{"gene":"FGB","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2009,"finding":"A deep intronic point mutation (FGB c.115-600A>G) in intron 1 creates a consensus heptad motif recognized by SF2/ASF splicing factor, causing inclusion of a 50-bp cryptic exon. The aberrant mRNA encodes a truncated Bβ chain that prevents fibrinogen synthesis. Introducing a second mutation into the enhancer motif abolished SF2/ASF binding and restored normal splicing. Antisense morpholino oligonucleotides blocked the protein-RNA interaction and restored normal splicing (~50% at 2 µM, ~90% at 10 µM).","method":"Minigene transfection, site-directed mutagenesis, antisense oligonucleotide treatment, RT-PCR","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro mutagenesis, functional rescue, and antisense correction all in one study with rigorous controls","pmids":["18853456"],"is_preprint":false},{"year":2003,"finding":"Nonsense mutation W467X in FGB produces a truncated Bβ chain; coexpression of mutant FGB cDNA with wild-type FGA and FGG cDNAs showed that fibrinogen molecules containing the truncated Bβ chain are not secreted into the culture medium, establishing that this mutation causes afibrinogenemia through failure of fibrinogen secretion.","method":"Recombinant co-expression of mutant and wild-type fibrinogen chains in cell culture, Western blot / ELISA of media vs. cell lysates","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in cell system with direct secretion assay, single lab but multiple orthogonal methods","pmids":["12511408"],"is_preprint":false},{"year":2003,"finding":"Missense mutation G444S in the C-terminal region of FGB allows fibrinogen assembly but prevents secretion. Coexpression of FGB-G444S with wild-type FGA and FGG showed fibrinogen molecules containing the mutant Bβ chain assemble but are retained intracellularly and not secreted.","method":"Recombinant co-expression of mutant FGB with wild-type FGA/FGG cDNAs, measurement of secretion into culture media","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution assay distinguishing assembly from secretion, single lab, two orthogonal readouts","pmids":["12893758"],"is_preprint":false},{"year":2013,"finding":"FGB IVS6 deletion of 4 nucleotides causes aberrant mRNA splicing: RT-PCR of CHO-transfected minigene showed inclusion of both introns 6 and 7 in the aberrant transcript. The resulting aberrant mRNA is predicted to undergo nonsense-mediated decay or produce a non-secreted variant chain, reducing plasma fibrinogen levels.","method":"Minigene transfection into CHO cells, RT-PCR, agarose gel electrophoresis, nucleotide sequencing","journal":"Clinica chimica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene functional assay with sequence confirmation, single lab, two methods","pmids":["20580695"],"is_preprint":false},{"year":2013,"finding":"Nonsense mutation FGB c.1105C>T (Bβ Q339Stop) causes deletion of Bβ residues 339–461; SDS-PAGE and RP-HPLC of purified plasma fibrinogen showed only normal-sized Bβ chain, establishing that fibrinogen molecules carrying the truncated chain are not secreted. Functional analyses revealed impaired fibrin polymerization, increased fibrin porosity, and reduced elasticity in the patient's plasma.","method":"SDS-PAGE, RP-HPLC, ESI-MS, laser scanning confocal microscopy, fibrin porosity and elasticity assays","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods, single lab","pmids":["23266225"],"is_preprint":false},{"year":2013,"finding":"Novel homozygous GTTT insertion in FGB exon 2 (between nucleotides 2833 and 2834) causes a frameshift; Western blot showed abnormal intracellular fibrinogen assembly (high-molecular-weight species) and absence of secreted fibrinogen in COS-7 cell culture media, while ELISA showed no significant difference in intracellular fibrinogen levels compared to wild-type, establishing that this mutation impairs assembly and secretion.","method":"Transfection of wild-type and mutant FGB constructs into COS-7 cells, Western blot (reducing and non-reducing), ELISA of media and cell lysates","journal":"Zhonghua xueyexue zazhi","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstitution in cell system, multiple orthogonal methods (WB + ELISA), single lab","pmids":["24103871"],"is_preprint":false},{"year":2011,"finding":"Missense mutation Bβ Y41N (fibrinogen Caracas VIII) in FGB impairs fibrin polymerization: plasma permeation (Darcy constant ~4x normal), increased clot pore size by scanning electron microscopy, thicker fibers (148 nm vs 120 nm controls), reduced storage modulus, and diminished interaction with endothelial cell monolayers by confocal microscopy. This establishes a role for the amino-terminal end of the Bβ chain in fibrin polymerization and clot organisation on endothelial surfaces.","method":"Turbidimetry, permeation assay, scanning electron microscopy, viscoelasticity measurement, confocal laser microscopy with endothelial cell monolayer","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional and structural assays on patient plasma, single lab","pmids":["21301788"],"is_preprint":false},{"year":2019,"finding":"SIRT1 represses FGB expression by deacetylating STAT3, leading to STAT3 destabilization and degradation; luciferase reporter assay confirmed FGB is a direct transcriptional target of STAT3. Co-immunoprecipitation confirmed SIRT1-STAT3 interaction. SIRT1 overexpression reduced FGB levels, and FGB overexpression rescued the anti-proliferative effect of SIRT1 overexpression in RCC cells in vitro and in vivo.","method":"Luciferase reporter assay, co-immunoprecipitation, Western blot, stable transfection, in vitro and in vivo proliferation assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional rescue, reporter assay, and Co-IP, single lab","pmids":["31201813"],"is_preprint":false},{"year":2020,"finding":"Compound heterozygous FGB mutations: a 35-bp deletion (c.1245-17_1262del) causes two aberrant mRNA products by aberrant splicing demonstrated in a CHO minigene system, leading