{"gene":"F12","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1977,"finding":"Prothrombin activation in blood and plasma proceeds primarily through removal of the combined activation fragment F1-2 (representing the amino-terminal half of prothrombin) as a single peptide, accounting for at least 90% of prothrombin conversion; the separate F1 fragment represents a minor pathway (<10%).","method":"Rapid purification (DEAE-cellulose, hydroxyapatite chromatography), isotope dilution, amino acid composition, antigenic characterization, thrombin hydrolysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution with multiple orthogonal characterization methods","pmids":["410831"],"is_preprint":false},{"year":2015,"finding":"Specific gain-of-function mutations in the F12 gene (e.g., p.Thr309Lys/p.Thr328Lys) cause hereditary angioedema with normal C1-inhibitor (HAE-FXII) through increased FXII activation leading to excess bradykinin generation; estrogen exposure is a key modifier of clinical penetrance.","method":"Genetic analysis, family studies, clinical phenotyping, laboratory complement/coagulation assays","journal":"Allergy","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple independent cohorts and labs with genetic and functional data","pmids":["25952149","25134986","23994767"],"is_preprint":false},{"year":2021,"finding":"The HAE-FXII variant FXII309Lys (c.1032C>A) results in a glycosylation-deficient FXII with increased sensitivity to fluid-phase activation; thrombin cleaves FXII309Lys to release a 37-kDa heavy chain fragment, priming it for subsequent kallikrein cleavage and generation of active βFXIIa, linking hypercoagulable states to angioedema episodes.","method":"Western blot, amidolytic assay, recombinant protein expression in S2 insect cells, neuraminidase treatment, fibrin generation assay, plasma activation studies","journal":"Clinical reviews in allergy & immunology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with recombinant variants, multiple orthogonal functional assays","pmids":["33725261"],"is_preprint":false},{"year":2018,"finding":"RNAi-mediated knockdown of liver-derived F12 mRNA (ALN-F12, GalNAc-siRNA) potently reduces plasma FXII levels in mice, rats, and non-human primates, and dose-dependently reduces vascular permeability in bradykinin-driven mouse models; ex vivo assays confirmed FXII-dependent HK cleavage and bradykinin generation.","method":"In vivo siRNA knockdown, ELISA for plasma FXII, vascular permeability models (Miles assay), ex vivo HK cleavage assay","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined cellular/physiological phenotype, replicated across species and models","pmids":["30463937"],"is_preprint":false},{"year":2020,"finding":"AAV-delivered shRNA targeting liver F12 mRNA reduces plasma FXII protein and provides dose-dependent protection against arterial and venous thrombosis in mice without affecting hemostasis (no increase in bleeding time or blood loss), establishing FXII's role in pathological but not hemostatic coagulation.","method":"AAV-shRNA knockdown in mice, ferric chloride arterial thrombosis model, electrolytic venous thrombosis model, saphenous vein and tail-transection bleeding models","journal":"Thrombosis research","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo KO with multiple orthogonal thrombosis and hemostasis models","pmids":["32896690"],"is_preprint":false},{"year":2019,"finding":"AAV-mediated shRNA targeting F12 effectively reduces FXII expression and inhibits thrombus formation in multiple mouse thrombosis models without causing hemorrhage, confirming FXII's role in thrombosis but not normal hemostasis.","method":"AAV-shRNA in vivo knockdown, coagulation function assays, tail bleeding, pathological sections","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with phenotypic readout, single lab","pmids":["30959404"],"is_preprint":false},{"year":2004,"finding":"The F12 46C→T polymorphism (rs1801020) in exon 1 causes reduced plasma FXII levels in a gene-dosage manner; homozygosity for the T allele (T/T genotype) is an independent genetic risk factor for venous thrombosis (adjusted OR 4.82) and ischemic stroke (adjusted OR 4.1).","method":"Family-based linkage scan (GAIT Project), case-control genotyping, plasma FXII activity measurement","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple independent case-control studies with functional FXII level data","pmids":["15116249","15232129","15257949"],"is_preprint":false},{"year":2009,"finding":"Bayesian quantitative trait nucleotide analysis of F12 re-sequencing identified that the rs1801020 (46C>T) variant alone accounts for the F12 QTL effect on plasma FXII levels; the T allele appeared ~100,000 years ago and spread by genetic drift.","method":"Re-sequencing of F12 in 40 individuals, genotyping of 26 SNPs in 398 family members (GAIT Project), measured genotype association analysis, Bayesian QTN analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — large family-based study with comprehensive sequencing and statistical fine-mapping","pmids":["19933701"],"is_preprint":false},{"year":2010,"finding":"The F12 -4C>T polymorphism (rs1801020) significantly prolongs aPTT and reduces thrombin generation (lower ETP, thrombin peak) in both patients and healthy controls in a gene-dosage manner; carriers also have significantly lower FIXc and FVIIc levels, demonstrating the downstream impact of FXII levels on the intrinsic coagulation pathway.","method":"Genotyping, plasma FXII activity, aPTT assay, calibrated automated thrombinography (CAT), factor assays in 566 participants","journal":"Blood coagulation & fibrinolysis","confidence":"High","confidence_rationale":"Tier 2 — large cohort with multiple orthogonal coagulation assays","pmids":["20814302"],"is_preprint":false},{"year":2016,"finding":"Polymorphisms at F12 (rs1801020) and KLKB1 (rs3733402) are associated with reduced active plasma renin; in vitro assays confirmed that kallikrein digests pro-renin to generate active renin, and active renin cleaves angiotensinogen to angiotensin-I; the F12 variant reduces FXII's ability to activate prekallikrein to kallikrein, thereby reducing renin activation.","method":"Cohort genotyping, in vitro recombinant pro-renin digestion assay, synthetic substrate assay for renin activity, co-localization by immunohistochemistry","journal":"BMC medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — combines genetic association with in vitro functional validation, single lab","pmids":["26969407"],"is_preprint":false},{"year":2019,"finding":"Factor XII deficiency in domestic cats is caused by two high-frequency F12 mutations (exon 13 missense c.1631G>C and exon 11 deletion c.1321delC); residual FXII:C correlates with mutation number and type; deficient cats show no abnormal bleeding, consistent with FXII's dispensability for hemostasis.","method":"Retrospective phenotypic review, coagulation assays, F12 gene sequencing of 26 FXII-deficient cats","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — natural loss-of-function model with genotype-phenotype correlation across multiple animals","pmids":["31022435"],"is_preprint":false},{"year":2020,"finding":"Missense variants p.Glu502Lys and p.Gly542Ser in the F12 gene reduce FXII secretion and activity: transfection of HEK293T