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Special Issue "Genetic Basis of Fibrinogen Disorders"

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 (15 November 2017).

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,

Congenital fibrinogen disorders, including afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia, are estimated to represent about 8% of rare inherited coagulopathies. In addition to the most obvious and frequent consequences of fibrinogen disorders, i.e., hemorrhagic and/or thrombotic manifestations, specific point mutations in the γ and in the Aα chain genes can also lead to organ damage; in the liver, due to endoplasmic accumulation of mutant fibrinogen molecules, and in the kidney as a result of an increased susceptibility to proteolysis of aggregation-prone fibrinogen peptides, leading to systemic amyloidosis.

Notwithstanding the significant effort to better assess their epidemiology and underlying molecular mechanisms, data on “true” prevalence rates, mutational spectra, and clinical management of these disorders are still not comprehensive.

In this Special Issue of the International Journal of Molecular Sciences, the focus will be the “Genetic Basis of Fibrinogen Disorders”, including insights into epidemiologic data, mutational spectra, and molecular pathogenesis. In this respect, studying fibrinogen spontaneous mutants in the population can represent a useful tool to inspect critical residues for fibrinogen assembly, secretion, function, and interaction with other proteins, as well as to elucidate molecular mechanisms underlying fibrinogen-chain mRNA processing. In addition, although the precise knowledge of the genetic defects responsible for fibrinogen disorders in each patient is of limited clinical utility, as genotype/phenotype correlations are weak, it still provides a valuable tool for diagnosis confirmation, identification of potential carriers, and prenatal diagnosis.

Assoc. Prof. Dr. Rosanna Asselta
Guest Editor

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Keywords

  • Afibrinogenemia
  • Hypofibrinogenemia
  • Dysfibrinogenemia
  • Hyperfibrinogenemia
  • Hepatic fibrinogen storage disease
  • Systemic amyloidosis
  • Mutational screening
  • Expression studies
  • Fibrinogen assembly and secretion
  • Regulation of fibrinogen expression

Published Papers (7 papers)

