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FLASH GENE
Symbol F8 contributors: mct - updated : 22-02-2017
HGNC name coagulation factor VIII, procoagulant component (hemophilia A)
HGNC id 3546
Corresponding disease
F8D hemophilia A, F8 deficiency
Location Xq28      Physical location : 154.064.069 - 154.250.998
Synonym name
  • factor VIIIF8B
  • antihemophilic factor
  • DNA segment on chromosome X (unique) 1253 expressed
  • procoagulant component
  • Synonym symbol(s) F8CNSL, F8B, F8C, AHF, HEMA, DXS1253E, FVIII
    DNA
    TYPE functioning gene
    SPECIAL FEATURE opposite orientation
    text
  • opposite orientation of F8A and F8B in the intron 22
  • one F8A copy in intron 22
  • F8B in intron 22 for F8B first exon and spliced to exon 23-26 of F8 gene
  • STRUCTURE 186.94 kb     26 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence
    text structure X controlling element (XCE) functioning similarly to the mouse Xce
    MAPPING cloned Y linked Y status confirmed
    Map cen - DXS477 - DXS296 - IDS - DXS460 - DXS304 - DXS334 - DXS341 - DXS455 - DXS49 - DXS497 - DXS256 - DXS374 - DXS258 - DXS175 - GABRA3 - DXS1104 - DXS33 - DXS134 - DXS52 - DXS15 - BGN - ALD - L1CAM - AVPR2 - RGCP@ - DXS439 - UBL4 ,FLNA-RPL10 - G6PD - IKBKG - IP2 - DXS1073 - MPP1 - DKC1 DKC1 - F8 ,DXS115 - DXS551E - VBP1 - DXYS64X - DXS1108 - DXS154 - qter
    Authors Poustka (91), Freije (92), Smahi (94), De Sario (96), Brinke (97), Heiss (98) and others
    Text see FLNA
    Physical map
    TAZ Xq28 tafazzin (cardiomyopathy, dilated 3A (X-linked); endocardial fibroelastosis 2; Barth syndrome) ATP6AP1 Xq28 ATPase, H+ transporting, lysosomal accessory protein 1 GDI1 Xq28 GDP dissociation inhibitor 1 DXS9928E Xq28 DNA segment on chromosome X (unique) 9928 expressed sequence PLXN3 Xq28 likely ortholog of mouse plexin 3 DXS9879E Xq28 DNA segment on chromosome X (unique) 9879 expressed sequence UBL4 Xq28 ubiquitin-like 4 SLC10A3 Xq28 solute carrier family 10 (sodium/bile acid cotransporter family), member 3 FAM3A Xq28 family with sequence similarity 3, member A G6PD Xq28 glucose-6-phosphate dehydrogenase IKBKG Xq28 inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma SPCX Xq28 SPCX LAGE2A  cancer/testis antigen 1-A CTAG1 Xq28 cancer/testis antigen 1 LOC340600 Xq28 cyclic-AMP-dependent transcription factor ATF-4 pseudogene deltaNEMO Xq28 deltaNEMO CTAG2 Xq28 cancer/testis antigen 2 LOC392561 X similar to olfactory receptor MOR255-2 GAB3 Xq28 GRB2-associated binding protein 3 DKC1 Xq28 dyskeratosis congenita 1, dyskerin MPP1 Xq28 membrane protein, palmitoylated 1, 55kDa LOC158957 Xq28 hypothetical LOC158957 F8 Xq28 coagulation factor VIII, procoagulant component (hemophilia A) HCBP6 Xq28 hepatitis C virus core-binding protein 6 MTCP1 Xq28 mature T-cell proliferation 1 C6.1A Xq28 c6.1A VBP1 Xq28 von Hippel-Lindau binding protein 1
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    26 - 9048 267 2351 - 2007 16487577
  • Variant 1
  • large glycoprotein, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex
  • 5 splicing 2617 - 216 - 2007 16487577
  • variant 2
  • missing exon 1 to 22 (exons 23 to 26 in reading frame)
  • including the phospholipid binding domain (F5/8 type C domain)
  • putative small protein, which consists primarily of the phospholipid binding domain of factor VIIIc (this domain is essential for coagulant activity)
  • EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrineneuroendocrinepituitary  highly
     parathyroid   highly
    Nervousnerve   highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticmonocyte Homo sapiens
    Cardiovascularendothelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion plasma
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES basic Hydrophobic
    STRUCTURE
    motifs/domains
  • a factor VIII C1b and C2 domains (cooperation between the C1 and C2 domains is necessary for full activity of the factor Xase complex) (
  • role of C1 domain is co-operative with other domains of the intact F8 molecule
  • a F8 A2 domain that is a key structural element
  • a motif implicated in cell adhesion
  • domain F5/8 type C2 responsible for phospholipid binding
  • three domain F5/8 type A composed of two plastocyanin-like repeats in each and two domains F5/8 type C, behind the hydrophobic surface lies a ring of positively charged residues
