus), [87] (corpus - promoter HNF4), [88] (corpus), [91] (corpus); gene2pubmed: [5],[9],[15],[16],[17],[18],[19],[20],[21],[22],[24],[25],[27],[28],[29],[30].\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1986,\n      \"finding\": \"Human factor VII (FVII) was characterized from cDNA: it is synthesized with a prepro-leader sequence, the mature plasma protein is a 406-amino-acid single-chain polypeptide activated by cleavage between Arg and Ile to form a light chain (152 aa, containing Gla and EGF-like domains) and a heavy chain (254 aa, containing the serine protease domain) linked by a disulfide bond. FVII activates factor X and/or factor IX in the presence of tissue factor and calcium.\",\n      \"method\": \"cDNA cloning from human liver and HepG2 libraries, amino acid sequencing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cDNA characterization with protein sequence validation, foundational paper (398 citations)\",\n      \"pmids\": [\"3486420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The human F7 gene spans ~12.8 kb and contains 8 essential exons encoding domains conserved among vitamin K-dependent proteins (Gla, EGF-like, serine protease domains). Alternative splicing produces a transcript with an additional exon encoding a larger prepro-leader sequence. The intron positions relative to protein domains are shared with factor IX, factor X, protein C, and prothrombin, indicating a common evolutionary origin. The gene contains five regions of tandem oligonucleotide repeat elements.\",\n      \"method\": \"Genomic cloning, DNA sequencing of two overlapping genomic clones\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete gene sequence with functional domain mapping, foundational (287 citations)\",\n      \"pmids\": [\"3037537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Human plasma factor VIIa contains 10 gamma-carboxyglutamic acid (Gla) residues at the N-terminus and 2 N-glycosylated asparagines (Asn145 and Asn322). No beta-hydroxyaspartic acid was detected. Recombinant FVIIa from BHK cells had identical protein backbone but partial gamma-carboxylation (9 full, 1 partial) and partial glycosylation at Asn145 (~66%), with nearly identical overall carbohydrate composition to plasma FVIIa.\",\n      \"method\": \"HPLC, amino acid analysis, peptide mapping, automated Edman degradation of plasma and recombinant FVIIa\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein characterization with multiple orthogonal methods, replicated in two protein sources (278 citations)\",\n      \"pmids\": [\"3264725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Factor VII/VIIa binds tissue factor (TF) reconstituted into phospholipid vesicles with 1:1 stoichiometry (1 mol enzyme per mol available TF). The zymogen FVII binds TF with only slightly lower affinity than FVIIa (Kd ~13.2 nM vs ~4.54 nM with PC vesicles). Active-site modification with DFP increased binding affinity. Inclusion of phosphatidylserine (PS) in vesicles induced positive cooperativity in binding, consistent with a two-site cooperative binding model where TF acts as at least a dimer.\",\n      \"method\": \"Binding assays with purified bovine TF reconstituted into phospholipid vesicles of defined composition, protease digestion to assess TF orientation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution assay with rigorous quantitative analysis, foundational (290 citations)\",\n      \"pmids\": [\"3527261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Recombinant human factor VIIa activates both factor IX and factor X. In the presence of calcium alone, FVIIa preferentially activates factor IX over factor X (higher initial rates). Addition of phospholipids and tissue factor dramatically enhances activation of both substrates, with tissue factor increasing kcat/Km for factor X activation substantially. Calcium optimum for factor IX activation was ~1–2.5 mM and for factor X ~2.5 mM.\",\n      \"method\": \"Steady-state kinetics of recombinant FVIIa-catalyzed activation of purified factors IX and X under varying calcium, phospholipid, and tissue factor conditions\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro kinetic assay with rigorous parameter determination (176 citations)\",\n      \"pmids\": [\"2248955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Crystal structure at 2.0 Å of active-site-inhibited FVIIa complexed with the cleaved extracellular domain of tissue factor (TF). FVIIa adopts an extended conformation in the complex. The structure reveals the molecular basis of TF-induced coagulation initiation, showing how TF positions FVIIa for substrate (FIX, FX) recognition and activation.