to nonsense-mediated mRNA decay and hypofibrinogenemia; the missense mutation Bβ N170K (c.510T>A) on the other allele produces a fibrinogen that is normally secreted but causes dysfibrinogenemia by delaying lateral aggregation as shown by thrombin-catalyzed fibrin polymerization assay on purified patient fibrinogen.","method":"Minigene transfection into CHO cells, RT-PCR, recombinant expression of Bβ N170K variant, thrombin-catalyzed fibrin polymerization assay, Western blot","journal":"Thrombosis research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — minigene splicing assay plus recombinant expression plus functional polymerization assay, single lab","pmids":["32871307"],"is_preprint":false},{"year":2022,"finding":"Four FGB missense/nonsense mutations (BβY416C, BβA68S, BβY345*, BβW403*) cause congenital fibrinogen disorders through distinct mechanisms: BβA68S impairs fibrinopeptide B release (measured by RP-HPLC); BβY416C and BβW403* alter plasmin-induced fibrin degradation kinetics; all four mutations alter fibrin polymerization (decreased maximal absorbance) and clot fiber morphology (scanning electron microscopy shows altered fiber thickness and density). Homology modeling of BβA68S shows negligible structural alteration, suggesting the fibrinopeptide B release impairment is functional rather than structural.","method":"Fibrin polymerization turbidimetry, reverse-phase HPLC fibrinopeptide release assay, scanning electron microscopy, homology protein modeling","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays on patient material, single lab","pmids":["35054908"],"is_preprint":false},{"year":2016,"finding":"Missense mutation Bβ Gly272Arg (p.Gly302Arg) in FGB causes afibrinogenemia; in silico structural analysis locates the substitution in a highly conserved region critical for the core fold of the C-terminal β-chain, predicting disruption of core fold via interactions with adjacent acidic residues (Asp291, Asp297, Asp311) or interference with molecular chaperone action, leading to impaired secretion of the Bβ chain.","method":"In silico structural modeling, conservation analysis","journal":"Hamostaseologie","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation of the proposed mechanism","pmids":["27824214"],"is_preprint":false}],"current_model":"FGB encodes the fibrinogen Bβ chain, the rate-limiting subunit in hepatic fibrinogen hexamer assembly; loss-of-function mutations (nonsense, frameshift, splice-site, or specific missense mutations in the C-terminal β-nodule) impair either intracellular assembly or secretion of the fibrinogen molecule, causing afibrinogenemia or hypofibrinogenemia, while other missense mutations (e.g., Bβ Y41N, Bβ N170K, Bβ A68S) produce dysfunctional fibrinogen with impaired fibrinopeptide B release, defective lateral aggregation, or abnormal clot architecture; at the transcriptional level, FGB is a direct STAT3 target gene whose expression is repressed by SIRT1-mediated deacetylation and destabilization of STAT3."},"narrative":{"mechanistic_narrative":"FGB encodes the fibrinogen Bβ chain, a subunit required for assembly and secretion of the hepatic fibrinogen molecule and for normal fibrin clot formation [PMID:12511408, PMID:23266225]. Bβ is the limiting partner in assembly with the FGA and FGG chains: nonsense (W467X) and missense (G444S) mutations permit or block intracellular assembly but in both cases abolish secretion of the assembled molecule, while a frameshift insertion produces abnormal high-molecular-weight intracellular species and no secreted protein, establishing distinct loss-of-function mechanisms underlying afibrinogenemia [PMID:12511408, PMID:12893758, PMID:24103871]. Splicing defects constitute a second route to deficiency: a deep intronic mutation creates an SF2/ASF-dependent cryptic exon, and other intronic and deletion mutations drive aberrant transcripts subject to nonsense-mediated decay, reducing plasma fibrinogen in hypofibrinogenemia [PMID:18853456, PMID:20580695, PMID:32871307]. A separate class of secretion-competent missense variants yields dysfunctional fibrinogen: amino-terminal Bβ Y41N and Bβ N170K impair fibrin polymerization and delay lateral aggregation, while Bβ A68S impairs fibrinopeptide B release, collectively producing altered clot fiber architecture, porosity, and viscoelasticity [PMID:21301788, PMID:32871307, PMID:35054908]. At the transcriptional level FGB is a direct STAT3 target gene whose expression is repressed when SIRT1 deacetylates and destabilizes STAT3 [PMID:31201813].","teleology":[{"year":2003,"claim":"Established that distinct FGB mutations cause afibrinogenemia by blocking fibrinogen secretion either before or after chain assembly, separating assembly competence from secretion competence as independent failure points.","evidence":"Co-expression of mutant FGB (W467X nonsense; G444S missense) with wild-type FGA/FGG in cultured cells, secretion assays of media versus lysate","pmids":["12511408","12893758"],"confidence":"High","gaps":["The intracellular trafficking step or quality-control machinery retaining the assembled mutant is not identified","Single-lab reconstitution without independent replication"]},{"year":2009,"claim":"Demonstrated that a deep intronic FGB mutation causes deficiency by an RNA splicing mechanism, recruiting SF2/ASF to a cryptic enhancer, and showed antisense correction is feasible.","evidence":"Minigene transfection, site-directed mutagenesis abolishing the enhancer, and antisense morpholino rescue with RT-PCR readout","pmids":["18853456"],"confidence":"High","gaps":["Therapeutic antisense correction shown only in minigene/cell context, not in vivo or in patient hepatocytes","Does not address whether the truncated protein has any residual effect beyond loss of synthesis"]},{"year":2013,"claim":"Extended the splicing and truncation failure modes to additional intronic and nonsense mutations, linking aberrant transcripts to NMD or non-secreted truncated chains and to measurable clot architectural