cells with expression plasmids encoding these variants showed reduced FXII:C and FXII:Ag in supernatant and cell lysate compared to wild-type, demonstrating that these mutations impair FXII synthesis and secretion.","method":"Site-directed mutagenesis, transient transfection in 293T cells, FXII:C clotting assay, FXII:Ag ELISA, Western blot","journal":"Chinese journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro expression with mutagenesis and functional assays, single lab","pmids":["32335876"],"is_preprint":false},{"year":2023,"finding":"An evolutionary analysis established that F12 (encoding a serine protease with defense and hemostatic roles) emerged ~425 Mya in vertebrates, was secondarily lost in cetaceans during their transition to aquatic lifestyle, and has acquired new roles in pathological activation by blood-contacting devices and nanoparticles.","method":"Comparative genomics, phylogenetic analysis","journal":"BioEssays","confidence":"Low","confidence_rationale":"Tier 4 — computational/evolutionary analysis only","pmids":["37750435"],"is_preprint":false}],"current_model":"Human F12 encodes coagulation Factor XII (Hageman factor), a plasma serine protease that initiates the contact activation pathway: upon surface or fluid-phase activation (including by the HAE-FXII gain-of-function variants sensitized to thrombin and kallikrein cleavage), active FXIIa drives the kallikrein-kinin system to generate bradykinin (causing angioedema) and activates the intrinsic coagulation cascade; the 46C>T promoter polymorphism reduces plasma FXII levels in a gene-dosage manner, prolonging aPTT and influencing thrombotic risk, while FXII knockdown (by siRNA or shRNA) prevents pathological thrombosis without impairing hemostasis, establishing FXII as dispensable for normal hemostasis but important for pathological thrombus formation."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that a common F12 coding-region polymorphism (46C>T, rs1801020) quantitatively determines plasma FXII levels and influences thrombotic risk answered the question of whether genetic variation in FXII contributes to venous thrombosis and stroke.","evidence":"Family-based linkage scan (GAIT Project) and independent case-control genotyping with plasma FXII activity measurement","pmids":["15116249","15232129","15257949"],"confidence":"High","gaps":["Mechanism by which reduced FXII paradoxically increases thrombotic risk was not explained","Effect on arterial thrombosis versus venous thrombosis not fully dissected","No functional assay demonstrating altered translation from the T allele"]},{"year":2009,"claim":"Fine-mapping by Bayesian QTN analysis resolved the F12 QTL to rs1801020 as the sole causal nucleotide governing plasma FXII levels, ruling out other linked variants.","evidence":"Re-sequencing of F12 locus in 40 individuals, genotyping 26 SNPs in 398 GAIT family members with measured genotype analysis","pmids":["19933701"],"confidence":"High","gaps":["Molecular mechanism of translational or transcriptional regulation by the 46C>T variant not demonstrated","Population-level replication outside the GAIT cohort limited"]},{"year":2010,"claim":"Demonstrating that rs1801020 gene-dosage reduction of FXII propagates downstream to reduce thrombin generation (ETP, peak), FIXc, and FVIIc established FXII as a rate-limiting initiator of the intrinsic pathway in vivo.","evidence":"Calibrated automated thrombinography and coagulation factor assays in 566 participants stratified by genotype","pmids":["20814302"],"confidence":"High","gaps":["Whether reduced thrombin generation explains the paradoxical thrombotic risk of low FXII remains unresolved","No intervention study to confirm causality"]},{"year":2015,"claim":"Identification of gain-of-function F12 mutations (p.Thr309Lys) as causative for hereditary angioedema with normal C1-inhibitor (HAE-FXII) answered how FXII hyperactivation links to bradykinin-mediated vascular permeability in humans.","evidence":"Genetic analysis and family studies across multiple independent cohorts with clinical phenotyping","pmids":["25952149","25134986","23994767"],"confidence":"High","gaps":["Estrogen's mechanism in modifying clinical penetrance was not delineated at the molecular level","Whether other HAE-FXII variants operate by the same mechanism was unknown"]},{"year":2016,"claim":"Connecting the F12 rs1801020 variant to reduced plasma active renin via diminished FXII-driven prekallikrein activation broadened FXII's physiological role beyond coagulation to the renin-angiotensin system.","evidence":"Cohort genotyping combined with in vitro recombinant pro-renin digestion assay and kallikrein activity assays","pmids":["26969407"],"confidence":"Medium","gaps":["In vivo validation of FXII–kallikrein–prorenin axis not performed","Quantitative contribution of FXII to renin homeostasis versus other activation pathways unclear","Single-lab finding without independent replication"]},{"year":2019,"claim":"RNAi and shRNA knockdown of hepatic F12 in multiple species demonstrated that reducing circulating FXII prevents thrombosis without impairing hemostasis, answering whether FXII is a safe antithrombotic target.","evidence":"GalNAc-siRNA (ALN-F12) in mice, rats, and non-human primates; AAV-shRNA in mouse FeCl3 arterial and electrolytic venous thrombosis models with tail-bleeding controls","pmids":["30463937","30959404","32896690"],"confidence":"High","gaps":["Efficacy and safety of FXII knockdown in humans not yet established","Long-term consequences of sustained FXII depletion (infection susceptibility, wound healing) not assessed"]},{"year":2021,"claim":"Biochemical reconstitution of the HAE-FXII variant FXII309Lys revealed the molecular mechanism: loss of an O-glycan increases sensitivity to thrombin priming cleavage, generating a 37-kDa heavy chain that is then fully activated by kallikrein to βFXIIa, linking hypercoagulable states to angioedema.","evidence":"Recombinant wild-type and variant FXII expressed in S2 cells, Western blot, amidolytic assays, neuraminidase treatment, fibrin generation assay","pmids":["33725261"],"confidence":"High","gaps":["Structural basis for how glycan loss exposes the thrombin cleavage site not resolved","Whether pharmacological glycosylation rescue could treat HAE-FXII not tested"]},{"year":null,"claim":"The structural basis for FXII surface activation, the full repertoire of physiological FXII activators in vivo, and whether FXII inhibition/knockdown is safe and effective as an antithrombotic or anti-angioedema therapy in humans remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of full-length FXII in active or zymogen form","In vivo FXII activating surfaces in physiology versus pathology not systematically defined","Human clinical trial data for FXII-targeted therapeutics not available in this literature"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3,4,8,9]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,4,6,8]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,4,5,6,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,3]}],"complexes":[],"partners":["KLKB1","F2","SERPING1","KNG1"],"other_free_text":[]},"mechanistic_narrative":"F12 encodes coagulation Factor XII (Hageman factor), a plasma serine protease that initiates the contact activation pathway, driving both the intrinsic coagulation cascade and the kallikrein-kinin system to generate bradykinin. The 46C>T promoter polymorphism (rs1801020) reduces plasma FXII levels in a gene-dosage manner, prolonging aPTT and diminishing thrombin generation, and also attenuates kallikrein-mediated pro-renin activation [PMID:15116249, PMID:20814302, PMID:26969407]. Gain-of-function mutations such as p.Thr309Lys cause hereditary angioedema with normal C1-inhibitor (HAE-FXII) by producing a glycosylation-deficient FXII with increased sensitivity to thrombin and kallikrein cleavage, leading to excess bradykinin generation [PMID:25952149, PMID:33725261]. RNAi-mediated knockdown of F12 in vivo prevents pathological arterial and venous thrombosis without impairing hemostasis, establishing FXII as dispensable for normal hemostatic function but essential for pathological thrombus formation [PMID:30463937, PMID:32896690]."