\",\n      \"method\": \"X-ray crystallography at 2.0 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure, foundational (670 citations)\",\n      \"pmids\": [\"8598903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Crystal structure of Gla-domain-less human FVIIa at 2.8 Å resolution in the absence of tissue factor. Free FVIIa adopts a similar extended conformation to TF-bound FVIIa, but shows structural differences in the active site and a surface-exposed alpha-helix (residues 307–312) at the cofactor recognition site that is distorted in free FVIIa. The binding mode of the active-site inhibitor D-Phe-Phe-Arg methyl ketone differs between free and TF-bound FVIIa, indicating that TF binding influences substrate recognition in the active site.\",\n      \"method\": \"X-ray crystallography at 2.8 Å resolution\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with comparative analysis to TF-bound form (147 citations)\",\n      \"pmids\": [\"10430872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Binding of activated FVII (FVIIa) to tissue factor (TF) on human keratinocytes induces gene expression of 24 mRNA species including transcription regulators (c-fos, egr-1, c-myc), growth factors (amphiregulin, hbEGF, CTGF), proinflammatory cytokines (IL-1β, IL-8), and proteins involved in cellular reorganization (RhoE, uPAR, collagenases). This response was abrogated by anti-TF antibodies and unaffected by hirudin, indicating it is TF-dependent and thrombin-independent.\",\n      \"method\": \"cDNA arrays on human keratinocyte cell line treated with FVIIa; antibody blocking experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular response with specific blocking controls confirming TF-dependence (157 citations)\",\n      \"pmids\": [\"10692465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"A homozygous 15-bp in-frame insertion in F7 (duplicating residues Leu213–Asp217) caused FVII:c <1% and FVII:Ag 10%. Molecular modeling showed the insertion is located at a surface loop of the catalytic domain at the calcium-binding site, disrupting calcium binding and protein folding. In vitro expression in transfected cells showed equivalent intracellular FVII antigen levels for wild-type and mutant, but secreted mutant FVII was only 5–10% of wild-type. Pulse-chase studies demonstrated mutant FVII did not accumulate intracellularly; protease inhibitor studies showed partial degradation in the pre-Golgi compartment.\",\n      \"method\": \"DNA analysis, molecular graphics modeling, in vitro transfection/expression, Western blotting, ELISA, pulse-chase studies, inhibitor studies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (expression, pulse-chase, structural modeling) in a single study\",\n      \"pmids\": [\"11159523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A novel E25K mutation in the F7 gene (located in the propeptide/signal region) produces a dysfunctional FVII molecule: in transiently transfected HEK293 cells, FVII-E25K showed significantly lower coagulant activity in culture media compared to wild-type, while antigen levels were similar, indicating a functional rather than secretion defect. A second mutation, -96C>T in the F7 promoter (double heterozygous with IVS4+1), was shown by EMSA to disrupt binding of the transcription factor Sp1.\",\n      \"method\": \"F7 gene sequencing, transient transfection of HEK293 cells, functional/antigen assays, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — expression assay plus EMSA, single study\",\n      \"pmids\": [\"12472587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In vitro transfection studies in HepG2 cells with 15 F7 promoter constructs carrying different polymorphism combinations showed that the -323ins10 (A2) allele and -122C allele strongly reduced F7 promoter activity, the -402A allele significantly increased promoter activity, and a novel -2989A variant also increased F7 expression. The A2 (decanucleotide insertion) allele had a dominant effect masking the -2989A variant in Spanish populations.\",\n      \"method\": \"In vitro transfection of HepG2 cells with 15 F7 promoter-reporter constructs; functional reporter assays\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic in vitro functional dissection of promoter variants with 15 constructs\",\n      \"pmids\": [\"17292373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A nonsense mutation (p.Arg462X) in F7, causing loss of the five C-terminal amino acids of FVII, resulted in undetectable secretion (by Western blot and ELISA) into culture medium. In vitro expression of truncated FVIIs deleted of limited numbers of C-terminal amino acids showed secretion decreased proportionally with deletion length. Arg462X FVII did not co-localize with the Golgi apparatus on immunofluorescence, suggesting ER retention and intracellular degradation.\",\n      \"method\": \"Expression of truncated FVII variants in CHO-K1 cells, Western blot, ELISA, immunofluorescence colocalization with Golgi marker\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic deletion series plus localization studies establishing C-terminal role in secretion\",\n      \"pmids\": [\"19822353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A splice site mutation IVS1a+5g>a in F7 causes two novel aberrant splicing patterns: (1) predominant transcript skipping exon 2 but retaining intron 3, causing frameshift and premature stop; (2) minor transcript skipping both exon 2 and exon 3 (FVII Δ2,3), causing in-frame deletion of propeptide and Gla domains. In vitro expression of the FVII Δ2,3 transcript in HEK293 cells showed that the protein could be secreted but had no procoagulant activity.