defects.","evidence":"Minigene RT-PCR in CHO cells; SDS-PAGE/RP-HPLC/ESI-MS of patient fibrinogen plus fibrin porosity and elasticity assays","pmids":["20580695","23266225","24103871"],"confidence":"Medium","gaps":["NMD of aberrant transcripts inferred but not directly measured for all variants","Assembly intermediate identity in frameshift case not structurally resolved"]},{"year":2011,"claim":"Identified the amino-terminal end of the Bβ chain as functionally required for fibrin polymerization and clot organization on endothelial surfaces, defining a dysfibrinogenemia mechanism in secretion-competent variants.","evidence":"Patient-plasma turbidimetry, permeation/Darcy, scanning electron microscopy, viscoelasticity, and confocal imaging on endothelial monolayers for Bβ Y41N","pmids":["21301788"],"confidence":"Medium","gaps":["Molecular basis of reduced endothelial interaction not defined","Single patient/single-lab functional characterization"]},{"year":2019,"claim":"Placed FGB downstream of a transcriptional control axis, showing it is a direct STAT3 target repressed via SIRT1-mediated STAT3 deacetylation and destabilization, with functional consequences for cell proliferation.","evidence":"Luciferase reporter, SIRT1-STAT3 co-immunoprecipitation, Western blot, and reciprocal overexpression/rescue proliferation assays in RCC cells in vitro and in vivo","pmids":["31201813"],"confidence":"Medium","gaps":["STAT3 binding site within the FGB promoter not mapped","Relevance of this regulation to hepatic fibrinogen production versus tumor context unclear","Single-lab study"]},{"year":2020,"claim":"Showed compound heterozygosity can combine a splicing/NMD null allele with a secretion-competent missense allele, the latter causing dysfibrinogenemia by delayed lateral aggregation, clarifying how mixed deficiency-plus-dysfunction phenotypes arise.","evidence":"CHO minigene splicing assay for the 35-bp deletion plus recombinant expression and thrombin-catalyzed polymerization of Bβ N170K","pmids":["32871307"],"confidence":"Medium","gaps":["Quantitative contribution of each allele to plasma phenotype not dissected","Structural basis of delayed lateral aggregation not resolved"]},{"year":2022,"claim":"Resolved that different Bβ missense/nonsense variants act through mechanistically distinct steps — fibrinopeptide B release, plasmin-mediated degradation kinetics, and polymerization/fiber morphology — and that functional impairment can occur without detectable structural change.","evidence":"Turbidimetry, RP-HPLC fibrinopeptide release, scanning electron microscopy, and homology modeling for Bβ Y416C, A68S, Y345*, W403*","pmids":["35054908"],"confidence":"Medium","gaps":["Mechanism by which A68S impairs fibrinopeptide B release without structural change is undefined","Patient-derived material rather than purified recombinant variants"]},{"year":2016,"claim":"Proposed that a conserved C-terminal β-nodule substitution disrupts the core fold and impairs Bβ secretion, offering a structural rationale for afibrinogenemia.","evidence":"In silico structural modeling and conservation analysis of Bβ Gly272Arg","pmids":["27824214"],"confidence":"Low","gaps":["Computational prediction only, no experimental validation of secretion impairment","Proposed chaperone interference unconfirmed"]},{"year":null,"claim":"How Bβ chain folding and assembly are surveilled to determine secretion versus intracellular retention, and how the STAT3/SIRT1 transcriptional axis integrates with hepatic fibrinogen synthesis in vivo, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identification of the quality-control machinery distinguishing assembled-but-retained from secreted fibrinogen","STAT3 binding site on FGB unmapped","Physiological role of SIRT1-STAT3-FGB axis in normal liver not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,6,9]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,4,6]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[4,6,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7]}],"complexes":["fibrinogen"],"partners":["FGA","FGG","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02675","full_name":"Fibrinogen beta chain","aliases":[],"length_aa":491,"mass_kda":55.9,"function":"Cleaved by the protease thrombin to yield monomers which, together with fibrinogen alpha (FGA) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization. Was originally thought to be essential for platelet aggregation, based on in vitro studies using anticoagulated blood. However subsequent studies have shown that it is not absolutely required for thrombus formation in vivo. Enhances expression of SELP in activated platelets. Maternal fibrinogen is essential for successful pregnancy. Fibrin deposition is also associated with infection, where it protects against IFNG-mediated hemorrhage. May also facilitate the antibacterial immune response via both innate and T-cell mediated pathways","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P02675/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FGB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FGB","total_profiled":1310},"omim":[{"mim_id":"616004","title":"DYSFIBRINOGENEMIA, CONGENITAL","url":"https://www.omim.org/entry/616004"},{"mim_id":"614390","title":"PREGNANCY LOSS, RECURRENT, SUSCEPTIBILITY TO, 2; RPRGL2","url":"https://www.omim.org/entry/614390"},{"mim_id":"614057","title":"MICRO RNA 409; MIR409","url":"https://www.omim.org/entry/614057"},{"mim_id":"605776","title":"FIBRINOGEN-LIKE 1; FGL1","url":"https://www.omim.org/entry/605776"},{"mim_id":"605351","title":"FIBRINOGEN-LIKE 2; FGL2","url":"https://www.omim.org/entry/605351"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":16764.8}],"url":"https://www.proteinatlas.org/search/FGB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P02675","domains":[{"cath_id":"3.90.215.10","chopping":"240-485","consensus_level":"high","plddt":96.9833,"start":240,"end":485},{"cath_id":"1.20.5","chopping":"149-226","consensus_level":"medium","plddt":95.5323,"start":149,"end":226}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02675","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02675-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02675-F1-predicted_aligned_error_v6.png","plddt_mean":84.