Fibrinogen gamma-chain splice variant γ′ alters fibrin formation and structure

Cooper, Amy V.; Standeven, Kristina F.; Ariëns, Robert A. S.

doi:10.1182/blood-2002-10-3150

Cited by 127 publications

(150 citation statements)

References 32 publications

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“…44 They also demonstrate reduced fiber diameter, increased branching, and reduced pore size (Table). 45 This seems clinically relevant because similar fibrin structures have previously been related to an increased risk of thrombosis, 13,21,46 and patients with coronary artery disease have higher ␥A/␥Ј fibrinogen levels, which is an effect that is independent of total fibrinogen levels. 47 …”

Section: Variations In the Splicing Of Fibrinogen Gene Transcriptsmentioning

confidence: 90%

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Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

138

129

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Abstract-The formation of a fibrin clot is one of the key events in atherothrombotic vascular disease. The structure of the fibrin clot and the genetic and environmental factors that modify it have effects on its biological function. Alterations in fibrin structure and function have implications for the clinical presentation of vascular disease. This review briefly describes the key features involved in the formation of a fibrin clot, its typical structure, and function. This is followed by a review of the current literature on genetic and environmental influences on fibrin structure/function and the relationship to clinical disease. Key Words: fibrin Ⅲ hemostatis Ⅲ genetic Ⅲ environment Ⅲ atherothrombosis D iseases associated with the development of thrombosis are a major cause of morbidity and mortality in the developed world. Atherothrombotic vascular disorders develop over many decades and involve the interaction of classic atherogenic risk factors such as diabetes, hyperlipidemia, and hypertension with abnormalities of the inflammatory and hemostatic systems. Arterial disease develops in a high-pressure, high-flow system, with lipid deposition and smooth muscle hyperplasia occurring to form an atherosclerotic plaque. 1 Subsequently, the plaque becomes unstable and ruptures exposing a prothrombotic lipid core activating the clotting cascade and leading to the development of a platelet-rich fibrin blood clot and arterial thrombotic occlusion. The extent of this process determines clinical outcome, ranging from no clinically noticeable event to acute coronary artery syndromes including myocardial infarction (MI), cerebrovascular and peripheral vascular disease, or sudden death. The Formation of a Fibrin ClotFibrin is the major protein constituent of the blood clot and is formed from fibrinogen, a glycoprotein that circulates largely inactively, in the blood stream. Fibrinogen consists of 6 polypeptide chains (A␣, B␤, ␥) 2 held together by disulphide bonds in a molecule with bilateral symmetry (Figure 1). The molecule consists of 3 main structural regions, 2,3 including a central region (E), which contains fibrinopeptides A and B and the amino acid termini of all 6 polypeptide chains, 2 distal regions (D) connected to the E region by 2 ␣-helical coiled segments and the D regions containing the carboxyl termini of the B␤ and ␥ chains, and those of the A␣ chain, which extend to form relatively flexible ␣C-domains, each ending in a globular domain. 2,3 In situations of tissue injury and inflammation, thrombin is generated after cleavage of prothrombin by the Xase complex. Thrombin subsequently binds to fibrinogen and cleaves the amino termini of the fibrinogen A␣ and B␤ chains at region E. This results in the release of fibrinopeptides A and B from fibrinogen, producing fibrin and initiating fibrin clot formation. Release of fibrinopeptide A by thrombin is fast and exposes a polymerization site on the E region of fibrin. 4,5 This combines with a complementary binding site on the ␥ chain in the D region of an adjac...

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Section: Variations In the Splicing Of Fibrinogen Gene Transcriptsmentioning

confidence: 90%

“…69 This may be one reason why associations between the clinical disease phenotype and single genetic polymorphisms in coagulation factors are inconsistent. 49 [42][43][44][45] Increases risk for MI 47 Fibrinogen A␣ E C Unknown None?…”

