The factor V gene encodes a protein comprising a leader peptide and heavy chain encoded by exons 1–12, a B domain encoded by exon 13, and a light chain encoded by exons 14–25. Factor V deficiency (also called Owren 's disease or parahemophilia ) is a bleeding disorder where individuals heterozygous for a FV deficiency may remain asymptomatic and homozygous individuals present with a moderate to severe bleeding disorder consisting of ecchymoses, epistaxis, and menorrhagia. Bleeding can also occur after trauma, surgery, or tooth extraction, but is usually easily controlled. Pathogenic variants in this gene have been related to susceptibility to several medical conditions, constituting a great phenotypic heterogeneity that includes not only factor V deficiency with an autosomal recessive inheritance mechanism, but also susceptibility to recurrent pregnancy loss 1 (RPRGL1) of autosomal dominant inheritance. which is defined as more than 3 consecutive losses before the 24th week of gestation; susceptibility to ischemic cerebrovascular event of multifactorial inheritance which is described as an acute neurological event that leads to neuronal death and results in loss of motor, sensory and cognitive function; susceptibility to thrombophilia due to factor V Leiden of autosomal dominant inheritance, which is significantly related to venous thromboembolisms; thrombophilia 2 due to activated protein c cofactor deficiency of autosomal dominant inheritance related to recurrent thromboembolic events; Budd Chiari syndrome of autosomal recessive inheritance characterized anatomical anomalies and hypercoagulability disorders, patients present with hepatomegaly, pain in the right upper quadrant and ascites.
This gene has Synonyms: activated protein C cofactor; proaccelerin labile factor , with Accession Identifiers: G66-30677 (MetaCyc), P12259 (UniProt), Menta P12259.
According to UNIPROT (https://www.uniprot.org/ ), this protein: Coagulation Factor V, consists of 2224 amino acids, is a central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa resulting in the activation of prothrombin to thrombin. Regulation of activity Inhibited by SERPINA5.
Coagulation factor Va is a protein of the coagulation system that is not enzymatically active. Rather, it functions as a coenzyme for factor Xa.
The protein, which is homologous to factor VIII, consists of six domains: A1-A2-B-A3-C1-C2. The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin and bind copper. The C domains belong to the phospholipid-binding discoidin domain family (unrelated to the C2 domain), and the C2 domain mediates membrane binding. The C-terminal end of the B domain acts as a cofactor for the activation of the anticoagulant Protein C by Protein S [Thorelli98, MacedoRibeiro99].
The protein circulates in the bloodstream in an inactive form until it encounters activated platelets, to which it binds. Upon binding, it is cleaved and activated by thrombin. Activation consists of the cleavage and release of domain B, leaving two chains: a heavy chain, consisting of domains A1-A2, and a light chain, consisting of domains A3-C1-C2. The two chains associate non-covalently in a calcium-dependent manner, forming the active factor Va.
Coagulation factor Va associates with factor Xa to form the prothrombinase complex , which catalyzes the conversion of prothrombin to thrombin. Assembly of the complex takes place on negatively charged phospholipid membranes in the presence of calcium ions.
Coagulation factor Va is inactivated by proteolysis catalyzed by protein C.
Additionally, a search for this variant was carried out in intelligence assistants
artificial. According to GenAI 's first genetic variant wizard, VarChat, the genomic variant c.2809del is a single nucleotide deletion that occurs within the coding sequence of the F5 gene. This deletion leads to a frameshift variant, designated p.Ser 937ValfsTer22, indicating that the serine at position 937 is replaced by a valine, and a premature stop codon is introduced 2224 amino acids into the translated protein. Frameshift variants result in a truncated factor V protein that is likely not functional due to the loss of critical C-terminal amino acid sequences.