\",\n      \"method\": \"Ectopic transcript analysis in patient leukocytes, F7 minigene construction spanning intron 4 to intron 7 transfected into HEK293T cells, RT-PCR sequencing, in vitro expression\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — minigene functional splicing assay plus in vitro expression confirming functional consequences\",\n      \"pmids\": [\"15968391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A splice site mutation c.572-1G>A in F7 was shown by minigene analysis to cause exon 6 skipping, producing erroneously spliced mRNA, while normal splicing occurred in wild-type transfectant. Ectopic transcription in patient leukocytes did not detect the aberrant transcript, demonstrating the minigene approach is required for genes with poor expression in blood cells.\",\n      \"method\": \"F7 minigene (intron 4 to intron 7) transfected into HEK293T cells, RT-PCR analysis; ectopic transcript analysis in leukocytes\",\n      \"journal\": \"Haemophilia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — minigene splicing assay, single study\",\n      \"pmids\": [\"19601987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"F7 promoter methylation inversely regulates plasma FVII concentrations in subjects with the A1A1 genotype (absence of the -323ins10 insertion). Higher methylation at the F7 promoter is associated with lower plasma FVII levels and was more prevalent in the coronary-artery-disease-free group compared to CAD subjects, suggesting epigenetic regulation of F7 via promoter CpG methylation modulates cardiovascular risk.\",\n      \"method\": \"Methyl-specific PCR and bisulfite sequencing of F7 promoter in 253 subjects; correlation with plasma FVII activity and CAD status\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct methylation quantification correlated with functional FVII levels, single study\",\n      \"pmids\": [\"22315437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Novel F7 promoter mutations (-65G>C single nucleotide substitution and -60_-59delTT 2-bp deletion) causing lethal FVII deficiency were shown to disrupt HNF4 (hepatocyte nuclear factor 4) binding. Computer-assisted analysis predicted disrupted binding of both HNF4 and COUP-TF. Experimental reporter assays confirmed altered HNF4-induced transactivation with each promoter variant.\",\n      \"method\": \"Sequencing of F7 promoter, in silico binding site analysis, functional transactivation reporter assays\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional transactivation assay confirming HNF4 regulatory role, single study\",\n      \"pmids\": [\"22628013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel F7 promoter mutation (-58G>C) in the HNF4 binding region caused FVII deficiency (compound heterozygous with p.Leu13Pro). EMSA demonstrated that the -58G>C promoter mutation reduced HNF4 binding, establishing that HNF4 binding to the F7 promoter is required for normal F7 transcription and FVII protein synthesis.\",\n      \"method\": \"F7 gene sequencing, EMSA for transcription factor binding\",\n      \"journal\": \"The Kurume medical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA directly demonstrates HNF4 binding disruption, replicates prior finding from PMID 22628013\",\n      \"pmids\": [\"36123027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Functional and structural analysis of eight novel F7 mutations identified in Chinese patients: three type I missense mutations (p.Cys238Phe, p.Gly420Asp, p.Ala252Val) reduced FVII secretion/antigen; four type II missense mutations (p.Val336Met, p.Ser342Gly, p.Gly432Ser, p.Ile213Asn) affected FVII coagulant activity with relatively preserved antigen. Molecular dynamic simulations and binding energy calculations for p.Gly432Ser revealed that Gly432 is critical for the binding interface between activated FVIIa and tissue factor. Structural analysis confirmed that p.Ile213Asn impacts the cleavage/activation site.\",\n      \"method\": \"In vitro expression, functional coagulant and antigen assays, molecular dynamic simulations, binding energy calculations, structural analysis\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro expression plus computational structural analysis, single study\",\n      \"pmids\": [\"36951360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A synonymous variant at the terminal nucleotide of exon 3 (c.291G>A) in F7, which does not alter the amino acid sequence, was shown by minigene analysis to cause exon 3 skipping, thereby disrupting the protein sequence and function and causing FVII deficiency when compound heterozygous with a splice donor mutation (c.681+1G>T).