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Special Issue "Molecular and Genetic Bases of Rare Inherited Coagulation Disorders (RICDs)"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2019).

Special Issue Editor

Prof. Dr. Rosanna Asselta
E-Mail Website
Guest Editor
Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, 20089 Rozzano, Milan, Italy
Interests: genetic and molecular bases of rare inherited coagulopathies (fibrinogen, factor V, and factor XI deficiencies); genetic bases of complex traits (multiple sclerosis, Parkinson’s disease, myocardial infarction); association studies (candidate genes, genome-wide association studies); metabolism of RNA (alternative splicing, microRNA-mediated regulation)
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Special Issue Information

Dear Colleagues,

Rare Inherited Coagulation Disorders (RICDs), which are frequently referred to also as RBDs (Rare Bleeding Disorders), comprise mainly bleeding disorders with a very low prevalence in the general population. RICDs include inherited deficiencies or defects in fibrinogen (FI), prothrombin (FII), coagulation factors V (FV), VII (FVII), X (FX), XI (FXI), and XIII (FXIII). These diseases can present as the isolated deficiency of one factor or, more rarely, as the combined deficiency of two (combined FV/FVIII deficiency) or many (vitamin K-dependent coagulation factor deficiency) coagulation factors. Collectively, RICDs account for approximately 3 to 5% of the coagulation disorders, the remaining 95-97% being represented by the more common X-linked hemophilias (deficiency of factor VIII or factor IX) and von Willebrand factor.

Notwithstanding the many efforts to better assess RICDs epidemiology and underlying molecular mechanisms, data on “true” prevalence rates and mutational spectra are still not comprehensive, especially for developing countries. In addition, even if a relatively large number of patients have been screened for mutations in the candidate genes, in most of the cases the underlying molecular mechanism has not been experimentally validated. This, besides leaving a knowledge gap between genetic data and the related pathophysiologic processes, is also responsible for a non-negligible proportion of errors in reporting “true” causal variants, a problem that is particularly frequent in rare recessive diseases.

In this respect, this Special Issue of the International Journal of Molecular Sciences will focus on providing novel genetic data and updated mutational spectra, as well as on giving insights in the molecular pathogenesis of RICDs. Indeed, spontaneous mutants in the population can represent a useful tool to inspect critical residues for coagulation factor assembly, secretion, function, and interaction with other proteins, as well as to elucidate molecular mechanisms underlying mRNA processing. This approach, that in the past century was fundamental for the discovery of most of the coagulation factors and for understanding the mechanisms of blood coagulation, still represents an extraordinary tool to study the molecular details of structure-function relationships of coagulation factors and to highlight novel strategies to improve RICDs therapy, which in most cases is based on the availability of a suitable factor-replacement product.

Prof. Dr. Rosanna Asselta
Guest Editor

Manuscript Submission Information

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Keywords

  • Rare coagulation factor deficiencies
  • Genetic bases
  • Mutations
  • Pathogenic mechanisms
  • Expression of recombinant proteins
  • RNA processing
  • Population genetics

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Published Papers (4 papers)