The introduction of a premature stop codon triggers nonsense-mediated mRNA decay (NMD), a cellular quality control mechanism that degrades mRNAs containing premature stop codons to prevent the synthesis of truncated and potentially harmful proteins. If the mRNA escapes NMD, the truncated protein may be subject to proteasomal degradation or may have dominant-negative effects if it interferes with the function of the wild-type protein.
Gene function:
The F5 gene encodes coagulation factor V, a protein that plays a crucial role in the blood clotting cascade. Factor V functions as a cofactor for the prothrombinase complex, which is responsible for the conversion of prothrombin to thrombin, a key step in the formation of a blood clot. Factor V is synthesized as an inactive precursor and activated by thrombin or factor Xa through specific cleavage. The active form of Factor V (Factor Va) is essential for the amplification of thrombin generation. Given its central role in coagulation, variants in the F5 gene may lead to bleeding disorders such as factor V deficiency or may contribute to thrombophilia, as seen in factor V Leiden thrombophilia, depending on the nature of the variant. and its impact on protein function. This variant is not described in the literature.
In accordance with various genomic intelligence platform as Mastermind reported that searched over 36 million abstracts, and over 9 million genomic full- text articles and found no related articles.
(https://mastermind.genomenon.com/articles?gene=f5&mutation=f5%3Ac.2809del&keyword=F5+c.2809del&gene_op=and&mutation_op=and&keyword_op=and ).
According to Alliance of Genome Resources predicts that this gene enables copper ion binding activity and signaling receptor activity. It is predicted to be involved in blood circulation and blood clotting. Located in extracellular vesicle and membrane. Implicated in several diseases, including arterial disease (multiple); end-stage kidney disease; factor V deficiency; liver disease (multiple); and nonarteritic anterior ischemic optic neuropathy. Colorectal adenoma biomarker; hepatitis; hepatic cirrhosis; and portal hypertension.
The gene was reported in genetic variation databases: BioMuta F5, DMDM 308153653, ClinGen HGNC:3542, GenCC HGNC:3542.
Enzyme and pathway databases: BioCyc MetaCyc: G66-30677-MONOMER.
RefSeq or Ensembl database:
Select Frameshift, Germline Classification, Frequencies Exomes: Not Found (CoV : 81.4) Genomes: Not Found ( CoV : 30.8), CHR1 Chromosome Scores, Position 169542281, Genome Browser UCSC Sequence REF T, Deletion Variant Type; Cytoband 1T24.2, HGVS F5(NM_000130.5):c. 2809del p.(Ser937ValfsTer22)conservation: phyloP100: 4,019; PhastCons100way 0.951.
- F5(ENST00000367797.9): c.2809del: Exome Frequencies: Not found (CoV : 81.4); Genomes: Not found (CoV : 30.8). This variant is located on Chromosome CHR1 Position 169542281 UCSC Genome Browser, REF T sequence, Deletion variant type, Cytoband 1T24.2, HGVS F5(ENST00000367797.9):c.2809del p.(Ser937ValfsTer22).
Reactome: R-HSA-114608 Platelet degranulation; R-HSA-140875Common pathway of fibrin clot formation; R-HSA-204005 COPII-mediated vesicle transport; R-HSA-381426 Regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor-binding proteins (IGFBPs); R-HSA-5694530ER load concentration; R-HSA-8957275Post-translational phosphorylation of proteins.
Proteomes Identifier UP000005640.
Protein-protein interaction databases: BioGRID 10845217 interactians
ComplexPortal CPX-6216; Coagulation Factor Complex Va, DIP DIP-47331N; IntAct P122599 interactians ; MINT P12259; STRING 9606.ENSP00000356771
Chemistry: BindingDB P12259, RNAct P12259Protein.
Genomic annotation databases:
Ensembl ENST00000367797,9ENSP00000356771,3ENSG00000198734, 12; GeneID 2153; KEGG has:2153;
MANE- Select ENST00000367797,9ENSP00000356771,3NM_000130,5NP_000121,2
UCSC: UC001GGG.2.