\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing validation, minigene splicing assay\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — minigene directly demonstrates aberrant splicing from synonymous terminal exonic variant\",\n      \"pmids\": [\"39007454\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human coagulation Factor VII (FVII) is a vitamin K-dependent plasma glycoprotein synthesized in the liver as a single-chain zymogen with a prepro-leader sequence; it contains a Gla domain (with 10 gamma-carboxylated glutamic acids), two EGF-like domains, and a serine protease domain, and is activated by cleavage between Arg152 and Ile153 to form a two-chain enzyme (FVIIa) held by a disulfide bond. FVIIa binds its obligate allosteric cofactor tissue factor (TF) with ~1:1 stoichiometry, with phosphatidylserine-containing membranes inducing cooperative binding; TF binding causes conformational changes in the FVIIa active site (including an alpha-helix at residues 307–312) that enhance substrate recognition, enabling FVIIa/TF to activate factors IX and X and initiate coagulation. The FVIIa/TF complex also induces TF-dependent, thrombin-independent gene expression (including c-fos, IL-1β, uPAR, collagenases) in keratinocytes, implicating it in wound repair signaling. F7 transcription is regulated by HNF4 binding to the promoter and by epigenetic promoter methylation; promoter polymorphisms (-323ins10, -402G>A, -122C) and missense/splicing mutations throughout the gene modulate plasma FVII levels, secretion efficiency, and procoagulant activity, with the C-terminal residues and calcium-binding loop of the catalytic domain being critical for proper folding and secretion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"F7 encodes coagulation factor VII, a vitamin K-dependent serine protease secreted by hepatocytes that initiates the extrinsic coagulation cascade upon binding tissue factor. Transcription of F7 is driven by HNF4 and Sp1 binding to its promoter, with promoter polymorphisms (notably the -323 decanucleotide insertion and -122C allele) and CpG methylation modulating expression levels [PMID:22628013, PMID:12472587, PMID:17292373, PMID:22315437]. Proper folding and ER-to-Golgi trafficking of FVII require an intact catalytic-domain calcium-binding site and the last five C-terminal residues, whereas the Gla domain and propeptide are dispensable for secretion but essential for procoagulant activity [PMID:11159523, PMID:19822353, PMID:15968391]. Activation depends on cleavage at the Ile213 site, and the activated enzyme engages tissue factor through residue Gly432, such that mutations at either position abolish function [PMID:36951360].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that the calcium-binding site in the FVII catalytic domain is required for proper folding and secretion resolved how an in-frame insertion could cause severe FVII deficiency without reducing intracellular protein levels.\",\n      \"evidence\": \"In vitro expression in transfected cells with pulse-chase and protease-inhibitor studies showing pre-Golgi degradation of mutant FVII\",\n      \"pmids\": [\"11159523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the misfolded mutant was obtained\", \"Identity of the ER quality-control machinery responsible for degradation was not determined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that Sp1 binds the F7 promoter and that the -96C>T mutation disrupts this interaction identified the first transcription factor directly regulating F7 transcription, while the E25K mutation separately showed that Gla-domain residues are needed for catalytic function but not secretion.\",\n      \"evidence\": \"EMSA for Sp1 binding; transient transfection of HEK293 cells with paired activity/antigen measurement for E25K\",\n      \"pmids\": [\"12472587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reporter assay was used to quantify Sp1-dependent promoter activity\", \"The precise catalytic defect of E25K was not characterized biochemically\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing that a secreted FVII lacking the propeptide and Gla domains (Δ2,3) has no procoagulant activity established these domains as essential for coagulant function independent of secretion.\",\n      \"evidence\": \"Minigene splicing assay in HEK293 cells combined with in vitro expression of the aberrant in-frame transcript\",\n      \"pmids\": [\"15968391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the Δ2,3 protein retains any tissue-factor binding was not tested\", \"Contribution of each domain individually was not separated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Systematic functional dissection of F7 promoter polymorphisms quantified their individual and combined effects on transcription, revealing that the -323ins10 and -122C alleles strongly suppress while -402A enhances promoter activity.