},"prefetch_data":{"uniprot":{"accession":"P00748","full_name":"Coagulation factor XII","aliases":["Hageman factor","HAF"],"length_aa":615,"mass_kda":67.8,"function":"Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa (PubMed:2019570, PubMed:21304106, PubMed:8427954)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P00748/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/F12","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/F12","total_profiled":1310},"omim":[{"mim_id":"621184","title":"TAYOUN-MAAWALI SYNDROME; TYMAS","url":"https://www.omim.org/entry/621184"},{"mim_id":"616462","title":"ACROFACIAL DYSOSTOSIS, CINCINNATI TYPE; AFDCIN","url":"https://www.omim.org/entry/616462"},{"mim_id":"616404","title":"POLYMERASE I, RNA, SUBUNIT A; POLR1A","url":"https://www.omim.org/entry/616404"},{"mim_id":"615802","title":"NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FEATURES, SPASTICITY, AND BRAIN ABNORMALITIES; NEDDSBA","url":"https://www.omim.org/entry/615802"},{"mim_id":"613585","title":"TRANSMEMBRANE PROTEIN 147; TMEM147","url":"https://www.omim.org/entry/613585"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":593.2}],"url":"https://www.proteinatlas.org/search/F12"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P00748","domains":[{"cath_id":"2.10.10.10","chopping":"38-123","consensus_level":"medium","plddt":84.3123,"start":38,"end":123},{"cath_id":"2.10.25.10","chopping":"135-206","consensus_level":"high","plddt":93.1154,"start":135,"end":206},{"cath_id":"2.40.20.10","chopping":"216-295","consensus_level":"medium","plddt":77.5406,"start":216,"end":295},{"cath_id":"2.40.10.10","chopping":"388-468","consensus_level":"medium","plddt":91.7406,"start":388,"end":468},{"cath_id":"2.40.10.10","chopping":"500-613","consensus_level":"medium","plddt":79.8005,"start":500,"end":613}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00748","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00748-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00748-F1-predicted_aligned_error_v6.png","plddt_mean":76.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=F12","jax_strain_url":"https://www.jax.org/strain/search?query=F12"},"sequence":{"accession":"P00748","fasta_url":"https://rest.uniprot.org/uniprotkb/P00748.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00748/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00748"}},"corpus_meta":[{"pmid":"2355013","id":"PMC_2355013","title":"Purification and characterization of canine myocardial cytosolic phospholipase A2. A calcium-independent phospholipase with absolute f1-2 regiospecificity for diradyl glycerophospholipids.","date":"1990","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2355013","citation_count":228,"is_preprint":false},{"pmid":"22462842","id":"PMC_22462842","title":"Explicitly correlated Wn theory: W1-F12 and W2-F12.","date":"2012","source":"The Journal of chemical physics","url":"https://pubmed.ncbi.nlm.nih.gov/22462842","citation_count":158,"is_preprint":false},{"pmid":"410831","id":"PMC_410831","title":"Generation of the combined prothrombin activation peptide (F1-2) during the clotting of blood and plasma.","date":"1977","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/410831","citation_count":124,"is_preprint":false},{"pmid":"25952149","id":"PMC_25952149","title":"Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations.","date":"2015","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/25952149","citation_count":106,"is_preprint":false},{"pmid":"28010093","id":"PMC_28010093","title":"Perturbative triples correction for local pair natural orbital based explicitly correlated CCSD(F12*) using Laplace transformation techniques.","date":"2016","source":"The Journal of chemical physics","url":"https://pubmed.ncbi.nlm.nih.gov/28010093","citation_count":72,"is_preprint":false},{"pmid":"2241173","id":"PMC_2241173","title":"Fibronectin and proteoglycan synthesis in long term cultures of cartilage explants in Ham's F12 supplemented with insulin and calcium: effects of the addition of TGF-beta.","date":"1990","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/2241173","citation_count":68,"is_preprint":false},{"pmid":"27905115","id":"PMC_27905115","title":"Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII).","date":"2016","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/27905115","citation_count":66,"is_preprint":false},{"pmid":"23994767","id":"PMC_23994767","title":"Novel duplication in the F12 gene in a patient with recurrent angioedema.","date":"2013","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/23994767","citation_count":63,"is_preprint":false},{"pmid":"15116249","id":"PMC_15116249","title":"Association after linkage analysis indicates that homozygosity for the 46C-->T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis.","date":"2004","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/15116249","citation_count":63,"is_preprint":false},{"pmid":"29128335","id":"PMC_29128335","title":"Hereditary Angioedema with Normal C1 Inhibitor and F12 Mutations in 42 Brazilian Families.","date":"2017","source":"The journal of allergy and clinical immunology. In practice","url":"https://pubmed.ncbi.nlm.nih.gov/29128335","citation_count":51,"is_preprint":false},{"pmid":"31059956","id":"PMC_31059956","title":"Paternal benzo[a]pyrene exposure alters the sperm DNA methylation levels of imprinting genes in F0 generation mice and their unexposed F1-2 male offspring.","date":"2019","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/31059956","citation_count":46,"is_preprint":false},{"pmid":"15232129","id":"PMC_15232129","title":"Homozygosity of the T allele of the 46 C->T polymorphism in the F12 gene is a risk factor for ischemic stroke in the Spanish population.","date":"2004","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/15232129","citation_count":40,"is_preprint":false},{"pmid":"20195521","id":"PMC_20195521","title":"Vaccinia protein F12 has structural similarity to kinesin light chain and contains a motor binding motif required for virion export.","date":"2010","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/20195521","citation_count":39,"is_preprint":false},{"pmid":"19207726","id":"PMC_19207726","title":"An E2-F12 complex is required for intracellular enveloped virus morphogenesis during vaccinia