In this article, we report the case of an adolescent patient with heterogeneous clinical manifestations associated with hematological involvement, with suspected coagulation disorder, due to altered paraclinics, but without related family history, no consanguinity; Therefore, a targeted molecular study for the FV gene is requested.
This patient has a homozygous genomic variant causing factor V deficiency of autosomal recessive inheritance, which explains her phenotype. The risk of inheriting this variant to your offspring is 100%; However, the likelihood of your children inheriting the disease will depend on your partner's carrier status.
The F5 gene variant reported in this case was c.2809del; p.Ser 937ValfsTer22; homozygous, frameshift type , when consulting the different databases – genetic records, more missense (5)type variants are described .
In 2022 in Taiwan, the first report of simultaneous variants found in the same sequencing of the F5 gene of two patients from the same family was made, where 8 different variants were found, of which 7 were heterozygous, some located in exon 13. and a homozygote located in exon16 (Met1736Val) which correlates with the reported clinical manifestations; where their carriers had no history of major bleeding, with factor V activity of 3.2% and 2% classified as moderate deficiency, who had a requirement for fresh frozen plasma in the event of major bleeding related to surgical interventions. (10)In
In 2023, an analysis of 363 genetic variants related to F5 was carried out, which explained the different phenotypes described. The most reported pathogenic variants are c.6304C>T (p.Arg 2102Cys), c.1258G>T (p.Gly420Cys ), c.5189A>G (p.Tyr1730Cys) and the probably most reported pathogenic one is c.6304C>T (p.Arg2102Cys) (5).
Bleeding can also occur after trauma, surgery, or tooth extraction, but is usually easily controlled. Pathogenic variants in this gene have been related to susceptibility to several medical conditions, constituting great phenotypic heterogeneity, not only factor V deficiency with an autosomal recessive inheritance mechanism, but also susceptibility to recurrent pregnancy loss 1 (RPRGL1) of autosomal dominant inheritance. which is defined as more than 3 consecutive losses before the 24th week of gestation; susceptibility to ischemic cerebrovascular event of multifactorial inheritance which is described as an acute neurological event that leads to neuronal death and results in loss of motor, sensory and cognitive function; susceptibility to thrombophilia due to factor V Leiden of autosomal dominant inheritance, which is significantly related to venous thromboembolisms; thrombophilia 2 due to activated protein c cofactor deficiency of autosomal dominant inheritance related to recurrent thromboembolic events; Budd Chiari syndrome of autosomal recessive inheritance characterized anatomical anomalies and hypercoagulability disorders, patients present with hepatomegaly, pain in the right hypochondrium and ascites. HPO (Human Phenotype Ontology), NCBIGene:2153.
When performing an updated search in different databases (HGMD, ClinVar , LOVD, dbSNP and gnomAD v.4), there is no description of a variant like the one reported in this case. As of January 2024, 450 clinically significant variants and approximately 3942 variants related to the F5 gene have been reported.
When searching for this variant in artificial intelligence assistants, according to GenAI 's first genetic variant assistant, VarChat, others such as Alphafold, Mastermind, the latter reported that searched over 36 million abstracts, and over 9 million genomic full- text articles and found no related articles. ( https://mastermind.genomenon.com/articles?gene=f5&mutation=f5%3Ac.2809del&keyword=F5+c.2809del&gene_op=and&mutation_op=and&keyword_op=and ).
Two predictors in silico report this variant as deleterious.
Uniprot platform, Alliance of Genome Resources which predicts that this gene enables copper ion binding activity and signaling receptor activity. It is predicted to be involved in blood circulation and blood clotting. Located in extracellular vesicle and membrane.
It appears reported in enzyme and pathway databases: BioCyc MetaCyc: G66-30677-MONOMER.
RefSeq or Ensembl database:
In gene interaction databases, a relationship between F5 and 25 other genes related mainly to Binding, Expression, Modification mechanisms has been found. Which explains its great phenotypic heterogeneity.