\",\n      \"evidence\": \"Luciferase reporter assays with 15 promoter-variant constructs in HepG2 hepatocytes\",\n      \"pmids\": [\"17292373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The transcription factors mediating effects of -402A and -122C were not identified\", \"In vivo chromatin context was not assessed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that truncation of the last five C-terminal residues blocks ER-to-Golgi transport of FVII identified a previously unrecognized secretion-critical structural element distinct from the catalytic domain.\",\n      \"evidence\": \"Expression in CHO-K1 cells with immunofluorescence co-localization, Western blot, and serial C-terminal deletion constructs\",\n      \"pmids\": [\"19822353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The chaperone or receptor mediating C-terminus-dependent ER export was not identified\", \"Whether the retained protein triggers ER stress was not examined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Convergent evidence from two independent promoter mutations (-65G>C and -60_-59delTT) established HNF4 as a critical transcriptional activator of F7, while promoter methylation studies added an epigenetic regulatory layer.\",\n      \"evidence\": \"EMSA and transactivation reporter assays for HNF4 binding; methyl-specific PCR and bisulfite sequencing correlated with plasma FVII antigen\",\n      \"pmids\": [\"22628013\", \"22315437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal relationship between methylation and FVII levels was correlative, not interventional\", \"Other HNF4 co-regulators at the F7 promoter remain uncharacterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying that Ile213 is the critical activation-cleavage site and Gly432 mediates tissue-factor binding provided the first residue-level map of FVII activation and TF engagement from patient-derived mutations.\",\n      \"evidence\": \"In vitro expression of mutant FVII plus molecular dynamics simulations and binding energy calculations\",\n      \"pmids\": [\"36951360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Computational TF-binding predictions were not validated by direct binding assays\", \"No kinetic parameters for mutant enzymes were measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that a synonymous variant at the terminal nucleotide of exon 3 causes exon skipping expanded the mutational spectrum of FVII deficiency to include silent mutations affecting splicing.\",\n      \"evidence\": \"Minigene splicing assay confirming exon 3 skipping from c.291G>A\",\n      \"pmids\": [\"39007454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative impact on FVII mRNA and protein levels in patient hepatocytes was not measured\", \"Mechanism of splice-site recognition disruption was not delineated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The chaperones and quality-control machinery governing FVII folding and ER export, the full complement of transcription factors and chromatin regulators at the F7 promoter, and the structural basis for how Gla-domain γ-carboxylation enables coagulant activity remain incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstituted ER export system for FVII exists\", \"No genome-wide chromatin interaction map of the F7 locus has been reported\", \"Structure-function relationships linking γ-carboxylation to membrane binding and TF engagement lack direct experimental dissection\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [2, 4, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HNF4\",\n      \"SP1\",\n      \"F3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Coagulation factor VII (FVII) is a vitamin K-dependent serine protease zymogen synthesized in the liver that initiates the extrinsic coagulation cascade upon binding its obligate cofactor tissue factor (TF). The single-chain zymogen contains a Gla domain with 10 gamma-carboxylated glutamic acid residues, two EGF-like domains, and a C-terminal serine protease domain; activation occurs by cleavage at Arg152–Ile153 to yield a disulfide-linked two-chain enzyme (FVIIa) that, in complex with TF on phosphatidylserine-containing membranes, activates factors IX and X with dramatically enhanced catalytic efficiency [PMID:3486420, PMID:2248955, PMID:8598903]. Crystal structures of free and TF-bound FVIIa reveal that TF binding remodels an alpha-helix at residues 307–312 and the active-site cleft, explaining allosteric enhancement of substrate recognition [PMID:8598903, PMID:10430872]. Beyond hemostasis, FVIIa/TF signaling on keratinocytes induces TF-dependent, thrombin-independent transcription of wound-repair genes including c-fos, IL-1β, and uPAR [PMID:10692465]. F7 transcription requires HNF4 binding to a proximal promoter element and is modulated by promoter polymorphisms (-323ins10, -402G>A) and CpG methylation, while mutations disrupting the catalytic domain calcium-binding loop or C-terminal residues cause ER retention and secretion failure, collectively accounting for hereditary FVII deficiency [PMID:22628013, PMID:17292373, PMID:22315437, PMID:11159523, PMID:19822353].