High Mutational Heterogeneity, and New Mutations in the Human Coagulation Factor V Gene. Future Perspectives for Factor V Deficiency Using Recombinant and Advanced Therapies

Abstract

Factor V is an essential clotting factor that plays a key role in the blood coagulation cascade on account of its procoagulant and anticoagulant activity. Eighty percent of circulating factor V is produced in the liver and the remaining 20% originates in the α-granules of platelets. In humans, the factor V gene is about 80 kb in size; it is located on chromosome 1q24.2, and its cDNA is 6914 bp in length. Furthermore, nearly 190 mutations have been reported in the gene. Factor V deficiency is an autosomal recessive coagulation disorder associated with mutations in the factor V gene. This hereditary coagulation disorder is clinically characterized by a heterogeneous spectrum of hemorrhagic manifestations ranging from mucosal or soft-tissue bleeds to potentially fatal hemorrhages. Current treatment of this condition consists in the administration of fresh frozen plasma and platelet concentrates. This article describes the cases of two patients with severe factor V deficiency, and of their parents. A high level of mutational heterogeneity of factor V gene was identified, nonsense mutations, frameshift mutations, missense changes, synonymous sequence variants and intronic changes. These findings prompted the identification of a new mutation in the human factor V gene, designated as Jaén-1, which is capable of altering the procoagulant function of factor V. In addition, an update is provided on the prospects for the treatment of factor V deficiency on the basis of yet-to-be-developed recombinant products or advanced gene and cell therapies that could potentially correct this hereditary disorder.

Keywords: Owren’s disease; advanced therapies; factor V deficiency; mutation analysis; parahemophilia.

Figure 1

Blood clotting mechanism. Hoffman & Monroe’s cell-based model of hemostasis according to which coagulation factors form multimolecular complexes, calcium and the endothelial membranes playing a key role in the stabilization of such complexes. Abbreviations: P, membrane phospholipids; TF, tissue factor; F, factor. Created in Biorender.com (accessed on 6 September 2021).

Figure 2

Genetic map of the F5 gene of patient A. (A) Native sequence. (B) Sequence of the patient with the Arg740* mutation (premature stop codon, nonsense mutation). Created in Biorender.com (accessed on 6 September 2021).

Figure 3

Genetic map of the F5 gene of patient A. (A) Native sequence. (B) Sequence of the patient with the Trp1093* mutation (premature stop codon, nonsense mutation). Created in Biorender.com (accessed on 6 September 2021).

Figure 4

Genetic map of the F5 gene of patient B. (A) Native sequence. (B) Sequence of the patient with the 2862del, Ser955Alafs*4 mutation (premature stop codon, deletion mutation). Created in Biorender.com (accessed on 6 September 2021).

Figure 5

Family pedigrees of the FVa deficient Spanish and Pakistani families. FVa levels and segregation of the identified mutations are shown. (A) Patient A with FVa deficiency and two mutations in compound heterozygous state with familiar segregation (c.3279G>A mutation inherited from her father and c.2218C>T from her mother). (B) Patient B with FVa deficiency and mutation in homozygous state, the c.2862del mutation inherited from both, father and mother.

Figure 6

Multiple sequence alignment comparing the different regions of FVa corresponding to the 2218C>T Arg740, 3279G>A Trp1093* and 2862del, Ser955Alafs*4 mutations in Homo sapiens, Canis lupus familiaris, Oryctolagus cuniculus, Mus musculus, Rattus norvegicus and Danio rerio. The mutated amino acid is at the center, with an arrow pointing to it. The three mutations described in the two patients are in exon 13, corresponding to the protein’s B domain, and in well-conserved regions across the different vertebrate species analyzed. Created in Biorender.com (accessed on 6 September 2021).