Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications

Shahbazi, Shirin; Mahdian, Reza

doi:10.29252/ibj.23.3.165

Cited by 14 publications

(29 citation statements)

References 63 publications

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“…21 Because exon 8 is relatively long and is the Approximately 4% of FVII protein circulates in the plasma in the form of FVIIa, which is almost inactive in the absence of TF. 11 When vascular tissue is injured, FVII combines with TF to form a TF/FVIIa complex. The conversion from FVII to FVIIa occurs by breaking the chain between amino acids Ile153 and Arg152.…”

Section: Discussionmentioning

confidence: 99%

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A novel compound heterozygous variant linked to hematuria in a family with hereditary factor VII deficiency

Gan

Zhang

et al. 2021

The Journal of Gene Medicine

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Background: Hereditary factor VII deficiency (FVIID) is a rare congenital autosomal recessive bleeding disorder. In clinical manifestations, its onset is caused by variant of the F7 gene (NM_019616) with strong heterogeneity. We identified a family with hematuria caused by a novel F7 compound heterozygous variant and investigated the FVIID-dependent mechanism impacted by these variants.Methods: Coagulation factors in the proband were functionally verified. We located pathogenic variants in relevant genes using next-generation sequencing after target enrichment and verified them by Sanger sequencing. We examined the coagulation activity and secretion pattern of recombinant FVII variants expressed in cells and observed their location and stability by immunofluorescence.Results: We found a missense variant c.1207G>A (p.Gly403Ser) and a frameshift variant c.154_155del (p.Arg53fs) in the F7 gene of the proband. FVII activity tests showed that the variants significantly decreased its presence in the cell culture supernatant. Moreover, the R53fs mutant lacked the FVII functional domain and had no detectable activity. Immunofluorescence indicated that the p.Gly403Ser variant was distributed to the cell membrane and cytoplasm, whereas the FVII R53fs variant was not detected. Deficient FVII protein function and severe coagulation disorder are the likely causes of hematuria and other bleeding symptoms in the proband. Conclusions:The newly discovered F7 gene variants enrich the spectrum of hereditary FVII deficiency and provide a new foundation for the diagnosis and treatment of this type of coagulation disorder.

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Section: Discussionmentioning

confidence: 99%

“…For example, R79Q destroyed the ability of FVII to bind to TF, but did not affect its expression. 11,33 The R152Q variant severely affected the protease activity of FVII. Q100R, F328S, and P303T changed the conformation of FVII, weakening its protease activity and diminishing affinity for TF.…”

Section: Discussionmentioning

confidence: 99%

A novel compound heterozygous variant linked to hematuria in a family with hereditary factor VII deficiency

Gan

Zhang

et al. 2021

The Journal of Gene Medicine

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“…The precursor FVII has a peptide that directs the γ-carboxylation of 10 glutamic acids. The Gla residues are essential for FVII to obtain calcium-dependent conformation and bind to phospholipid surfaces (10,11).…”

Section: Fvii Proteinmentioning

confidence: 99%

“…The activation domain provides a proteolytic cleavage site. In the presence of calcium ions and phospholipids, the single-chained FVII is quickly hydrolyzed by FXa (activated FX) and thrombin and converted into a two-chained form (6,11). Activation of FVII involves cleavage of the peptide bond between Arg 152 and Ile 153 in the activation domain creating a heavy and a light chain that remain attached by disulfide bonds.…”

Section: Fvii Proteinmentioning

confidence: 99%

Coagulation Factor VII: Genetic, Molecular, and Clinical Characteristics

Mashayekhi

Ghasemi

2022

Trends in Med Sci

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: Coagulation factor VII (FVII) is a vitamin K-dependent serine protease that plays a pivotal role in normal hemostasis. Mature FVII is a glycoprotein comprised γ-carboxyglutamic acid-rich (Gla) domain, two epidermal growth factor (EGF)-like domains, an activation domain, and a serine protease domain. FVII requires proteolytic activation followed by tissue factor (TF) binding for maximal activity. The F7 gene (14.8 kb) is located on 13q34, composed of nine exons and eight introns. The congenital FVII deficiency is a rare coagulopathy with an autosomal recessive pattern of inheritance that occurs due to mutation in the F7 gene. A considerable number of mutations of different types have been identified throughout this gene affecting the expression, structure, and post-translational alterations of the protein. FVII deficiency is the most frequently recessively inherited bleeding disorder. Subjects with FVII deficiency show a wide range of symptoms, including cutaneous hemorrhage, mucosal hemorrhage, gastrointestinal bleeding, joint bleeding, and central nervous system (CNS) hemorrhage. Unlike other coagulation factor deficiencies, serum levels of FVII do not demonstrate the severity of the disease, and there is no direct correlation between serum levels and clinical complications. Replacement therapy is the treatment of choice for FVII deficiency. Various therapeutic products such as prothrombin complex concentrate, plasma-derived FVII concentrate, fresh frozen plasma, and activated recombinant FVII are available to treat FVII deficient individuals. This review aims to provide information on molecular, biochemical, and clinical aspects of coagulation FVII, its role in hemostasis, and the consequences of its deficiency.