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FGB","jax_strain_url":"https://www.jax.org/strain/search?query=FGB"},"sequence":{"accession":"P02675","fasta_url":"https://rest.uniprot.org/uniprotkb/P02675.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02675/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02675"}},"corpus_meta":[{"pmid":"32610551","id":"PMC_32610551","title":"Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32610551","citation_count":55,"is_preprint":false},{"pmid":"18853456","id":"PMC_18853456","title":"A deep intronic mutation in FGB creates a consensus exonic splicing enhancer motif that results in afibrinogenemia caused by aberrant mRNA splicing, which can be corrected in vitro with antisense oligonucleotide treatment.","date":"2009","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/18853456","citation_count":54,"is_preprint":false},{"pmid":"12511408","id":"PMC_12511408","title":"Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12511408","citation_count":42,"is_preprint":false},{"pmid":"12893758","id":"PMC_12893758","title":"Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12893758","citation_count":37,"is_preprint":false},{"pmid":"31201813","id":"PMC_31201813","title":"SIRT1 downregulated FGB expression to inhibit RCC tumorigenesis by destabilizing STAT3.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31201813","citation_count":35,"is_preprint":false},{"pmid":"23129316","id":"PMC_23129316","title":"Apo A5 -1131T/C, FgB -455G/A, -148C/T, and CETP TaqIB gene polymorphisms and coronary artery disease in the Chinese population: a meta-analysis of 15,055 subjects.","date":"2012","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23129316","citation_count":31,"is_preprint":false},{"pmid":"31576477","id":"PMC_31576477","title":"FGB and FGG derived from plasma exosomes as potential biomarkers to distinguish benign from malignant pulmonary nodules.","date":"2019","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31576477","citation_count":31,"is_preprint":false},{"pmid":"33322159","id":"PMC_33322159","title":"A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype.","date":"2020","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/33322159","citation_count":27,"is_preprint":false},{"pmid":"24560896","id":"PMC_24560896","title":"FGB mutations leading to congenital quantitative fibrinogen deficiencies: an update and report of four novel mutations.","date":"2014","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/24560896","citation_count":24,"is_preprint":false},{"pmid":"24352576","id":"PMC_24352576","title":"Benign FGB (148Lys→Asn, and 448Arg→Lys), and novel causative γ211Tyr→His mutation distinguished by time of flight mass spectrometry in a family with hypofibrinogenaemia.","date":"2013","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/24352576","citation_count":23,"is_preprint":false},{"pmid":"28306188","id":"PMC_28306188","title":"Protein modelling to understand FGB mutations leading to congenital hypofibrinogenaemia.","date":"2017","source":"Haemophilia : the official journal of the World Federation of Hemophilia","url":"https://pubmed.ncbi.nlm.nih.gov/28306188","citation_count":20,"is_preprint":false},{"pmid":"17115186","id":"PMC_17115186","title":"TagSNP evaluation for the association of 42 inflammation loci and vascular disease: evidence of IL6, FGB, ALOX5, NFKBIA, and IL4R loci effects.","date":"2006","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17115186","citation_count":17,"is_preprint":false},{"pmid":"20580695","id":"PMC_20580695","title":"In vitro transcription of compound heterozygous hypofibrinogenemia Matsumoto IX; first identification of FGB IVS6 deletion of 4 nucleotides and FGG IVS3-2A>G causing abnormal RNA splicing.","date":"2010","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20580695","citation_count":9,"is_preprint":false},{"pmid":"35054908","id":"PMC_35054908","title":"Structural and Functional Characterization of Four Novel Fibrinogen Mutations in FGB Causing Congenital Fibrinogen Disorder.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35054908","citation_count":9,"is_preprint":false},{"pmid":"16697386","id":"PMC_16697386","title":"Analysis of the effect of multiple genetic variants of cardiovascular disease risk on insulin concentration variability in healthy adults of the STANISLAS cohort. The role of FGB-455 G/A polymorphism.","date":"2006","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/16697386","citation_count":9,"is_preprint":false},{"pmid":"37953225","id":"PMC_37953225","title":"Circ_16601 facilitates Hippo pathway signaling via the miR-5580-5p/FGB axis to promote my-CAF recruitment in the TME and LUAD progression.","date":"2023","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/37953225","citation_count":7,"is_preprint":false},{"pmid":"35469231","id":"PMC_35469231","title":"miR-139-5p Suppresses Proliferation and Angiogenesis of Intracranial Aneurysm via FGB.","date":"2022","source":"Journal of healthcare engineering","url":"https://pubmed.ncbi.nlm.nih.gov/35469231","citation_count":7,"is_preprint":false},{"pmid":"36438895","id":"PMC_36438895","title":"miR-877-5p Inhibits Epithelial Mesenchymal Transformation of Breast Cancer Cells by Targeting FGB.","date":"2022","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/36438895","citation_count":7,"is_preprint":false},{"pmid":"22576285","id":"PMC_22576285","title":"Combined congenital dysfibrinogenemia and factor VII deficiency from mutations in the FGB and F7 genes.","date":"2012","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/22576285","citation_count":7,"is_preprint":false},{"pmid":"21301788","id":"PMC_21301788","title":"A novel missense mutation in the FGB g. 3354 T>A (p. Y41N), fibrinogen