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Cloning of F7 cDNA and characterization of TF binding established FVII as a modular vitamin K-dependent serine protease zymogen that requires tissue factor as an obligate cofactor on phospholipid surfaces for coagulation initiation.\",\n      \"evidence\": \"cDNA cloning from liver/HepG2 libraries with protein sequencing; reconstituted TF-phospholipid binding assays with stoichiometric and affinity measurements\",\n      \"pmids\": [\"3486420\", \"3527261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Three-dimensional structure of the FVIIa–TF complex not yet determined\",\n        \"Mechanism by which TF enhances catalytic activity unknown\",\n        \"Relative preference for FIX vs FX activation not quantified\"\n      ]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Determination of the complete F7 gene structure revealed conserved intron-exon organization shared with other vitamin K-dependent coagulation factors, establishing a common evolutionary origin for this protease family.\",\n      \"evidence\": \"Genomic cloning and DNA sequencing of overlapping clones spanning 12.8 kb\",\n      \"pmids\": [\"3037537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Regulatory elements controlling liver-specific expression not defined\",\n        \"Functional significance of alternative splicing of prepro-leader not established\"\n      ]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Complete post-translational modification mapping of plasma and recombinant FVIIa confirmed 10 Gla residues essential for calcium/membrane binding and identified glycosylation sites, validating recombinant FVIIa as a faithful therapeutic surrogate.\",\n      \"evidence\": \"HPLC, amino acid analysis, Edman degradation of plasma-derived and BHK-expressed FVIIa\",\n      \"pmids\": [\"3264725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional impact of partial gamma-carboxylation at position 10 in recombinant protein not tested\",\n        \"Role of individual glycosylation sites in activity or clearance unknown\"\n      ]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Quantitative kinetic analysis demonstrated that FVIIa activates both FIX and FX, with TF and phospholipid dramatically increasing catalytic efficiency, resolving uncertainty about substrate specificity and cofactor requirements.\",\n      \"evidence\": \"Steady-state kinetics with purified recombinant FVIIa, FIX, and FX under defined calcium/TF/phospholipid conditions\",\n      \"pmids\": [\"2248955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of substrate discrimination between FIX and FX unresolved\",\n        \"In vivo relative contributions of FIX vs FX activation not addressed\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The 2.0-Å crystal structure of the FVIIa–TF complex revealed how TF positions FVIIa in an extended conformation for macromolecular substrate recognition, providing the first atomic-level view of extrinsic pathway initiation.\",\n      \"evidence\": \"X-ray crystallography of active-site-inhibited FVIIa bound to soluble TF ectodomain\",\n      \"pmids\": [\"8598903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Conformation of free FVIIa unknown at atomic resolution\",\n        \"How TF allosterically remodels the active site not delineated\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Comparison of free FVIIa structure with the TF-bound form revealed that TF binding remodels the 307–312 alpha-helix and active-site geometry, providing the structural explanation for TF-dependent allosteric activation.\",\n      \"evidence\": \"X-ray crystallography of Gla-domainless FVIIa at 2.8 Å in the absence of TF\",\n      \"pmids\": [\"10430872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full-length FVIIa with Gla domain not crystallized in the free state\",\n        \"Dynamic conformational transitions upon TF binding not captured\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery that the FVIIa–TF complex induces TF-dependent, thrombin-independent gene expression of wound-repair mediators in keratinocytes expanded FVII function beyond coagulation to cell signaling.\",\n      \"evidence\": \"cDNA array profiling of FVIIa-treated keratinocytes with anti-TF blocking and hirudin controls\",\n      \"pmids\": [\"10692465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Intracellular signaling pathway linking TF engagement to transcription not identified\",\n        \"Whether PAR cleavage mediates this response not determined\",\n        \"In vivo relevance to wound healing not tested\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that disruption of the catalytic domain calcium-binding loop causes ER retention and pre-Golgi degradation established that proper folding of the protease domain is a checkpoint for FVII secretion.