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Research

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Open AccessArticle
Identification of Potential Novel Interacting Partners for Coagulation Factor XIII B (FXIII-B) Subunit, a Protein Associated with a Rare Bleeding Disorder
Int. J. Mol. Sci. 2019, 20(11), 2682; https://doi.org/10.3390/ijms20112682 - 31 May 2019
Abstract
Coagulation factor XIII (FXIII) is a plasma-circulating heterotetrameric pro-transglutaminase complex that is composed of two catalytic FXIII-A and two protective/regulatory FXIII-B subunits. FXIII acts by forming covalent cross-links within a preformed fibrin clots to prevent its premature fibrinolysis. The FXIII-A subunit is known [...] Read more.
Coagulation factor XIII (FXIII) is a plasma-circulating heterotetrameric pro-transglutaminase complex that is composed of two catalytic FXIII-A and two protective/regulatory FXIII-B subunits. FXIII acts by forming covalent cross-links within a preformed fibrin clots to prevent its premature fibrinolysis. The FXIII-A subunit is known to have pleiotropic roles outside coagulation, but the FXIII-B subunit is a relatively unexplored entity, both structurally as well as functionally. Its discovered roles so far are limited to that of the carrier/regulatory protein of its partner FXIII-A subunit. In the present study, we have explored the co-presence of protein excipients in commercial FXIII plasma concentrate FibrogamminP by combination of protein purification and mass spectrometry-based verification. Complement factor H was one of the co-excipients observed in this analysis. This was followed by performing pull down assays from plasma in order to detect the putative novel interacting partners for the FXIII-B subunit. Complement system proteins, like complement C3 and complement C1q, were amongst the proteins that were pulled down. The only protein that was observed in both experimental set ups was alpha-2-macroglobulin, which might therefore be a putative interacting partner of the FXIII/FXIII-B subunit. Future functional investigations will be needed to understand the physiological significance of this association. Full article
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Open AccessArticle
Disruption of Structural Disulfides of Coagulation FXIII-B Subunit; Functional Implications for a Rare Bleeding Disorder
Int. J. Mol. Sci. 2019, 20(8), 1956; https://doi.org/10.3390/ijms20081956 - 22 Apr 2019
Cited by 2
Abstract
Congenital FXIII deficiency is a rare bleeding disorder in which mutations are detected in F13A1 and F13B genes that express the two subunits of coagulation FXIII, the catalytic FXIII-A, and protective FXIII-B. Mutations in FXIII-B subunit are considerably rarer compared to FXIII-A. Three [...] Read more.
Congenital FXIII deficiency is a rare bleeding disorder in which mutations are detected in F13A1 and F13B genes that express the two subunits of coagulation FXIII, the catalytic FXIII-A, and protective FXIII-B. Mutations in FXIII-B subunit are considerably rarer compared to FXIII-A. Three mutations in the F13B gene have been reported on its structural disulfide bonds. In the present study, we investigate the structural and functional importance of all 20 structural disulfide bonds in FXIII-B subunit. All disulfide bonds were ablated by individually mutating one of its contributory cysteine’s, and these variants were transiently expressed in HEK293t cell lines. The expression products were studied for stability, secretion, the effect on oligomeric state, and on FXIII-A activation. The structural flexibility of these disulfide bonds was studied using classical MD simulation performed on a FXIII-B subunit monomer model. All 20 FXIII-B were found to be important for the secretion and stability of the protein since ablation of any of these led to a secretion deficit. However, the degree of effect that the disruption of disulfide bond had on the protein differed between individual disulfide bonds reflecting a functional hierarchy/diversity within these disulfide bonds. Full article
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Open AccessArticle
Understanding the Impact of Aberrant Splicing in Coagulation Factor V Deficiency
Int. J. Mol. Sci. 2019, 20(4), 910; https://doi.org/10.3390/ijms20040910 - 20 Feb 2019
Cited by 1
Abstract
Rare inherited coagulation disorders (RICDs) are congenital deficiencies of the plasma proteins that are involved in blood coagulation, which generally lead to lifelong bleeding manifestations. These diseases are generally qualitative and/or quantitative defects that are associated with monoallelic or biallelic mutations in the [...] Read more.
Rare inherited coagulation disorders (RICDs) are congenital deficiencies of the plasma proteins that are involved in blood coagulation, which generally lead to lifelong bleeding manifestations. These diseases are generally qualitative and/or quantitative defects that are associated with monoallelic or biallelic mutations in the relevant gene. Among RICDs, factor V (FV) deficiency is one of the least characterized at the molecular level. Here, we investigated four unrelated patients with reduced plasma FV levels (three severe, one mild), which were associated with a moderately severe bleeding tendency. Sequence analysis of the FV gene identified seven different variants, five hitherto unknown (p.D1669G, c.5789-11C>A, c.5789-12C>A, c.5789-5T>G, and c.6528G>C), and two previously reported (c.158+1G>A and c.5789G>A). The possible pathogenic role of the newly identified missense variant was studied by in silico approaches. The remaining six genetic defects (all putative splicing mutations) were investigated for their possible effects on pre-mRNA splicing by transient transfection experiments in HeLa cells with plasmids expressing appropriate hybrid minigenes. The preparation of minigene constructs was instrumental to demonstrate that the two adjacent variants c.5789-11C>A and c.5789-12C>A are indeed present in cis in the analyzed FV-deficient patient (thus leading to the c.5789-11_12CC>AA mutation). Ex vivo experiments demonstrated that each variant causes either a skipping of the relevant exon or the activation of cryptic splice sites (exonic or intronic), eventually leading to the introduction of a premature termination codon. Full article
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Review

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Open AccessReview
Molecular Mechanisms and Determinants of Innovative Correction Approaches in Coagulation Factor Deficiencies
Int. J. Mol. Sci. 2019, 20(12), 3036; https://doi.org/10.3390/ijms20123036 - 21 Jun 2019
Cited by 2
Abstract
Molecular strategies tailored to promote/correct the expression and/or processing of defective coagulation factors would represent innovative therapeutic approaches beyond standard substitutive therapy. Here, we focus on the molecular mechanisms and determinants underlying innovative approaches acting at DNA, mRNA and protein levels in inherited [...] Read more.
Molecular strategies tailored to promote/correct the expression and/or processing of defective coagulation factors would represent innovative therapeutic approaches beyond standard substitutive therapy. Here, we focus on the molecular mechanisms and determinants underlying innovative approaches acting at DNA, mRNA and protein levels in inherited coagulation factor deficiencies, and in particular on: (i) gene editing approaches, which have permitted intervention at the DNA level through the specific recognition, cleavage, repair/correction or activation of target sequences, even in mutated gene contexts; (ii) the rescue of altered pre-mRNA processing through the engineering of key spliceosome components able to promote correct exon recognition and, in turn, the synthesis and secretion of functional factors, as well as the effects on the splicing of missense changes affecting exonic splicing elements; this section includes antisense oligonucleotide- or siRNA-mediated approaches to down-regulate target genes; (iii) the rescue of protein synthesis/function through the induction of ribosome readthrough targeting nonsense variants or the correction of folding defects caused by amino acid substitutions. Overall, these approaches have shown the ability to rescue the expression and/or function of potentially therapeutic levels of coagulation factors in different disease models, thus supporting further studies in the future aimed at evaluating the clinical translatability of these new strategies. Full article
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