Caracas VIII.","date":"2011","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/21301788","citation_count":6,"is_preprint":false},{"pmid":"27812779","id":"PMC_27812779","title":"A novel mutation in exon 2 of FGB caused by c.221G>T † substitution, predicting the replacement of the native Arginine at position 74 with a Leucine (p.Arg74Leu † ) in a proband from a Kurdish family with dysfibrinogenaemia and familial venous and arterial thrombosis.","date":"2017","source":"Journal of thrombosis and thrombolysis","url":"https://pubmed.ncbi.nlm.nih.gov/27812779","citation_count":5,"is_preprint":false},{"pmid":"32871307","id":"PMC_32871307","title":"Congenital fibrinogen disorder with a compound heterozygote possessing two novel FGB mutations, one qualitative and the other quantitative.","date":"2020","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/32871307","citation_count":5,"is_preprint":false},{"pmid":"23266225","id":"PMC_23266225","title":"A novel mutation in the FGB: c.1105C>T turns the codon for amino acid Bβ Q339 into a stop codon causing hypofibrinogenemia.","date":"2012","source":"Blood cells, molecules & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23266225","citation_count":5,"is_preprint":false},{"pmid":"31259773","id":"PMC_31259773","title":"Phenotypic and genetic analysis of hypofibrinogenemia because of a novel missense mutation in the FGB: Leu121Arg.","date":"2019","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/31259773","citation_count":4,"is_preprint":false},{"pmid":"25867317","id":"PMC_25867317","title":"Association between the FGB gene polymorphism and ischemic stroke: a meta-analysis.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/25867317","citation_count":3,"is_preprint":false},{"pmid":"15300640","id":"PMC_15300640","title":"[Relationship between fibrinogen B beta gene FGB -455G/A polymorphism and atherosclerotic cerebral infarction].","date":"2004","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/15300640","citation_count":3,"is_preprint":false},{"pmid":"24720800","id":"PMC_24720800","title":"FGB gene - 148C>T polymorphism is associated with increased risk of ischemic stroke in a Chinese population: a meta-analysis based on 18 case-control studies.","date":"2014","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/24720800","citation_count":2,"is_preprint":false},{"pmid":"33245842","id":"PMC_33245842","title":"Afibrinogenemia caused by a novel homozygous missense mutation, FGB p.Cys241Tyr, in a male patient with recurrent intracranial bleeding: case report and review of literature.","date":"2020","source":"Haemophilia : the official journal of the World Federation of Hemophilia","url":"https://pubmed.ncbi.nlm.nih.gov/33245842","citation_count":2,"is_preprint":false},{"pmid":"27824214","id":"PMC_27824214","title":"A novel missense mutation in the FGB gene (p.Gly302Arg) leading to afibrinogenemia. Predicted structure and function consequences.","date":"2016","source":"Hamostaseologie","url":"https://pubmed.ncbi.nlm.nih.gov/27824214","citation_count":2,"is_preprint":false},{"pmid":"32289806","id":"PMC_32289806","title":"Genetic Analysis of Afibrinogenemia and Hypofibrinogenemia: Novel Mutations in the FGB Gene in the Turkish Population.","date":"2020","source":"Acta haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/32289806","citation_count":1,"is_preprint":false},{"pmid":"40774334","id":"PMC_40774334","title":"Recurrent Venous Thrombosis in a Hypofibrinogenemic Patient Despite a Heterozygous Deletion of the Fibrinogen Gene Cluster and Hemizygous FGB p.Pro265Leu Variant Mimicking a Homozygous Genotype.","date":"2025","source":"Hamostaseologie","url":"https://pubmed.ncbi.nlm.nih.gov/40774334","citation_count":1,"is_preprint":false},{"pmid":"32228225","id":"PMC_32228225","title":"Congenital fibrinogen disorder caused by digenic mutations of the FGA and FGB genes.","date":"2020","source":"Hematology (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/32228225","citation_count":1,"is_preprint":false},{"pmid":"34523592","id":"PMC_34523592","title":"Polymorphisms of F2 (G20210A), F5 (G1691A), F 7 (G10976A), F 13(G13T), FGB, ITGA2, ITGB3, PAI-I genes and its association with thrombotic complications in patients suffering from Takayasu aortoarteritis of Urals population.","date":"2021","source":"Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir","url":"https://pubmed.ncbi.nlm.nih.gov/34523592","citation_count":1,"is_preprint":false},{"pmid":"15575509","id":"PMC_15575509","title":"[Association of polymorphic marker G(-455)A of gene FGB with coronary artery disease].","date":"2004","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/15575509","citation_count":1,"is_preprint":false},{"pmid":"41090172","id":"PMC_41090172","title":"Quantitative proteomic and glycoproteomic analysis identifies CLCA1, FBN1, and FGB as potential biomarkers for ulcerative colitis.","date":"2025","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/41090172","citation_count":0,"is_preprint":false},{"pmid":"38669223","id":"PMC_38669223","title":"Identification of the FGB gene polymorphism and analysis of its association with fat deposition traits in Hu sheep.","date":"2024","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38669223","citation_count":0,"is_preprint":false},{"pmid":"33804389","id":"PMC_33804389","title":"Congenital Hypofibrinogenemia in a Neonate with a Novel Mutation in the FGB Gene.","date":"2021","source":"Pediatric reports","url":"https://pubmed.ncbi.nlm.nih.gov/33804389","citation_count":0,"is_preprint":false},{"pmid":"24103871","id":"PMC_24103871","title":"[Congenital afibrinogenemia caused by a novel insertion mutation in the FGB gene].","date":"2013","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/24103871","citation_count":0,"is_preprint":false},{"pmid":"40506718","id":"PMC_40506718","title":"A heterozygous nonsense mutation in the FGB gene (c.1299G > A) causes congenital fibrinogen disorder across four consecutive generations.","date":"2025","source":"Thrombosis