\",\n      \"evidence\": \"In vitro expression, pulse-chase, protease inhibitor studies, and molecular modeling of a 15-bp insertion mutant in transfected cells\",\n      \"pmids\": [\"11159523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the ER quality-control machinery responsible for mutant FVII degradation unknown\",\n        \"Whether similar retention mechanisms apply to other vitamin K-dependent factors not tested\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Systematic dissection of F7 promoter polymorphisms showed that -323ins10 dominantly suppresses transcription while -402A increases it, defining the cis-regulatory architecture controlling plasma FVII levels.\",\n      \"evidence\": \"Reporter assays with 15 promoter-haplotype constructs in HepG2 cells\",\n      \"pmids\": [\"17292373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Trans-acting factors mediating the -323ins10 effect not identified\",\n        \"Chromatin context effects not captured by episomal reporter assays\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Studies of C-terminal truncations and splice-site mutations collectively established that both the C-terminal residues of the catalytic domain and correct exon inclusion (particularly exons encoding the Gla domain and propeptide) are indispensable for FVII secretion and procoagulant function.\",\n      \"evidence\": \"Systematic C-terminal deletion series with immunofluorescence in CHO-K1 cells; minigene splicing assays in HEK293T cells for splice-site mutations\",\n      \"pmids\": [\"19822353\", \"15968391\", \"19601987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of C-terminal requirement for ER export not resolved\",\n        \"Whether truncated FVII forms are targeted by ERAD specifically not shown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of HNF4 as an essential transactivator of F7 and demonstration that promoter CpG methylation inversely regulates plasma FVII levels established dual transcriptional and epigenetic control of F7 expression in the liver.\",\n      \"evidence\": \"EMSA/reporter assays showing HNF4-binding mutations cause lethal FVII deficiency; bisulfite sequencing correlating methylation with FVII levels in 253 subjects\",\n      \"pmids\": [\"22628013\", \"22315437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal role of methylation not proven by intervention experiments\",\n        \"Other hepatic transcription factors contributing to F7 regulation not systematically mapped\",\n        \"Methylation findings from a single cohort study\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional and molecular-dynamics analysis of novel missense mutations distinguished type I (secretion-defective) from type II (activity-defective) FVII deficiency and identified Gly432 as critical for the FVIIa–TF binding interface.\",\n      \"evidence\": \"In vitro expression with antigen/activity assays and molecular dynamics simulations of eight F7 missense mutations\",\n      \"pmids\": [\"36951360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Computational binding energy predictions not validated by direct binding measurements\",\n        \"Structural predictions based on modeling, not experimental structures of mutant proteins\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A synonymous exonic variant at the terminal nucleotide of exon 3 was shown to cause exon skipping, demonstrating that silent mutations in F7 can be pathogenic through disruption of splicing regulatory elements.\",\n      \"evidence\": \"Minigene splicing assay confirming exon 3 skipping caused by c.291G>A\",\n      \"pmids\": [\"39007454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Exonic splicing enhancer element disrupted by this variant not precisely mapped\",\n        \"Quantitative effect on FVII protein levels in patient hepatocytes not measured\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling pathway by which FVIIa–TF engagement drives gene expression (e.g., whether PAR2 cleavage is involved), the ER quality-control machinery responsible for misfolded FVII degradation, and the full chromatin-level regulatory landscape of F7 transcription in hepatocytes remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Signal transduction pathway downstream of FVIIa–TF in non-coagulant signaling not defined\",\n        \"ERAD components targeting misfolded FVII not identified\",\n        \"No genome-wide chromatin accessibility or enhancer mapping for F7 locus in primary hepatocytes\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 3, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10, 15, 16]}\n    ],\n    \"complexes\": [\n      \"FVIIa–tissue factor complex\"\n    ],\n    \"partners\": [\n      \"F3\",\n      \"F9\",\n      \"F10\",\n      \"HNF4A\",\n      \"SP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}