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Research

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Open AccessArticle
Identification of Two Novel Fibrinogen Bβ Chain Mutations in Two Slovak Families with Quantitative Fibrinogen Disorders
Int. J. Mol. Sci. 2018, 19(1), 100; https://doi.org/10.3390/ijms19010100 - 29 Dec 2017
Cited by 3
Abstract
Congenital fibrinogen disorders are caused by mutations in one of the three fibrinogen genes that affect the synthesis, assembly, intracellular processing, stability or secretion of fibrinogen. Functional studies of mutant Bβ-chains revealed the importance of individual residues as well as three-dimensional structures for [...] Read more.
Congenital fibrinogen disorders are caused by mutations in one of the three fibrinogen genes that affect the synthesis, assembly, intracellular processing, stability or secretion of fibrinogen. Functional studies of mutant Bβ-chains revealed the importance of individual residues as well as three-dimensional structures for fibrinogen assembly and secretion. This study describes two novel homozygous fibrinogen Bβ chain mutations in two Slovak families with afibrinogenemia and hypofibrinogenemia. Peripheral blood samples were collected from all subjects with the aim of identifying the causative mutation. Coagulation-related tests and rotational thromboelastometry were performed. All exons and exon–intron boundaries of the fibrinogen genes (FGA, FGB and FGG) were amplified by PCR followed by direct sequencing. Sequence analysis of the three fibrinogen genes allowed us to identify two novel homozygous mutations in the FGB gene. A novel Bβ chain truncation (BβGln180Stop) was detected in a 28-year-old afibrinogenemic man with bleeding episodes including repeated haemorrhaging into muscles, joints, and soft tissues, and mucocutaneous bleeding and a novel Bβ missense mutation (BβTyr368His) was found in a 62-year-old hypofibrinogenemic man with recurrent deep and superficial venous thromboses of the lower extremities. The novel missense mutation was confirmed by molecular modelling. Both studying the molecular anomalies and the modelling of fibrinogenic mutants help us to understand the extremely complex machinery of fibrinogen biosynthesis and finally better assess its correlation with the patient’s clinical course. Full article
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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Open AccessArticle
Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage
Int. J. Mol. Sci. 2017, 18(12), 2717; https://doi.org/10.3390/ijms18122717 - 15 Dec 2017
Abstract
p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen γ. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, [...] Read more.
p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen γ. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB–lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the “end-to-end” interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon. Full article
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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Open AccessArticle
Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains
Int. J. Mol. Sci. 2017, 18(12), 2711; https://doi.org/10.3390/ijms18122711 - 14 Dec 2017
Cited by 10
Abstract
Fibrinogen is a highly pleiotropic protein that is involved in the final step of the coagulation cascade, wound healing, inflammation, and angiogenesis. Heterozygous mutations in Aα, Bβ, or γ fibrinogen-chain genes (FGA, FGB, FGG) have been described as being [...] Read more.
Fibrinogen is a highly pleiotropic protein that is involved in the final step of the coagulation cascade, wound healing, inflammation, and angiogenesis. Heterozygous mutations in Aα, Bβ, or γ fibrinogen-chain genes (FGA, FGB, FGG) have been described as being responsible for fibrinogen deficiencies (hypofibrinogenemia, hypo-dysfibrinogenemia, dysfibrinogenemia) and for more rare conditions, such as fibrinogen storage disease and hereditary renal amyloidosis. Instead, biallelic mutations have been associated with afibrinogenemia/severe hypofibrinogenemia, i.e., the severest forms of fibrinogen deficiency, affecting approximately 1–2 cases per million people. However, the “true” prevalence for these conditions on a global scale is currently not available. Here, we defined the mutational burden of the FGA, FGB, and FGG genes, and estimated the prevalence of inherited fibrinogen disorders through a systematic analysis of exome/genome data from ~140,000 individuals belonging to the genome Aggregation Database. Our analysis showed that the world-wide prevalence for recessively-inherited fibrinogen deficiencies could be 10-fold higher than that reported so far (prevalence rates vary from 1 in 106 in East Asians to 24.5 in 106 in non-Finnish Europeans). The global prevalence for autosomal-dominant fibrinogen disorders was estimated to be ~11 in 1000 individuals, with heterozygous carriers present at a frequency varying from 3 every 1000 individuals in Finns, to 1–2 every 100 individuals among non-Finnish Europeans and Africans/African Americans. Our analysis also allowed for the identification of recurrent (i.e., FGG-p.Ala108Gly, FGG-Thr47Ile) or ethnic-specific mutations (e.g., FGB-p.Gly103Arg in Admixed Americans, FGG-p.Ser245Phe in Africans/African Americans). Full article
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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Open AccessArticle
A Novel Mutation in the Fibrinogen Bβ Chain (c.490G>A; End of Exon 3) Causes a Splicing Abnormality and Ultimately Leads to Congenital Hypofibrinogenemia
Int. J. Mol. Sci. 2017, 18(11), 2470; https://doi.org/10.3390/ijms18112470 - 20 Nov 2017
Abstract
We found a novel heterozygous mutation in the fibrinogen Bβ chain (c.490G>A) of a 3-year-old girl with congenital hypofibrinogenemia. To clarify the complex genetic mechanism, we made a mini-gene including a FGB c.490G>A mutation region, transfected it into a Chinese Hamster Ovary (CHO) [...] Read more.
We found a novel heterozygous mutation in the fibrinogen Bβ chain (c.490G>A) of a 3-year-old girl with congenital hypofibrinogenemia. To clarify the complex genetic mechanism, we made a mini-gene including a FGB c.490G>A mutation region, transfected it into a Chinese Hamster Ovary (CHO) cell line, and analyzed reverse transcription (RT) products. The assembly process and secretion were examined using recombinant mutant fibrinogen. Direct sequencing demonstrated that the mutant RT product was 99 bp longer than the wild-type product, and an extra 99 bases were derived from intron 3. In recombinant expression, a mutant Bβ-chain was weakly detected in the transfected CHO cell line, and aberrant fibrinogen was secreted into culture media; however, an aberrant Bβ-chain was not detected in plasma. Since the aberrant Bβ-chain was catabolized faster in cells, the aberrant Bβ-chain in a small amount of secreted fibrinogen may catabolize in the bloodstream. FGB c.490G>A indicated the activation of a cryptic splice site causing the insertion of 99 bp in intron 3. This splicing abnormality led to the production of a Bβ-chain possessing 33 aberrant amino acids, including two Cys residues in the coiled-coil domain. Therefore, a splicing abnormality may cause impaired fibrinogen assembly and secretion. Full article
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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Review

