Affinage

FGB

Fibrinogen beta chain · UniProt P02675

Length
491 aa
Mass
55.9 kDa
Annotated
2026-06-09
43 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 High

    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

    PMID:12511408 PMID:12893758

    Open questions at the time
    • The intracellular trafficking step or quality-control machinery retaining the assembled mutant is not identified
    • Single-lab reconstitution without independent replication
  2. 2009 High

    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

    PMID:18853456

    Open questions at the time
    • 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
  3. 2013 Medium

    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

    PMID:20580695 PMID:23266225 PMID:24103871

    Open questions at the time
    • NMD of aberrant transcripts inferred but not directly measured for all variants
    • Assembly intermediate identity in frameshift case not structurally resolved
  4. 2011 Medium

    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

    PMID:21301788

    Open questions at the time
    • Molecular basis of reduced endothelial interaction not defined
    • Single patient/single-lab functional characterization
  5. 2019 Medium

    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

    PMID:31201813

    Open questions at the time
    • STAT3 binding site within the FGB promoter not mapped
    • Relevance of this regulation to hepatic fibrinogen production versus tumor context unclear
    • Single-lab study
  6. 2020 Medium

    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

    PMID:32871307

    Open questions at the time
    • Quantitative contribution of each allele to plasma phenotype not dissected
    • Structural basis of delayed lateral aggregation not resolved
  7. 2022 Medium

    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*

    PMID:35054908

    Open questions at the time
    • Mechanism by which A68S impairs fibrinopeptide B release without structural change is undefined
    • Patient-derived material rather than purified recombinant variants
  8. 2016 Low

    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

    PMID:27824214

    Open questions at the time
    • Computational prediction only, no experimental validation of secretion impairment
    • Proposed chaperone interference unconfirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-109582 Hemostasis 3 R-HSA-74160 Gene expression (Transcription) 1
Partners
FGAFGGSTAT3
Complex memberships
fibrinogen

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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). Minigene transfection, site-directed mutagenesis, antisense oligonucleotide treatment, RT-PCR Human mutation High 18853456
2003 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. Recombinant co-expression of mutant and wild-type fibrinogen chains in cell culture, Western blot / ELISA of media vs. cell lysates Blood High 12511408
2003 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. Recombinant co-expression of mutant FGB with wild-type FGA/FGG cDNAs, measurement of secretion into culture media Blood High 12893758
2013 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. Minigene transfection into CHO cells, RT-PCR, agarose gel electrophoresis, nucleotide sequencing Clinica chimica acta Medium 20580695
2013 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. SDS-PAGE, RP-HPLC, ESI-MS, laser scanning confocal microscopy, fibrin porosity and elasticity assays Blood cells, molecules & diseases Medium 23266225
2013 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. Transfection of wild-type and mutant FGB constructs into COS-7 cells, Western blot (reducing and non-reducing), ELISA of media and cell lysates Zhonghua xueyexue zazhi Medium 24103871
2011 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. Turbidimetry, permeation assay, scanning electron microscopy, viscoelasticity measurement, confocal laser microscopy with endothelial cell monolayer Thrombosis and haemostasis Medium 21301788
2019 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. Luciferase reporter assay, co-immunoprecipitation, Western blot, stable transfection, in vitro and in vivo proliferation assays Experimental cell research Medium 31201813
2020 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. Minigene transfection into CHO cells, RT-PCR, recombinant expression of Bβ N170K variant, thrombin-catalyzed fibrin polymerization assay, Western blot Thrombosis research Medium 32871307
2022 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. Fibrin polymerization turbidimetry, reverse-phase HPLC fibrinopeptide release assay, scanning electron microscopy, homology protein modeling International journal of molecular sciences Medium 35054908
2016 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. In silico structural modeling, conservation analysis Hamostaseologie Low 27824214