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“…The sheer number of minicircles, each with four conserved regions containing CA-rich sequence motifs, may be the dominant characteristic influencing the high frequency of this serendipitous mutagenic events that may influence the endogenous host genes [184,185]. The transposable elements that replicate within the host genome may contribute to somatic mosaicism and, thus potent regulatory polygenic modifications in the diseased state [186,187] play a role in the pathogenesis of inflammatory autoimmune Chagas disease [35,41,57,172,188]. In so far, the polygenic modifications involved in the genesis of cancer [189][190][191][192][193] have not been ascribed to any Ambiental factor inducer of the lateral exogenous kDNA transfer.…”

Section: Cross-kingdom Dna Transfer Evolution Natural Selection and Chagas Diseasementioning

confidence: 99%

The Trypanosoma cruzi kinetoplast DNA minicircle sequences transfer biomarker of the multidrug treatment of Chagas disease

Teixeira

Sousa

Gomes

et al. 2021

Preprint

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BackgroundThe Trypanosoma cruzi infection renders the transfer of the mitochondrion kinetoplast DNA minicircle sequences into the host’s genome. The Aves are refractory to the infection, but chicks hatched from the T. cruzi inoculated eggs integrate the DNA minicircle sequences into the germ line cells. Rabbits, mice and chickens with the minicircle sequences mutations develop the Chagas cardiomyopathy and the DNA transfer underpins the heart disease.MethodologyThe PCR with the specific primer sets revealed the Protist nuclear DNA and the kinetoplast DNA in the agarose gels bands probed with the radiolabel specific sequences from tissues of the T. cruzi-infected rabbits and of the mice. A target- primer TAIL-PCR amplification employing primer sets from the chickens, rabbits and mice, in combination with primer sets from the the T. cruzi kinetoplast minicircle sequences was used. This approach led us to disclose the integration sites of the kinetoplast DNA biomarker, then, used to monitor the effect of multidrug treatment of the T. cruzi infected mice.Principal findingsThe Southern hybridization, clone and sequence of the amplification products revealed the DNA minicircle sequences integrations sites in the LINE transposable elements. An array of inhibitors of eukaryote cells division was used to arrest the DNA transfer. It was shown that nine out of 12 inhibitors prevented the kinetoplast DNA integration into the macrophage genome. The multidrug treatment of the acutely T. cruzi-infected mice with Benznidazole, Azidothymidine and Ofloxacin lessened circa 2.5-fold the rate of the minicircle sequences integrations in the mouse genome and inhibited the rejection of the target heart cells.Conclusion and significanceThe T. cruzi mitochondrion kinetoplast minicircle sequences transfer driven pathogenesis of Chagas disease is an ancient Cross-Kingdom DNA phenomenon of evolution and, therefore, paradigm research with effective purposing inhibitors is needed.Authors summaryChagas disease is considered the main cause of human heart failure in the Western Hemisphere. The treatment of the clinically manifested Chagas heart disease is considered unsatisfactory. Perhaps the most important problem in the field of Chagas disease is determination of the pathogenesis of the target heart cells lysis. We showed the transfer of the T. cruzi kDNA minicircle sequences into the genome of rabbits and mice, and to Bird refractory to the infections. The inoculation of a few T. cruzi in the fertile chicken eggs renders the kDNA sequences integration in the stem cells. Interestingly, the chicks that hatched retain the kDNA and develop the Chagas-like cardiomyopathy indistinguishable to that in the rabbits and mice. This result prompted the multidrug treatment of the Chagas heart disease with inhibitors of the eukaryotic cells division. We showed that nine out of 12 inhibitors prevented the transfer of the kDNA mutations into the macrophage genome, and that the treatment of the acutely T. cruzi-infected mice with Benznidazole + Ofloxacin + Azidothymidine lowered circa 2.5-fold the rate of the mutations in the chromosomes. These findings translated to the pathology showing inhibition of the heart lesions in the treated T. cruzi-infected mice. We suggest purposing new inhibitors should be tested to overturning the Chagas heart disease.

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Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications

Cited by 14 publications

References 63 publications

A novel compound heterozygous variant linked to hematuria in a family with hereditary factor VII deficiency

A novel compound heterozygous variant linked to hematuria in a family with hereditary factor VII deficiency

Coagulation Factor VII: Genetic, Molecular, and Clinical Characteristics

The Trypanosoma cruzi kinetoplast DNA minicircle sequences transfer biomarker of the multidrug treatment of Chagas disease

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