journal","url":"https://pubmed.ncbi.nlm.nih.gov/40506718","citation_count":0,"is_preprint":false},{"pmid":"40573382","id":"PMC_40573382","title":"Antiviral Intervention of COVID-19: Linkage of Disease Severity with Genetic Markers FGB (rs1800790), NOS3 (rs2070744) and TMPRSS2 (rs12329760).","date":"2025","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/40573382","citation_count":0,"is_preprint":false},{"pmid":"35773760","id":"PMC_35773760","title":"[Analysis of two pedigrees affected with inherited dysfibrinogenemia due to a novel c.1115 T>A variant of the FGB gene].","date":"2022","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/35773760","citation_count":0,"is_preprint":false},{"pmid":"20873219","id":"PMC_20873219","title":"[Polymorphic markers G(-455)A of gene FGB and C(-1654)T of gene PROC and genetic predisposition to unfavorable outcomes patients undergoing acute coronary syndrome].","date":"2010","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/20873219","citation_count":0,"is_preprint":false},{"pmid":"41233956","id":"PMC_41233956","title":"Congenital hypofibrinogenemia with bleeding risk: mutations in the FGA, FGB, and FGG genes.","date":"2026","source":"Laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41233956","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23345,"output_tokens":3053,"usd":0.057915,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10555,"output_tokens":3062,"usd":0.064662,"stage2_stop_reason":"end_turn"},"total_usd":0.122577,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"A deep intronic point mutation (FGB c.115-600A>G) in intron 1 creates a consensus heptad motif recognized by SF2/ASF splicing factor, causing inclusion of a 50-bp cryptic exon. The aberrant mRNA encodes a truncated Bβ chain that prevents fibrinogen synthesis. Introducing a second mutation into the enhancer motif abolished SF2/ASF binding and restored normal splicing. Antisense morpholino oligonucleotides blocked the protein-RNA interaction and restored normal splicing (~50% at 2 µM, ~90% at 10 µM).\",\n      \"method\": \"Minigene transfection, site-directed mutagenesis, antisense oligonucleotide treatment, RT-PCR\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro mutagenesis, functional rescue, and antisense correction all in one study with rigorous controls\",\n      \"pmids\": [\"18853456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nonsense mutation W467X in FGB produces a truncated Bβ chain; coexpression of mutant FGB cDNA with wild-type FGA and FGG cDNAs showed that fibrinogen molecules containing the truncated Bβ chain are not secreted into the culture medium, establishing that this mutation causes afibrinogenemia through failure of fibrinogen secretion.\",\n      \"method\": \"Recombinant co-expression of mutant and wild-type fibrinogen chains in cell culture, Western blot / ELISA of media vs. cell lysates\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in cell system with direct secretion assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12511408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Missense mutation G444S in the C-terminal region of FGB allows fibrinogen assembly but prevents secretion. Coexpression of FGB-G444S with wild-type FGA and FGG showed fibrinogen molecules containing the mutant Bβ chain assemble but are retained intracellularly and not secreted.\",\n      \"method\": \"Recombinant co-expression of mutant FGB with wild-type FGA/FGG cDNAs, measurement of secretion into culture media\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution assay distinguishing assembly from secretion, single lab, two orthogonal readouts\",\n      \"pmids\": [\"12893758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FGB IVS6 deletion of 4 nucleotides causes aberrant mRNA splicing: RT-PCR of CHO-transfected minigene showed inclusion of both introns 6 and 7 in the aberrant transcript. The resulting aberrant mRNA is predicted to undergo nonsense-mediated decay or produce a non-secreted variant chain, reducing plasma fibrinogen levels.\",\n      \"method\": \"Minigene transfection into CHO cells, RT-PCR, agarose gel electrophoresis, nucleotide sequencing\",\n      \"journal\": \"Clinica chimica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene functional assay with sequence confirmation, single lab, two methods\",\n      \"pmids\": [\"20580695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nonsense mutation FGB c.1105C>T (Bβ Q339Stop) causes deletion of Bβ residues 339–461; SDS-PAGE and RP-HPLC of purified plasma fibrinogen showed only normal-sized Bβ chain, establishing that fibrinogen molecules carrying the truncated chain are not secreted. Functional analyses revealed impaired fibrin polymerization, increased fibrin porosity, and reduced elasticity in the patient's plasma.\",\n      \"method\": \"SDS-PAGE, RP-HPLC, ESI-MS, laser scanning confocal microscopy, fibrin porosity and elasticity assays\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods, single lab\",\n      \"pmids\": [\"23266225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Novel homozygous GTTT insertion in FGB exon 2 (between nucleotides 2833 and 2834) causes a frameshift; Western blot showed abnormal intracellular fibrinogen assembly (high-molecular-weight species) and absence of secreted fibrinogen in COS-7 cell culture media, while ELISA showed no significant difference in intracellular fibrinogen levels compared to wild-type, establishing that this mutation impairs assembly and secretion.\",\n      \"method\": \"Transfection of wild-type and mutant FGB constructs into COS-7 cells, Western blot (reducing and non-reducing), ELISA of media and cell lysates\",\n      \"journal\": \"Zhonghua xueyexue zazhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in cell system, multiple orthogonal methods (WB + ELISA), single lab\",\n      \"pmids\": [\"24103871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Missense mutation Bβ Y41N (fibrinogen Caracas VIII) in FGB impairs fibrin polymerization: plasma permeation (Darcy constant ~4x normal), increased clot pore size by scanning electron microscopy, thicker fibers (148 nm vs 120 nm controls), reduced storage modulus, and diminished interaction with endothelial cell monolayers by confocal microscopy. This establishes a role for the amino-terminal end of the Bβ chain in fibrin polymerization and clot organisation on endothelial surfaces.