Section: Genetic and Environmental Interaction On Fibrinogen Levelsmentioning

confidence: 99%

Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

138

129

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“…So while ' on one hand protects thrombin against degradation and increases thrombin generation in plasma, it inhibits exosite II driven procoagulant reactions on the other hand. Exosite I driven reactions such as the cleavage of fibrinopeptide A by thrombin remain unaffected [24]. Some of these functions are not compatible with antithrombin activity, but highlight a modulating activity of thrombin activity by ' consistent with the inhibition of exosite II directed reactions, hence the term thrombomodulin II to more accurately describe the interactions between ' and thrombin.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ′ as thrombomobulin II

Duval

Ariëns

2017

Matrix Biology

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ReuseUnless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ÔØ Å ÒÙ× Ö ÔØ A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractFibrin is an important matrix protein that provides the backbone to the blood clot, promoting tissue repair and wound healing. Its precursor fibrinogen is one of the most heterogenous proteins, with an estimated 1 million different forms due to alterations in glycosylation, oxidation, single nucleotide polymorphisms, splice variation and other variations. Furthermore, ligation by transglutamimase factor XIII (cross-linking) adds to the complexity of the fibrin network. The structure and function of the fibrin network is in part determined by this natural variation in the fibrinogen molecule, with major effects from slice variation and cross-linking. This mini-review will discuss the direct effects of fibrinogen EC and fibrinogen ' splice variation on clot structure and function and also discuss the additional role of fibrinogen ' as thrombomodulin II. Furthermore, the effects of crosslinking on clot function will be described. Splice variation and cross-linking are major determinants of the structure and function of fibrin and may therefore impact on diseases affecting bleeding, thrombosis and tissue repair.

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“…In normal human hepatocytes, two kinds of γ-chain are translated from FGG, one constructed with 411 amino acids (85-92%), and the other with 427 amino acids, named γ'-chain (8-15%) [11]. The γ'-chain is an alternative splicing product and is translated by extension of exon 9 and terminating at codon 428.…”

Section: Discussionmentioning

confidence: 99%

Nonsense-mediated mRNA decay was demonstrated in two hypofibrinogenemias caused by heterozygous nonsense mutations of FGG, Shizuoka III and Kanazawa II

Soya

Takezawa

Okumura

et al. 2013

Thrombosis Research

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SummaryWe report two novel hypofibrinogenemias, Shizuoka III and Kanazawa II, which are caused by heterozygous mutations in FGG. Shizuoka III showed c.147delT and 147_149insACA in FGG exon 3 and a subsequent frameshift mutation, resulting in γ23X (stop codon), and Kanazawa II showed c.1205G>A in FGG exon 9, resulting in γ376X.To determine whether the truncated γ-chains, γ23X and γ376X, were synthesized and participated in the assembly of fibrinogen, mutant-type cDNA vectors were transfected into Chinese hamster ovary (CHO) cells. Significant levels of mutant fibrinogen were not detected by ELISA in the culture media and cell lysates. Immunoblot analysis of cell lysates revealed that the mutant γ-chain of γ376X was observed but intact fibrinogen was not. On the other hand, mutant γ-chain was not observed in γ23X-expressing cells.To demonstrate the involvement of the mechanisms of nonsense-mediated mRNA decay (NMD), we cloned wild-and mutant-type mini-genes containing γ23-or γ376-codon and transfected these into CHO cell lines in the absence or presence of cycloheximide (CHX) as an NMD inhibitor. mRNA levels were determined using real-time quantitative RT-PCR in CHO cells. In the absence of CHX, levels of mRNAs transcribed from the mutant gene were lower than from the wild-type gene whereas, in the presence of CHX, levels of mRNAs transcribed from the mutant gene increased dose-dependently. 3Finally, these results demonstrated that aberrant mRNAs containing γ23X or γ376X are degraded by the NMD system and translation decrease in hepatocytes, resulting in hypofibrinogenemias.4

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Fibrinogen gamma-chain splice variant γ′ alters fibrin formation and structure

Cited by 127 publications

References 32 publications

Genetic and Environmental Determinants of Fibrin Structure and Function

Genetic and Environmental Determinants of Fibrin Structure and Function

Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ′ as thrombomobulin II

Nonsense-mediated mRNA decay was demonstrated in two hypofibrinogenemias caused by heterozygous nonsense mutations of FGG, Shizuoka III and Kanazawa II

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