Molecular Basis of Fibrinogen Deficiency

Neerman-Arbez, Marguerite

doi:10.1159/000093566

Cited by 24 publications

(27 citation statements)

References 62 publications

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“…The mutations we describe have hitherto fore not been described in Germany. Fibrinogen is a coagulation plasma protein synthesized mainly in the liver [16]. The fibrinogen molecule is a 45-nm structure consisting of two sets of disulfide-bridged Aα-, Bβ-, and γ-chains.…”

Section: Discussionmentioning

confidence: 99%

“…The FGA gene spans over 7 kb and contains six exons. Alternative splicing results in two isoforms, which vary in the carboxyterminus [16]. Although FGA mutations are rare, their effects are profound, namely dysfibrinogenemia, hypofibrinogenemia, afibrinogenemia, or AFib amyloidosis [16].…”

Section: Discussionmentioning

confidence: 99%

“…Alternative splicing results in two isoforms, which vary in the carboxyterminus [16]. Although FGA mutations are rare, their effects are profound, namely dysfibrinogenemia, hypofibrinogenemia, afibrinogenemia, or AFib amyloidosis [16]. All six AFib amyloidosis mutations observed thus far are located in exon 5 and affect one ore more residues at amino acid positions 517-554.…”

Section: Discussionmentioning

confidence: 99%

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Three German fibrinogen Aα-chain amyloidosis patients with the p.Glu526Val mutation

et al. 2008

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Plasma protein fibrinogen variants cause fibrinogen A alpha-chain (AFib) amyloidosis, which presents with hypertension, proteinuria, and azotemia. Six AFib mutations have been reported thus far. We identified three patients who presented with marked proteinuria and serum creatinine elevations. Their kidney biopsies revealed destruction of the glomerular architecture by amyloid deposits with typical, apple-green birefringence in polarized light after Congo red staining. We found immunoreactivity against fibrinogen, which is typical for this type of amyloidosis. We sequenced the FGA exon 5 and demonstrated heterozygosity for the p.Glu526Val mutation in all three cases. This amino acid substitution is the most common fibrinogen A alpha-chain variant causing AFib amyloidosis. The mutation has been reported in individuals of European and American descent but not yet in German patients. AFib amyloidosis should therefore be considered an important differential diagnosis in German patients with renal amyloidosis. In the cases described here, the use of antibodies directed against fibrinogen, followed by direct gene sequencing, revealed the underlying cause.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Three German fibrinogen Aα-chain amyloidosis patients with the p.Glu526Val mutation

et al. 2008

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“…The inability to properly form or degrade a fibrin clot can have profound clinical consequences resulting in thrombotic or hemorrhagic events [15]. Polymorphisms or mutations of fibrinogen are numerous and can result in either normal circulating levels of fibrinogen with abnormal function termed dysfibrinogenemia, or reduced or absent fibrinogen in circulation termed hypofibrinogenemia and afibrinogenemia respectively [16].…”

Section: Fig (1) Soluble Fibrinogen Is Converted To Insoluble Fibrinmentioning

confidence: 99%

Fibrinogen Signal Transduction as a Mediator and Therapeutic Target in Inflammation:Lessons from Multiple Sclerosis

Adams

Schachtrup²,

Davalos³

et al. 2007

CMC

135

123

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The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the molecular nexus of coagulation, inflammation and immunity. Studies in animal models and in human disease have demonstrated that extravascular fibrinogen that is deposited in tissues upon vascular rupture is not merely a marker, but a mediator of diseases with an inflammatory component, such as rheumatoid arthritis, multiple sclerosis, sepsis, myocardial infarction and bacterial infection. The present article focuses on the recent discoveries of specific cellular targets and receptors for fibrinogen within tissues that have extended the role of fibrinogen from a coagulation factor to a regulator of inflammation and immunity. Fibrinogen has the potential for selective drug targeting that would target its proinflammatory properties without affecting its beneficial effects in hemostasis, since it interacts with different receptors to mediate blood coagulation and inflammation. Strategies to target receptors for fibrinogen and fibrin within the tissue microenvironment could reveal selective and disease-specific agents for therapeutic intervention in a variety of human diseases associated with fibrin deposition.

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“…Mutations in one of the fibrinogen genes can cause afibrinogenemia, but causal mutations have been found predominantly in FGA. 2 Afibrinogenemia is rare, affecting about 1 in 10 6 individuals, and can be treated by replacement therapy. However, as with other heritable bleeding disorders, the variable phenotype of afibrinogenemia is not fully understood, and an experimental system where genetic and environmental influences on phenotype could be assessed would be a useful research tool.…”

Section: Introductionmentioning

confidence: 99%

Targeted mutation of zebrafish fga models human congenital afibrinogenemia

Fish

Sanza

Neerman-Arbez

2014

Blood

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Mutations in the human fibrinogen genes can lead to the absence of circulating fibrinogen and cause congenital afibrinogenemia. This rare bleeding disorder is associated with a variable phenotype, which may be influenced by environment and genotype. Here, we present a zebrafish model of afibrinogenemia. We introduced targeted mutations into the zebrafish fga gene using zinc finger nuclease technology. Animals carrying 3 distinct frameshift mutations in fga were raised and bred to produce homozygous mutants. Using a panel of anti-zebrafish fibrinogen antibodies, fibrinogen was undetectable in plasma preparations from homozygous mutant fish. We observed hemorrhaging in fga mutants and reduced survival compared with control animals. This model will now serve in the search for afibrinogenemia modifying genes or agents and, to our knowledge, is the first transmissible zebrafish model of a defined human bleeding disorder

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Molecular Basis of Fibrinogen Deficiency

Cited by 24 publications

References 62 publications

Three German fibrinogen Aα-chain amyloidosis patients with the p.Glu526Val mutation

Three German fibrinogen Aα-chain amyloidosis patients with the p.Glu526Val mutation

Fibrinogen Signal Transduction as a Mediator and Therapeutic Target in Inflammation:Lessons from Multiple Sclerosis

Targeted mutation of zebrafish fga models human congenital afibrinogenemia

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