\",\n      \"method\": \"Turbidimetry, permeation assay, scanning electron microscopy, viscoelasticity measurement, confocal laser microscopy with endothelial cell monolayer\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional and structural assays on patient plasma, single lab\",\n      \"pmids\": [\"21301788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT1 represses FGB expression by deacetylating STAT3, leading to STAT3 destabilization and degradation; luciferase reporter assay confirmed FGB is a direct transcriptional target of STAT3. Co-immunoprecipitation confirmed SIRT1-STAT3 interaction. SIRT1 overexpression reduced FGB levels, and FGB overexpression rescued the anti-proliferative effect of SIRT1 overexpression in RCC cells in vitro and in vivo.\",\n      \"method\": \"Luciferase reporter assay, co-immunoprecipitation, Western blot, stable transfection, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional rescue, reporter assay, and Co-IP, single lab\",\n      \"pmids\": [\"31201813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Compound heterozygous FGB mutations: a 35-bp deletion (c.1245-17_1262del) causes two aberrant mRNA products by aberrant splicing demonstrated in a CHO minigene system, leading to nonsense-mediated mRNA decay and hypofibrinogenemia; the missense mutation Bβ N170K (c.510T>A) on the other allele produces a fibrinogen that is normally secreted but causes dysfibrinogenemia by delaying lateral aggregation as shown by thrombin-catalyzed fibrin polymerization assay on purified patient fibrinogen.\",\n      \"method\": \"Minigene transfection into CHO cells, RT-PCR, recombinant expression of Bβ N170K variant, thrombin-catalyzed fibrin polymerization assay, Western blot\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — minigene splicing assay plus recombinant expression plus functional polymerization assay, single lab\",\n      \"pmids\": [\"32871307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Four FGB missense/nonsense mutations (BβY416C, BβA68S, BβY345*, BβW403*) cause congenital fibrinogen disorders through distinct mechanisms: BβA68S impairs fibrinopeptide B release (measured by RP-HPLC); BβY416C and BβW403* alter plasmin-induced fibrin degradation kinetics; all four mutations alter fibrin polymerization (decreased maximal absorbance) and clot fiber morphology (scanning electron microscopy shows altered fiber thickness and density). Homology modeling of BβA68S shows negligible structural alteration, suggesting the fibrinopeptide B release impairment is functional rather than structural.\",\n      \"method\": \"Fibrin polymerization turbidimetry, reverse-phase HPLC fibrinopeptide release assay, scanning electron microscopy, homology protein modeling\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays on patient material, single lab\",\n      \"pmids\": [\"35054908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Missense mutation Bβ Gly272Arg (p.Gly302Arg) in FGB causes afibrinogenemia; in silico structural analysis locates the substitution in a highly conserved region critical for the core fold of the C-terminal β-chain, predicting disruption of core fold via interactions with adjacent acidic residues (Asp291, Asp297, Asp311) or interference with molecular chaperone action, leading to impaired secretion of the Bβ chain.\",\n      \"method\": \"In silico structural modeling, conservation analysis\",\n      \"journal\": \"Hamostaseologie\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation of the proposed mechanism\",\n      \"pmids\": [\"27824214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FGB encodes the fibrinogen Bβ chain, the rate-limiting subunit in hepatic fibrinogen hexamer assembly; loss-of-function mutations (nonsense, frameshift, splice-site, or specific missense mutations in the C-terminal β-nodule) impair either intracellular assembly or secretion of the fibrinogen molecule, causing afibrinogenemia or hypofibrinogenemia, while other missense mutations (e.g., Bβ Y41N, Bβ N170K, Bβ A68S) produce dysfunctional fibrinogen with impaired fibrinopeptide B release, defective lateral aggregation, or abnormal clot architecture; at the transcriptional level, FGB is a direct STAT3 target gene whose expression is repressed by SIRT1-mediated deacetylation and destabilization of STAT3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FGB encodes the fibrinogen Bβ chain, a subunit required for assembly and secretion of the hepatic fibrinogen molecule and for normal fibrin clot formation [#1, #4]. Bβ is the limiting partner in assembly with the FGA and FGG chains: nonsense (W467X) and missense (G444S) mutations permit or block intracellular assembly but in both cases abolish secretion of the assembled molecule, while a frameshift insertion produces abnormal high-molecular-weight intracellular species and no secreted protein, establishing distinct loss-of-function mechanisms underlying afibrinogenemia [#1, #2, #5]. Splicing defects constitute a second route to deficiency: a deep intronic mutation creates an SF2/ASF-dependent cryptic exon, and other intronic and deletion mutations drive aberrant transcripts subject to nonsense-mediated decay, reducing plasma fibrinogen in hypofibrinogenemia [#0, #3, #8]. A separate class of secretion-competent missense variants yields dysfunctional fibrinogen: amino-terminal Bβ Y41N and Bβ N170K impair fibrin polymerization and delay lateral aggregation, while Bβ A68S impairs fibrinopeptide B release, collectively producing altered clot fiber architecture, porosity, and viscoelasticity [#6, #8, #9]. At the transcriptional level FGB is a direct STAT3 target gene whose expression is repressed when SIRT1 deacetylates and destabilizes STAT3 [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that distinct FGB mutations cause afibrinogenemia by blocking fibrinogen secretion either before or after chain assembly, separating assembly competence from secretion competence as independent failure points.