infection.","date":"2009","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19207726","citation_count":39,"is_preprint":false},{"pmid":"30463937","id":"PMC_30463937","title":"An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema.","date":"2018","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30463937","citation_count":34,"is_preprint":false},{"pmid":"30275455","id":"PMC_30275455","title":"Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30275455","citation_count":33,"is_preprint":false},{"pmid":"25744496","id":"PMC_25744496","title":"Characterization of patients with angioedema without wheals: the importance of F12 gene screening.","date":"2015","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/25744496","citation_count":31,"is_preprint":false},{"pmid":"25134986","id":"PMC_25134986","title":"Hereditary angioedema with F12 mutation: factors modifying the clinical phenotype.","date":"2014","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/25134986","citation_count":28,"is_preprint":false},{"pmid":"10590138","id":"PMC_10590138","title":"cis expression of the F12 human immunodeficiency virus (HIV) Nef allele transforms the highly productive NL4-3 HIV type 1 to a replication-defective strain: involvement of both Env gp41 and CD4 intracytoplasmic tails.","date":"2000","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10590138","citation_count":28,"is_preprint":false},{"pmid":"11413327","id":"PMC_11413327","title":"Nef from human immunodeficiency virus type 1(F12) inhibits viral production and infectivity.","date":"2001","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/11413327","citation_count":27,"is_preprint":false},{"pmid":"19052096","id":"PMC_19052096","title":"Vaccinia virus protein F12 associates with intracellular enveloped virions through an interaction with A36.","date":"2008","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/19052096","citation_count":25,"is_preprint":false},{"pmid":"11602785","id":"PMC_11602785","title":"Genetic and functional analysis of the human immunodeficiency virus (HIV) type 1-inhibiting F12-HIVnef allele.","date":"2001","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/11602785","citation_count":25,"is_preprint":false},{"pmid":"19933701","id":"PMC_19933701","title":"Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19933701","citation_count":25,"is_preprint":false},{"pmid":"20490261","id":"PMC_20490261","title":"Obstetrical Complications and Outcome in Two Families with Hereditary Angioedema due to Mutation in the F12 Gene.","date":"2010","source":"Obstetrics and gynecology international","url":"https://pubmed.ncbi.nlm.nih.gov/20490261","citation_count":25,"is_preprint":false},{"pmid":"14585677","id":"PMC_14585677","title":"v-src oncogene-specific carboxy-terminal peptide is immunoprotective against Rous sarcoma growth in chickens with MHC class I allele B-F12.","date":"2003","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/14585677","citation_count":24,"is_preprint":false},{"pmid":"28277987","id":"PMC_28277987","title":"EndoC-βH1 cells display increased sensitivity to sodium palmitate when cultured in DMEM/F12 medium.","date":"2017","source":"Islets","url":"https://pubmed.ncbi.nlm.nih.gov/28277987","citation_count":24,"is_preprint":false},{"pmid":"24262729","id":"PMC_24262729","title":"Antihistamine-resistant angioedema in women with negative family history: estrogens and F12 gene mutations.","date":"2013","source":"The American journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24262729","citation_count":20,"is_preprint":false},{"pmid":"25760349","id":"PMC_25760349","title":"Vaccinia virus protein complex F12/E2 interacts with kinesin light chain isoform 2 to engage the kinesin-1 motor complex.","date":"2015","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/25760349","citation_count":20,"is_preprint":false},{"pmid":"23801027","id":"PMC_23801027","title":"Supplemented αMEM/F12-based medium enables the survival and growth of primary ovarian follicles encapsulated in alginate hydrogels.","date":"2013","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/23801027","citation_count":20,"is_preprint":false},{"pmid":"27788882","id":"PMC_27788882","title":"Hereditary angioedema with F12 mutation: Clinical features and enzyme polymorphisms in 9 Southwestern Spanish families.","date":"2016","source":"Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27788882","citation_count":20,"is_preprint":false},{"pmid":"17408404","id":"PMC_17408404","title":"Homozygosity for the C46T polymorphism of the F12 gene is a risk factor for venous thrombosis during the first pregnancy.","date":"2007","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/17408404","citation_count":20,"is_preprint":false},{"pmid":"15474309","id":"PMC_15474309","title":"Transcriptome of 3D7 and its gametocyte-less derivative F12 Plasmodium falciparum clones during erythrocytic development using a gene-specific microarray assigned to gene regulation, cell cycle and transcription factors.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15474309","citation_count":20,"is_preprint":false},{"pmid":"26969407","id":"PMC_26969407","title":"Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system.","date":"2016","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26969407","citation_count":18,"is_preprint":false},{"pmid":"16039909","id":"PMC_16039909","title":"T Lymphocytes transduced with a lentiviral vector expressing F12-Vif are protected from HIV-1 infection in an APOBEC3G-independent manner.","date":"2005","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/16039909","citation_count":17,"is_preprint":false},{"pmid":"6697235","id":"PMC_6697235","title":"Improved survival and differentiation of newborn and adult mouse neurons in F12 defined medium by fibronectin.","date":"1984","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/6697235","citation_count":17,"is_preprint":false},{"pmid":"32896690","id":"PMC_32896690","title":"Knockdown of liver-derived factor XII by GalNAc-siRNA ALN-F12 prevents thrombosis in mice without impacting hemostatic function.","date":"2020","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/32896690","citation_count":16,"is_preprint":false},{"pmid":"15257949","id":"PMC_15257949","title":"Homozygosity of the T allele of the 46 C-->T polymorphism in the F12 gene is a risk factor for acute coronary artery disease in the Spanish population.","date":"2004","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/15257949","citation_count":16,"is_preprint":false},{"pmid":"6339412","id":"PMC_6339412","title":"Isolation and characterization of F12 adhesive fimbrial antigen from uropathogenic Escherichia coli strains.","date":"1983","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/6339412","citation_count":16,"is_preprint":false},{"pmid":"26584372","id":"PMC_26584372","title":"Interaction Energy of Large Molecules from Restrained Denominator MP2-F12.","date":"2014","source":"Journal of chemical theory and computation","url":"https://pubmed.ncbi.nlm.nih.gov/26584372","citation_count":16,"is_preprint":false},{"pmid":"19211937","id":"PMC_19211937","title":"The F12-Vif derivative Chim3 inhibits HIV-1 replication in CD4+ T lymphocytes and CD34+-derived macrophages by blocking HIV-1 DNA integration.