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 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. International journal of molecular sciences 55 32610551
2009 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. Human mutation 54 18853456
2003 Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family. Blood 42 12511408
2003 Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion. Blood 37 12893758
2019 SIRT1 downregulated FGB expression to inhibit RCC tumorigenesis by destabilizing STAT3. Experimental cell research 35 31201813
2019 FGB and FGG derived from plasma exosomes as potential biomarkers to distinguish benign from malignant pulmonary nodules. Clinical and experimental medicine 31 31576477
2012 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. Molecular biology reports 31 23129316
2020 A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype. Biomedicines 27 33322159
2014 FGB mutations leading to congenital quantitative fibrinogen deficiencies: an update and report of four novel mutations. Thrombosis research 24 24560896
2013 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. Thrombosis and haemostasis 23 24352576
2017 Protein modelling to understand FGB mutations leading to congenital hypofibrinogenaemia. Haemophilia : the official journal of the World Federation of Hemophilia 20 28306188
2006 TagSNP evaluation for the association of 42 inflammation loci and vascular disease: evidence of IL6, FGB, ALOX5, NFKBIA, and IL4R loci effects. Human genetics 17 17115186
2022 Structural and Functional Characterization of Four Novel Fibrinogen Mutations in FGB Causing Congenital Fibrinogen Disorder. International journal of molecular sciences 9 35054908
2010 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. Clinica chimica acta; international journal of clinical chemistry 9 20580695
2006 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. Atherosclerosis 9 16697386
2023 Circ_16601 facilitates Hippo pathway signaling via the miR-5580-5p/FGB axis to promote my-CAF recruitment in the TME and LUAD progression. Respiratory research 7 37953225
2022 miR-139-5p Suppresses Proliferation and Angiogenesis of Intracranial Aneurysm via FGB. Journal of healthcare engineering 7 35469231
2022 miR-877-5p Inhibits Epithelial Mesenchymal Transformation of Breast Cancer Cells by Targeting FGB. Disease markers 7 36438895
2012 Combined congenital dysfibrinogenemia and factor VII deficiency from mutations in the FGB and F7 genes. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 7 22576285
2011 A novel missense mutation in the FGB g. 3354 T>A (p. Y41N), fibrinogen Caracas VIII. Thrombosis and haemostasis 6 21301788
2020 Congenital fibrinogen disorder with a compound heterozygote possessing two novel FGB mutations, one qualitative and the other quantitative. Thrombosis research 5 32871307
2017 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. Journal of thrombosis and thrombolysis 5 27812779
2012 A novel mutation in the FGB: c.1105C>T turns the codon for amino acid Bβ Q339 into a stop codon causing hypofibrinogenemia. Blood cells, molecules & diseases 5 23266225
2019 Phenotypic and genetic analysis of hypofibrinogenemia because of a novel missense mutation in the FGB: Leu121Arg. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 4 31259773
2015 Association between the FGB gene polymorphism and ischemic stroke: a meta-analysis. Genetics and molecular research : GMR 3 25867317
2004 [Relationship between fibrinogen B beta gene FGB -455G/A polymorphism and atherosclerotic cerebral infarction]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 3 15300640
2020 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. Haemophilia : the official journal of the World Federation of Hemophilia 2 33245842
2016 A novel missense mutation in the FGB gene (p.Gly302Arg) leading to afibrinogenemia. Predicted structure and function consequences. Hamostaseologie 2 27824214
2014 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. Genetic testing and molecular biomarkers 2 24720800
2025 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. Hamostaseologie 1 40774334
2021 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. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 1 34523592
2020 Congenital fibrinogen disorder caused by digenic mutations of the FGA and FGB genes. Hematology (Amsterdam, Netherlands) 1 32228225
2020 Genetic Analysis of Afibrinogenemia and Hypofibrinogenemia: Novel Mutations in the FGB Gene in the Turkish Population. Acta haematologica 1 32289806
2004 [Association of polymorphic marker G(-455)A of gene FGB with coronary artery disease]. Genetika 1 15575509
2026 Congenital hypofibrinogenemia with bleeding risk: mutations in the FGA, FGB, and FGG genes. Laboratory medicine 0 41233956
2025 A heterozygous nonsense mutation in the FGB gene (c.1299G > A) causes congenital fibrinogen disorder across four consecutive generations. Thrombosis journal 0 40506718
2025 Antiviral Intervention of COVID-19: Linkage of Disease Severity with Genetic Markers FGB (rs1800790), NOS3 (rs2070744) and TMPRSS2 (rs12329760). Viruses 0 40573382
2025 Quantitative proteomic and glycoproteomic analysis identifies CLCA1, FBN1, and FGB as potential biomarkers for ulcerative colitis. RSC advances 0 41090172
2024 Identification of the FGB gene polymorphism and analysis of its association with fat deposition traits in Hu sheep. Animal biotechnology 0 38669223
2022 [Analysis of two pedigrees affected with inherited dysfibrinogenemia due to a novel c.1115 T>A variant of the FGB gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 35773760
2021 Congenital Hypofibrinogenemia in a Neonate with a Novel Mutation in the FGB Gene. Pediatric reports 0 33804389
2013 [Congenital afibrinogenemia caused by a novel insertion mutation in the FGB gene]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 0 24103871
2010 [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]. Molekuliarnaia biologiia 0 20873219

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