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Open AccessReview
Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders
Int. J. Mol. Sci. 2018, 19(6), 1597; https://doi.org/10.3390/ijms19061597 - 29 May 2018
Cited by 5
Abstract
Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been identified in individuals with fibrinogen disorders. The complexity of the fibrinogen molecules, formed by three non-identical chains and with a trinodal organization, renders the identification [...] Read more.
Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been identified in individuals with fibrinogen disorders. The complexity of the fibrinogen molecules, formed by three non-identical chains and with a trinodal organization, renders the identification of molecular causes and of clinical and biochemical phenotypes very challenging. However, the acknowledgement of the type of molecular defect is crucial for a safer therapy, which is going to improve the clinical management of these patients. In this review, some aspects concerning molecular and clinical findings available on congenital fibrinogen disorders will be discussed. Full article
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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Open AccessReview
Hereditary Fibrinogen Aα-Chain Amyloidosis in Asia: Clinical and Molecular Characteristics
Int. J. Mol. Sci. 2018, 19(1), 320; https://doi.org/10.3390/ijms19010320 - 22 Jan 2018
Cited by 3
Abstract
Hereditary fibrinogen Aα-chain amyloidosis (Aα-chain amyloidosis) is a type of autosomal dominant systemic amyloidosis caused by mutations in fibrinogen Aα-chain gene (FGA). Patients with Aα-chain amyloidosis have been mainly reported in Western countries but have been rarely reported in [...] Read more.
Hereditary fibrinogen Aα-chain amyloidosis (Aα-chain amyloidosis) is a type of autosomal dominant systemic amyloidosis caused by mutations in fibrinogen Aα-chain gene (FGA). Patients with Aα-chain amyloidosis have been mainly reported in Western countries but have been rarely reported in Asia, with only five patients with Aα-chain amyloidosis being reported in Korea, China, and Japan. Clinically, the most prominent manifestation in Asian patients with Aα-chain amyloidosis is progressive nephropathy caused by excessive amyloid deposition in the glomeruli, which is similar to that observed in patients with Aα-chain amyloidosis in Western countries. In molecular features in Asian Aα-chain amyloidosis, the most common variant, E526V, was found in only one Chinese kindred, and other four kindred each had a different variant, which have not been identified in other countries. These variants are located in the C-terminal region (amino acid residues 517–555) of mature Aα-chain, which was similar to that observed in patients with Aα-chain amyloidosis in other countries. The precise number of Asian patients with Aα-chain amyloidosis is unclear. However, patients with Aα-chain amyloidosis do exist in Asian countries, and the majority of these patients may be diagnosed with other types of systemic amyloidosis. Full article
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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Open AccessReview
Clinical Consequences and Molecular Bases of Low Fibrinogen Levels
Int. J. Mol. Sci. 2018, 19(1), 192; https://doi.org/10.3390/ijms19010192 - 08 Jan 2018
Cited by 9
Abstract
The study of inherited fibrinogen disorders, characterized by extensive allelic heterogeneity, allows the association of defined mutations with specific defects providing significant insight into the location of functionally important sites in fibrinogen and fibrin. Since the identification of the first causative mutation for [...] Read more.
The study of inherited fibrinogen disorders, characterized by extensive allelic heterogeneity, allows the association of defined mutations with specific defects providing significant insight into the location of functionally important sites in fibrinogen and fibrin. Since the identification of the first causative mutation for congenital afibrinogenemia, studies have elucidated the underlying molecular pathophysiology of numerous causative mutations leading to fibrinogen deficiency, developed cell-based and animal models to study human fibrinogen disorders, and further explored the clinical consequences of absent, low, or dysfunctional fibrinogen. Since qualitative disorders are addressed by another review in this special issue, this review will focus on quantitative disorders and will discuss their diagnosis, clinical features, molecular bases, and introduce new models to study the phenotypic consequences of fibrinogen deficiency. Full article
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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