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19211937","citation_count":15,"is_preprint":false},{"pmid":"1654059","id":"PMC_1654059","title":"Immunohistochemical detection of two small cell lung carcinoma-associated antigens defined by MAbs F12 and 123C3 in bronchoscopy biopsy tissues.","date":"1991","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/1654059","citation_count":14,"is_preprint":false},{"pmid":"19415820","id":"PMC_19415820","title":"The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13 ) on the effectiveness of statins: the GenHAT study.","date":"2009","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19415820","citation_count":14,"is_preprint":false},{"pmid":"25028568","id":"PMC_25028568","title":"Fluorescence resonance energy transfer-based real-time polymerase chain reaction method without DNA extraction for the genotyping of F5, F2, F12, MTHFR, and HFE.","date":"2014","source":"Journal of blood medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25028568","citation_count":13,"is_preprint":false},{"pmid":"28631604","id":"PMC_28631604","title":"Vaccinia virus egress mediated by virus protein A36 is reliant on the F12 protein.","date":"2017","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/28631604","citation_count":9,"is_preprint":false},{"pmid":"31022435","id":"PMC_31022435","title":"Factor XII deficiency is common in domestic cats and associated with two high frequency F12 mutations.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/31022435","citation_count":9,"is_preprint":false},{"pmid":"19857112","id":"PMC_19857112","title":"Characterization of the epitope region of F1-2 and F1-5, two monoclonal antibodies to Botulinum neurotoxin type A.","date":"2009","source":"Hybridoma (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/19857112","citation_count":9,"is_preprint":false},{"pmid":"20346176","id":"PMC_20346176","title":"The Mediterranean Sea as a barrier to gene flow: evidence from variation in and around the F7 and F12 genomic regions.","date":"2010","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/20346176","citation_count":9,"is_preprint":false},{"pmid":"20814302","id":"PMC_20814302","title":"Influence of the F12 -4 C>T polymorphism on hemostatic tests.","date":"2010","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/20814302","citation_count":8,"is_preprint":false},{"pmid":"22677666","id":"PMC_22677666","title":"[Association study of polymorphic markers of F12, PON1, PON2, NOS2, PDE4D, HIF1a, GPIba, CYP11B2 genes with ischemic stroke in Russian patients].","date":"2012","source":"Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova","url":"https://pubmed.ncbi.nlm.nih.gov/22677666","citation_count":8,"is_preprint":false},{"pmid":"20729721","id":"PMC_20729721","title":"Novel deleterious mutation in the F12 gene in a Korean family with severe coagulation factor XII deficiency.","date":"2010","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/20729721","citation_count":6,"is_preprint":false},{"pmid":"28007010","id":"PMC_28007010","title":"Genetic analysis of a hereditary factor XII deficiency pedigree of a consanguineous marriage due to a homozygous F12 gene mutation: Gly341Arg.","date":"2016","source":"Hematology (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/28007010","citation_count":6,"is_preprint":false},{"pmid":"1701827","id":"PMC_1701827","title":"Growth and characterization of normal human keratinocytes in F12 serum-free medium.","date":"1990","source":"Journal of the Formosan Medical Association = Taiwan yi zhi","url":"https://pubmed.ncbi.nlm.nih.gov/1701827","citation_count":6,"is_preprint":false},{"pmid":"1360613","id":"PMC_1360613","title":"Nucleotide sequences of the major subunits of F9 and F12 fimbriae of uropathogenic Escherichia coli.","date":"1992","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/1360613","citation_count":6,"is_preprint":false},{"pmid":"25374149","id":"PMC_25374149","title":"Chordopoxvirus protein F12 implicated in enveloped virion morphogenesis is an inactivated DNA polymerase.","date":"2014","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/25374149","citation_count":5,"is_preprint":false},{"pmid":"20569426","id":"PMC_20569426","title":"High resolution mapping of trypanosomosis resistance loci Tir2 and Tir3 using F12 advanced intercross lines with major locus Tir1 fixed for the susceptible allele.","date":"2010","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/20569426","citation_count":5,"is_preprint":false},{"pmid":"19422815","id":"PMC_19422815","title":"Rapid triplex asymmetric real-time PCR hybridization probe assay for the joint genotyping of F2, F5 and F12.","date":"2009","source":"Clinical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19422815","citation_count":4,"is_preprint":false},{"pmid":"39910111","id":"PMC_39910111","title":"Mycochemistry, antioxidant, anticancer activity, and molecular docking of compounds of F12 of ethyl acetate extract of Astraeus asiaticus with BcL2 and Caspase 3.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39910111","citation_count":4,"is_preprint":false},{"pmid":"8810997","id":"PMC_8810997","title":"The non-producer phenotype of the human immunodeficiency virus type 1 provirus F12/HIV-1 is the result of multiple genetic variations.","date":"1996","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/8810997","citation_count":4,"is_preprint":false},{"pmid":"38167092","id":"PMC_38167092","title":"Photoinactivation of the bacteriophage PhiX174 by UVA radiation and visible light in SM buffer and DMEM-F12.","date":"2024","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/38167092","citation_count":2,"is_preprint":false},{"pmid":"34925717","id":"PMC_34925717","title":"Comparison of Rat Primary Midbrain Neurons Cultured in DMEM/F12 and Neurobasal Mediums.","date":"2021","source":"Basic and clinical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34925717","citation_count":2,"is_preprint":false},{"pmid":"29587641","id":"PMC_29587641","title":"The prevalence of heterozygous F12 mutations in Chinese population and its relevance to incidents of thrombosis.","date":"2018","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29587641","citation_count":2,"is_preprint":false},{"pmid":"33725261","id":"PMC_33725261","title":"Thrombin in the Activation of the Fluid Contact Phase in Patients with Hereditary Angioedema Carrying the F12 P.Thr309Lys Variant.","date":"2021","source":"Clinical reviews in allergy & immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33725261","citation_count":2,"is_preprint":false},{"pmid":"37750435","id":"PMC_37750435","title":"An evolutionary history of F12 gene: Emergence, loss, and vulnerability with the environment as a driver.","date":"2023","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37750435","citation_count":1,"is_preprint":false},{"pmid":"36972937","id":"PMC_36972937","title":"[Analysis of F12 gene variants and molecular mechanisms in patients with coagulation factor Ⅻ deficiency].","date":"2023","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36972937","citation_count":1,"is_preprint":false},{"pmid":"37994133","id":"PMC_37994133","title":"[Analysis of a Chinese pedigree affected with Hereditary coagulation factor Ⅻ deficiency due to compound heterozygous variants of F12 