\",\n      \"evidence\": \"Co-expression of mutant FGB (W467X nonsense; G444S missense) with wild-type FGA/FGG in cultured cells, secretion assays of media versus lysate\",\n      \"pmids\": [\"12511408\", \"12893758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The intracellular trafficking step or quality-control machinery retaining the assembled mutant is not identified\", \"Single-lab reconstitution without independent replication\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that a deep intronic FGB mutation causes deficiency by an RNA splicing mechanism, recruiting SF2/ASF to a cryptic enhancer, and showed antisense correction is feasible.\",\n      \"evidence\": \"Minigene transfection, site-directed mutagenesis abolishing the enhancer, and antisense morpholino rescue with RT-PCR readout\",\n      \"pmids\": [\"18853456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic antisense correction shown only in minigene/cell context, not in vivo or in patient hepatocytes\", \"Does not address whether the truncated protein has any residual effect beyond loss of synthesis\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the splicing and truncation failure modes to additional intronic and nonsense mutations, linking aberrant transcripts to NMD or non-secreted truncated chains and to measurable clot architectural defects.\",\n      \"evidence\": \"Minigene RT-PCR in CHO cells; SDS-PAGE/RP-HPLC/ESI-MS of patient fibrinogen plus fibrin porosity and elasticity assays\",\n      \"pmids\": [\"20580695\", \"23266225\", \"24103871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NMD of aberrant transcripts inferred but not directly measured for all variants\", \"Assembly intermediate identity in frameshift case not structurally resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the amino-terminal end of the Bβ chain as functionally required for fibrin polymerization and clot organization on endothelial surfaces, defining a dysfibrinogenemia mechanism in secretion-competent variants.\",\n      \"evidence\": \"Patient-plasma turbidimetry, permeation/Darcy, scanning electron microscopy, viscoelasticity, and confocal imaging on endothelial monolayers for Bβ Y41N\",\n      \"pmids\": [\"21301788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of reduced endothelial interaction not defined\", \"Single patient/single-lab functional characterization\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed FGB downstream of a transcriptional control axis, showing it is a direct STAT3 target repressed via SIRT1-mediated STAT3 deacetylation and destabilization, with functional consequences for cell proliferation.\",\n      \"evidence\": \"Luciferase reporter, SIRT1-STAT3 co-immunoprecipitation, Western blot, and reciprocal overexpression/rescue proliferation assays in RCC cells in vitro and in vivo\",\n      \"pmids\": [\"31201813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"STAT3 binding site within the FGB promoter not mapped\", \"Relevance of this regulation to hepatic fibrinogen production versus tumor context unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed compound heterozygosity can combine a splicing/NMD null allele with a secretion-competent missense allele, the latter causing dysfibrinogenemia by delayed lateral aggregation, clarifying how mixed deficiency-plus-dysfunction phenotypes arise.\",\n      \"evidence\": \"CHO minigene splicing assay for the 35-bp deletion plus recombinant expression and thrombin-catalyzed polymerization of Bβ N170K\",\n      \"pmids\": [\"32871307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of each allele to plasma phenotype not dissected\", \"Structural basis of delayed lateral aggregation not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved that different Bβ missense/nonsense variants act through mechanistically distinct steps — fibrinopeptide B release, plasmin-mediated degradation kinetics, and polymerization/fiber morphology — and that functional impairment can occur without detectable structural change.\",\n      \"evidence\": \"Turbidimetry, RP-HPLC fibrinopeptide release, scanning electron microscopy, and homology modeling for Bβ Y416C, A68S, Y345*, W403*\",\n      \"pmids\": [\"35054908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which A68S impairs fibrinopeptide B release without structural change is undefined\", \"Patient-derived material rather than purified recombinant variants\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Proposed that a conserved C-terminal β-nodule substitution disrupts the core fold and impairs Bβ secretion, offering a structural rationale for afibrinogenemia.\",\n      \"evidence\": \"In silico structural modeling and conservation analysis of Bβ Gly272Arg\",\n      \"pmids\": [\"27824214\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only, no experimental validation of secretion impairment\", \"Proposed chaperone interference unconfirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Bβ chain folding and assembly are surveilled to determine secretion versus intracellular retention, and how the STAT3/SIRT1 transcriptional axis integrates with hepatic fibrinogen synthesis in vivo, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identification of the quality-control machinery distinguishing assembled-but-retained from secreted fibrinogen\", \"STAT3 binding site on FGB unmapped\", \"Physiological role of SIRT1-STAT3-FGB axis in normal liver not tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"fibrinogen\"],\n    \"partners\": [\"FGA\", \"FGG\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}