  • secondary structure
  • a beta sandwich core from which two beta turns and a loop display a group of solvent exposed hydrophobic residues
  • conjugated GlycoP
    isoforms Precursor undergoing multiple cleavage events, preprocoagulant component
    HOMOLOGY
    interspecies ortholog to murine F8
    Homologene
    FAMILY multicopper oxidase family
    CATEGORY regulatory
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
    intracellular,cytoplasm,organelle,lumen
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    text synthetized and secreted by the liver
    basic FUNCTION
  • coagulation for FIXa which converts FX to FXa in presence of Ca2+ and phospholipids
  • key component of the fluid phase of the blood coagulation system
  • functions as a cofactor for Factor IXa in a membrane-bound enzyme complex
  • is a novel heme-binding protein
  • light chain of F8, which is not biologically active for clot formation, is sufficient for accelerating proteolytic cleavage of VWF by ADAMTS13 under fluid shear stress and (patho) physiological conditions
  • may be involved in regulating VWF homeostasis under physiological conditions
  • role for F8 and thrombin/F2R in regulating hematopoiesis and its interplay with the bone structure
  • F8 stability and half-life is dependent on non-covalent complex formation with von Willebrand factor (VWF) to avoid proteolysis and clearance
  • glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS coagulation/hemostasis
    text intrinsic pathway of blood coagulation
    PATHWAY
    metabolism
    signaling
    a component
  • active cofactor, FVIIIa is a trimer composed of A1, A2 and A3-C1-C2 subunits (its role is to markedly increase the catalytic efficiency of factor IXa)
  • circulates as a heterodimer composed of heavy (A1A2B domains) and light (A3C1C2 domains) chains
  • INTERACTION
    DNA
    RNA
    small molecule metal binding, other,
  • calcium Ca2+
  • phospholipids
  • activated protein held in a complex with Cu++
  • protein
  • variant 1 associating with vWF (von Willebrand factor) in a covalent complex
  • interacting with MCFD2 and LMAN1, forming stable complexes in liver cells
  • binds to phosphatidylserine (PS)-containing membranes through its tandem, lectin-homology, C1 and C2 domains
  • F8 accelerates proteolytic cleavage of VWF by ADAMTS13 under fluid shear stress
  • light chain, particularly the a3 region in the light chain of F8, contains the major binding site for VWF
  • LMAN1 transports coagulation factors V (F5) and VIII (F8)
  • LDLR was shown to mediate clearance of blood coagulation factor VIII (F8) from the circulation
  • hydrophobic helical stack between the GLA and EGF1 domains of F9 is predicted to be primary interacting region with the A3-C2 domain interface of F8
  • LRP1 mediates clearance of blood coagulation factor VIII (F8)
  • F8 interacts likely with LRP1 via an extended surface of multiple lysine residues that starts at the bottom of the C1 domain and winds around the F8 molecule
  • VWF modulates the internalization and presentation of F8-derived peptides on major histocompatibility complex class II
  • cell & other
    REGULATION
    activated by by thrombin to form a non-covalently linked A1/A2/A3-C1-C2 heterotrimer
    Other VWF may reduce the immunogenicity of F8 by inhibiting the uptake of F8 by antigen presenting cells, the first step in the development of an immune response against a foreign antigen
    ASSOCIATED DISORDERS
    corresponding disease(s) F8D , DUPXQ28D
    related resource The Haemophilia A Mutation, Structure, Test and Resource Site (HAMSTeRS)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    FVIII levels above the 75(th) percentile are associated with a significant odds ratio for the occurrence of venous thromboembolism
    Susceptibility risk factor for venous thromboembolism
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target use of VWF in conjunction with F8 in the management of patients with haemophilia A (Lacroix-Desmazes 2008)
    ANIMAL & CELL MODELS
  • multiple eye defects and developmental alteractions in chimeric and transgenic mice are produced by a motif implicated in cell adhesion
  • F VIII deficient mice (Vanden Driessche, 99)
  • endothelial cells from multiple, but not all, tissues contribute to the plasma F8 pool in the mouse