gene].","date":"2023","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37994133","citation_count":1,"is_preprint":false},{"pmid":"30959404","id":"PMC_30959404","title":"Antithrombotic Effect of shRNA Target F12 Mediated by Adeno-Associated Virus.","date":"2019","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/30959404","citation_count":1,"is_preprint":false},{"pmid":"32335876","id":"PMC_32335876","title":"[Identification of compound heterozygous variants of F12 gene in a pedigree affected with inherited coagulation factor XII deficiency].","date":"2020","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32335876","citation_count":1,"is_preprint":false},{"pmid":"38501782","id":"PMC_38501782","title":"Complete genome sequence of Bacillus pumilus F12-21, a halotolerant bacterium with antibacterial properties isolated from a Big Bone Lick State Park salt spring.","date":"2024","source":"Microbiology resource announcements","url":"https://pubmed.ncbi.nlm.nih.gov/38501782","citation_count":1,"is_preprint":false},{"pmid":"23054819","id":"PMC_23054819","title":"Two-stage cultivation of Pseudomonas sp. F12 for the production of enzymes converting DL-2-amino-Δ²-thiazoline-4-carboxylic acid to L-cysteine.","date":"2012","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/23054819","citation_count":1,"is_preprint":false},{"pmid":"40673203","id":"PMC_40673203","title":"Case Report: Two children with factor XII deficiency caused by novel F12 compound heterozygous variants.","date":"2025","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40673203","citation_count":1,"is_preprint":false},{"pmid":"38926981","id":"PMC_38926981","title":"[Pedigree Analysis of Hereditary Coagulation Factor XII Deficiency Caused by Compound Heterozygous Mutation p.Gly175Cys and p.Gly542Ser of F12 Gene].","date":"2024","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/38926981","citation_count":1,"is_preprint":false},{"pmid":"38057855","id":"PMC_38057855","title":"Homozygous missense variant F12 (Gly506Asp) associated with severe factor XII deficiency: a case report.","date":"2023","source":"Journal of medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/38057855","citation_count":0,"is_preprint":false},{"pmid":"37790745","id":"PMC_37790745","title":"Analysis of an Inherited FXII Deficiency Pedigree Associated with Double Heterozygous Mutations in the F12 Gene.","date":"2023","source":"Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/37790745","citation_count":0,"is_preprint":false},{"pmid":"41890722","id":"PMC_41890722","title":"Transmission of F12-related hereditary angioedema through a sperm donor.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41890722","citation_count":0,"is_preprint":false},{"pmid":"37730224","id":"PMC_37730224","title":"[Analysis of a Chinese pedigree affected with Hereditary FⅫ deficiency due to compound heterozygous variants of F12 gene].","date":"2023","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37730224","citation_count":0,"is_preprint":false},{"pmid":"37102287","id":"PMC_37102287","title":"[Genetic analysis of a Chinese pedigree affected with Congenital coagulation factor XII deficiency due to a c.1A>G start codon variant of F12 gene].","date":"2023","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37102287","citation_count":0,"is_preprint":false},{"pmid":"27773491","id":"PMC_27773491","title":"Papillophlebitis versus paediatric venous thrombosis. A case with 46C/T polymorphism in the F12 coagulation gene.","date":"2016","source":"Archivos de la Sociedad Espanola de Oftalmologia","url":"https://pubmed.ncbi.nlm.nih.gov/27773491","citation_count":0,"is_preprint":false},{"pmid":"32619258","id":"PMC_32619258","title":"[Analysis of a pedigree affected with hereditary coagulation factor XII deficiency due to a homozygous 252delAsn deletion of F12 gene].","date":"2020","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32619258","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.19.671127","title":"Neonatal Mouse Ovary Culture: An In Vitro Model for Studying Primordial Follicle Regulation","date":"2025-08-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.19.671127","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.31.673107","title":"Urinary exfoliated cells exhibit mesodermal lineage differentiation potential in the absence of dedicated culture conditions","date":"2025-09-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.31.673107","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.04.641411","title":"Lipid rafts are the new Stress Granules regulators","date":"2025-03-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.04.641411","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.30.635763","title":"Platform-dependent effects of genetic variants on plasma APOL1","date":"2025-02-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.30.635763","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.05.636623","title":"Treatment of human oocytes with extracellular vesicles from follicular fluid during rescue in vitro maturation enhances maturation rates and modulates oocyte proteome and ultrastructure","date":"2025-02-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.05.636623","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.18.613665","title":"Basal activation of astrocytic Nrf2 in neuronal culture media: challenges and implications for neuron-astrocyte modelling","date":"2024-09-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.18.613665","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45477,"output_tokens":3113,"usd":0.091563},"stage2":{"model":"claude-opus-4-6","input_tokens":6487,"output_tokens":2161,"usd":0.12969},"total_usd":0.221253,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1977,\n      \"finding\": \"Prothrombin activation in blood and plasma proceeds primarily through removal of the combined activation fragment F1-2 (representing the amino-terminal half of prothrombin) as a single peptide, accounting for at least 90% of prothrombin conversion; the separate F1 fragment represents a minor pathway (<10%).\",\n      \"method\": \"Rapid purification (DEAE-cellulose, hydroxyapatite chromatography), isotope dilution, amino acid composition, antigenic characterization, thrombin hydrolysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with multiple orthogonal characterization methods\",\n      \"pmids\": [\"410831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Specific gain-of-function mutations in the F12 gene (e.g., p.Thr309Lys/p.Thr328Lys) cause hereditary angioedema with normal C1-inhibitor (HAE-FXII) through increased FXII activation leading to excess bradykinin generation; estrogen exposure is a key modifier of clinical penetrance.\",\n      \"method\": \"Genetic analysis, family studies, clinical phenotyping, laboratory complement/coagulation assays\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple independent cohorts and labs with genetic and functional data\",\n      \"pmids\": [\"25952149\", \"25134986\", \"23994767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The HAE-FXII variant FXII309Lys (c.1032C>A) results in a glycosylation-deficient FXII with increased sensitivity to fluid-phase activation; thrombin cleaves FXII309Lys to release a 37-kDa heavy chain fragment, priming it for subsequent kallikrein cleavage and generation of active βFXIIa, linking hypercoagulable states to angioedema episodes.\",\n      \"method\": \"Western blot, amidolytic assay, recombinant protein expression in S2 insect cells, neuraminidase treatment, fibrin generation assay, plasma activation studies\",\n      \"journal\": \"Clinical reviews in allergy & immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with recombinant variants, multiple orthogonal functional assays\",\n      \"pmids\": [\"33725261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RNAi-mediated knockdown of liver-derived F12 mRNA (ALN-F12, GalNAc-siRNA) potently reduces plasma FXII levels in mice, rats, and non-human primates, and dose-dependently reduces vascular permeability in bradykinin-driven mouse models; ex vivo assays confirmed FXII-dependent HK cleavage and bradykinin generation.\",\n      \"method\": \"In vivo siRNA knockdown, ELISA for plasma FXII, vascular permeability models (Miles assay), ex vivo HK cleavage assay\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular/physiological phenotype, replicated across species and models\",\n      \"pmids\": [\"30463937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AAV-delivered shRNA targeting liver F12 mRNA reduces plasma FXII protein and provides dose-dependent protection against arterial and venous thrombosis in mice without affecting hemostasis (no increase in bleeding time or blood loss), establishing FXII's role in pathological but not hemostatic coagulation.\",\n      \"method\": \"AAV-shRNA knockdown in mice, ferric chloride arterial thrombosis model, electrolytic venous thrombosis model, saphenous vein and tail-transection bleeding models\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KO with multiple orthogonal thrombosis and hemostasis models\",\n      \"pmids\": [\"32896690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AAV-mediated shRNA targeting F12 effectively reduces FXII expression and inhibits thrombus formation in multiple mouse thrombosis models without causing hemorrhage, confirming FXII's role in thrombosis but not normal hemostasis.\",\n      \"method\": \"AAV-shRNA in vivo knockdown, coagulation function assays, tail bleeding, pathological sections\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with phenotypic readout, single lab\",\n      \"pmids\": [\"30959404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The F12 46C→T polymorphism (rs1801020) in exon 1 causes reduced plasma FXII levels in a gene-dosage manner; homozygosity for the T allele (T/T genotype) is an independent genetic risk factor for venous thrombosis (adjusted OR 4.82) and ischemic stroke (adjusted OR 4.1).\",\n      \"method\": \"Family-based linkage scan (GAIT Project), case-control genotyping, plasma FXII activity measurement\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple independent case-control studies with functional FXII level data\",\n      \"pmids\": [\"15116249\", \"15232129\", \"15257949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Bayesian quantitative trait nucleotide analysis of F12 re-sequencing identified that the rs1801020 (46C>T) variant alone accounts for the F12 QTL effect on plasma FXII levels; the T allele appeared ~100,000 years ago and spread by genetic drift.\",\n      \"method\": \"Re-sequencing of F12 in 40 individuals, genotyping of 26 SNPs in 398 family members (GAIT Project), measured genotype association analysis, Bayesian QTN analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large family-based study with comprehensive sequencing and statistical fine-mapping\",\n      \"pmids\": [\"19933701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The F12 -4C>T polymorphism (rs1801020) significantly prolongs aPTT and reduces thrombin generation (lower ETP, thrombin peak) in both patients and healthy controls in a gene-dosage manner; carriers also have significantly lower FIXc and FVIIc levels, demonstrating the downstream impact of FXII levels on the intrinsic coagulation pathway.\",\n      \"method\": \"Genotyping, plasma FXII activity, aPTT assay, calibrated automated thrombinography (CAT), factor assays in 566 participants\",\n      \"journal\": \"Blood coagulation & fibrinolysis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large cohort with multiple orthogonal coagulation assays\",\n      \"pmids\": [\"20814302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Polymorphisms at F12 (rs1801020) and KLKB1 (rs3733402) are associated with reduced active plasma renin; in vitro assays confirmed that kallikrein digests pro-renin to generate active renin, and active renin cleaves angiotensinogen to angiotensin-I; the F12 variant reduces FXII's ability to activate prekallikrein to kallikrein, thereby reducing renin activation.\",\n      \"method\": \"Cohort genotyping, in vitro recombinant pro-renin digestion assay, synthetic substrate assay for renin activity, co-localization by immunohistochemistry\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — combines genetic association with in vitro functional validation, single lab\",\n      \"pmids\": [\"26969407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Factor XII deficiency in domestic cats is caused by two high-frequency F12 mutations (exon 13 missense c.1631G>C and exon 11 deletion c.1321delC); residual FXII:C correlates with mutation number and type; deficient cats show no abnormal bleeding, consistent with FXII's dispensability for hemostasis.\",\n      \"method\": \"Retrospective phenotypic review, coagulation assays, F12 gene sequencing of 26 FXII-deficient cats\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — natural loss-of-function model with genotype-phenotype correlation across multiple animals\",\n      \"pmids\": [\"31022435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Missense variants p.Glu502Lys and p.Gly542Ser in the F12 gene reduce FXII secretion and activity: transfection of HEK293T cells with expression plasmids encoding these variants showed reduced FXII:C and FXII:Ag in supernatant and cell lysate compared to wild-type, demonstrating that these mutations impair FXII synthesis and secretion.\",\n      \"method\": \"Site-directed mutagenesis, transient transfection in 293T cells, FXII:C clotting assay, FXII:Ag ELISA, Western blot\",\n      \"journal\": \"Chinese journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro expression with mutagenesis and functional assays, single lab\",\n      \"pmids\": [\"32335876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"An evolutionary analysis established that F12 (encoding a serine protease with defense and hemostatic roles) emerged ~425 Mya in vertebrates, was secondarily lost in cetaceans during their transition to aquatic lifestyle, and has acquired new roles in pathological activation by blood-contacting devices and nanoparticles.\",\n      \"method\": \"Comparative genomics, phylogenetic analysis\",\n      \"journal\": \"BioEssays\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/evolutionary analysis only\",\n      \"pmids\": [\"37750435\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human F12 encodes coagulation Factor XII (Hageman factor), a plasma serine protease that initiates the contact activation pathway: upon surface or fluid-phase activation (including by the HAE-FXII gain-of-function variants sensitized to thrombin and kallikrein cleavage), active FXIIa drives the kallikrein-kinin system to generate bradykinin (causing angioedema) and activates the intrinsic coagulation cascade; the 46C>T promoter polymorphism reduces plasma FXII levels in a gene-dosage manner, prolonging aPTT and influencing thrombotic risk, while FXII knockdown (by siRNA or shRNA) prevents pathological thrombosis without impairing hemostasis, establishing FXII as dispensable for normal hemostasis but important for pathological thrombus formation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"F12 encodes coagulation Factor XII (Hageman factor), a plasma serine protease that initiates the contact activation pathway, driving both the intrinsic coagulation cascade and the kallikrein-kinin system to generate bradykinin. The 46C>T promoter polymorphism (rs1801020) reduces plasma FXII levels in a gene-dosage manner, prolonging aPTT and diminishing thrombin generation, and also attenuates kallikrein-mediated pro-renin activation [PMID:15116249, PMID:20814302, PMID:26969407]. Gain-of-function mutations such as p.Thr309Lys cause hereditary angioedema with normal C1-inhibitor (HAE-FXII) by producing a glycosylation-deficient FXII with increased sensitivity to thrombin and kallikrein cleavage, leading to excess bradykinin generation [PMID:25952149, PMID:33725261]. RNAi-mediated knockdown of F12 in vivo prevents pathological arterial and venous thrombosis without impairing hemostasis, establishing FXII as dispensable for normal hemostatic function but essential for pathological thrombus formation [PMID:30463937, PMID:32896690].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that a common F12 coding-region polymorphism (46C>T, rs1801020) quantitatively determines plasma FXII levels and influences thrombotic risk answered the question of whether genetic variation in FXII contributes to venous thrombosis and stroke.\",\n      \"evidence\": \"Family-based linkage scan (GAIT Project) and independent case-control genotyping with plasma FXII activity measurement\",\n      \"pmids\": [\"15116249\", \"15232129\", \"15257949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which reduced FXII paradoxically increases thrombotic risk was not explained\", \"Effect on arterial thrombosis versus venous thrombosis not fully dissected\", \"No functional assay demonstrating altered translation from the T allele\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Fine-mapping by Bayesian QTN analysis resolved the F12 QTL to rs1801020 as the sole causal nucleotide governing plasma FXII levels, ruling out other linked variants.\",\n      \"evidence\": \"Re-sequencing of F12 locus in 40 individuals, genotyping 26 SNPs in 398 GAIT family members with measured genotype analysis\",\n      \"pmids\": [\"19933701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of translational or transcriptional regulation by the 46C>T variant not demonstrated\", \"Population-level replication outside the GAIT cohort limited\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that rs1801020 gene-dosage reduction of FXII propagates downstream to reduce thrombin generation (ETP, peak), FIXc, and FVIIc established FXII as a rate-limiting initiator of the intrinsic pathway in vivo.\",\n      \"evidence\": \"Calibrated automated thrombinography and coagulation factor assays in 566 participants stratified by genotype\",\n      \"pmids\": [\"20814302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether reduced thrombin generation explains the paradoxical thrombotic risk of low FXII remains unresolved\", \"No intervention study to confirm causality\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of gain-of-function F12 mutations (p.Thr309Lys) as causative for hereditary angioedema with normal C1-inhibitor (HAE-FXII) answered how FXII hyperactivation links to bradykinin-mediated vascular permeability in humans.\",\n      \"evidence\": \"Genetic analysis and family studies across multiple independent cohorts with clinical phenotyping\",\n      \"pmids\": [\"25952149\", \"25134986\", \"23994767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Estrogen's mechanism in modifying clinical penetrance was not delineated at the molecular level\", \"Whether other HAE-FXII variants operate by the same mechanism was unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connecting the F12 rs1801020 variant to reduced plasma active renin via diminished FXII-driven prekallikrein activation broadened FXII's physiological role beyond coagulation to the renin-angiotensin system.\",\n      \"evidence\": \"Cohort genotyping combined with in vitro recombinant pro-renin digestion assay and kallikrein activity assays\",\n      \"pmids\": [\"26969407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of FXII–kallikrein–prorenin axis not performed\", \"Quantitative contribution of FXII to renin homeostasis versus other activation pathways unclear\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"RNAi and shRNA knockdown of hepatic F12 in multiple species demonstrated that reducing circulating FXII prevents thrombosis without impairing hemostasis, answering whether FXII is a safe antithrombotic target.\",\n      \"evidence\": \"GalNAc-siRNA (ALN-F12) in mice, rats, and non-human primates; AAV-shRNA in mouse FeCl3 arterial and electrolytic venous thrombosis models with tail-bleeding controls\",\n      \"pmids\": [\"30463937\", \"30959404\", \"32896690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Efficacy and safety of FXII knockdown in humans not yet established\", \"Long-term consequences of sustained FXII depletion (infection susceptibility, wound healing) not assessed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Biochemical reconstitution of the HAE-FXII variant FXII309Lys revealed the molecular mechanism: loss of an O-glycan increases sensitivity to thrombin priming cleavage, generating a 37-kDa heavy chain that is then fully activated by kallikrein to βFXIIa, linking hypercoagulable states to angioedema.\",\n      \"evidence\": \"Recombinant wild-type and variant FXII expressed in S2 cells, Western blot, amidolytic assays, neuraminidase treatment, fibrin generation assay\",\n      \"pmids\": [\"33725261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how glycan loss exposes the thrombin cleavage site not resolved\", \"Whether pharmacological glycosylation rescue could treat HAE-FXII not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for FXII surface activation, the full repertoire of physiological FXII activators in vivo, and whether FXII inhibition/knockdown is safe and effective as an antithrombotic or anti-angioedema therapy in humans remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of full-length FXII in active or zymogen form\", \"In vivo FXII activating surfaces in physiology versus pathology not systematically defined\", \"Human clinical trial data for FXII-targeted therapeutics not available in this literature\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3, 4, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 4, 6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 4, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KLKB1\",\n      \"F2\",\n      \"SERPING1\",\n      \"KNG1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}