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Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders

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Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders International Journal of Molecular Sciences Review Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders Giovanni Luca Tiscia 1 and Maurizio Margaglione 2,* ID 1 Atherosclerosis and Thrombosis Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; [email protected] 2 Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy * Correspondence: [email protected]; Tel.: +39-0881-733-842 Received: 15 April 2018; Accepted: 25 May 2018; Published: 29 May 2018 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 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. Keywords: afibrinogenemia; hypofibrinogenemia; dysfibrinogenemia 1. Introduction Fibrinogen is a 45 nm-long plasma glycoprotein with a molecular weight of 340 KDa. It is synthetized in the liver [1] and has a plasma concentration of 1.5–3.5 g/L. Structurally, it consists of 2 identical monomers, each constituted by 3 non-identical polypeptide chains, namely alpha, beta and gamma chains [2–4], which interact through 17 crucial inter-chains disulfide bridges, to ensure structural stabilization of the fibrinogen molecules [5,6]. Fibrinogen has a typical trinodal organization, presenting one central (node E) and two distal nodes (nodes D) [7]. The central one is characterized by N-terminal ends of the six polypeptide chains, while the distal ones are made by C-terminal ends of beta and gamma chains, whereas the C-terminal of the alpha chain folds to further form the central node [8–10]. The central and distal nodes are connected through coiled-coil regions, built by three α-helices of the three fibrinogen chains, wound around each other. The fibrinogen has a well-established role in the clotting enzymatic cascade, representing the fibrin polymer precursor. The impaired mechanism of fibrinogen formation and fibrin polymerization can have a clinical impact on the occurrence and outcome of various diseases, such as coagulopathies, or ischemic stroke and also obstetrical complications [11]. Fibrinogen disorders may also have a clinical impact on afore-mentioned diseases. Fibrinogen is an acute phase protein that is part of the coagulation cascade and is converted into the insoluble protein fibrin during the clotting process. The activated thrombin or Factor II (FIIa) converts fibrinogen to fibrin in response to bleeding. FIIa rapidly proteolyses fibrinogen, releasing two peptides, fibrinopeptide A and fibrinopeptide B, from fibrin and, in turn, forms fibrin monomers, which spontaneously polymerize to form an insoluble gel. Then, fibrin molecules, the major component of the blood clot, combine to form long fibrin threads that entangle platelets, building up a spongy mass that gradually hardens and contracts to form the blood clot, blocking the damaged blood vessel and preventing further bleeding (Figure1). The polymerized Int. J. Mol. Sci. 2018, 19, 1597; doi:10.3390/ijms19061597 www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci.Sci. 20182018,, 1919,, 1597x FOR PEER REVIEW 2 2of of 12 12 bleeding (Figure 1). The polymerized fibrin molecules are held together by non-covalent and fibrinelectrostatic molecules forces are and held stabilized together by bythe non-covalenttransamidating and enzyme, electrostatic factor XIIIa, forces that and is stabilizedproduced by by the the transamidatingaction of FIIa on enzyme, FXIII. Traditio factor XIIIa,nally, thatthe fibrinogen is produced disorders by the actionare categorized of FIIa on as FXIII. quantitative Traditionally, and thefunctional fibrinogen disorders. disorders For are the categorized identification as quantitative of both classes and functionalof disease disorders.either immunological For the identification assays, ofwhich both classesare able of to disease quantify either complete immunological absence of assays, circulating which fibrinogen are able to molecules, quantify complete and functional absence ofmethods, circulating e.g., fibrinogen the Clauss molecules, method, and a functionalquantitative methods, assay which e.g., the allows Clauss measuring method, athe quantitative rate of assayconversion which of allows clottable measuring fibrinogen the rateinto of fibrin conversion [12], are of clottableused. Fibrinogen fibrinogen disorders into fibrin may [12 be], aredue used. to Fibrinogenacquired or disorders genetic causes. may be Liver due to diseases, acquired cancer, or genetic disseminated causes. Liver intravascular diseases, cancer, coagulation disseminated (DIC), intravascularpost-translational coagulation modifications, (DIC), post-translationalassay interferences modifications, are some of well-known assay interferences causes of are acquired some of well-knownfibrinogen disorders causes of [13]. acquired Inherited fibrinogen disorders disorders of fibrinogen [13]. Inherited molecules, disorders the topic of fibrinogen of this review, molecules, are thedue topic to genetic of this alterations review, are occurring due to genetic within alterations genes coding occurring for the within fibrinogen genes chains. coding These for the genes fibrinogen show chains.dissimilar These genomic genes sequences, show dissimilar although genomic they ha sequences,ve been found although to arise they from have a beencommon found ancestral to arise fromgene a[14]. common Recombinant ancestral DNA gene walking [14]. Recombinant experiments DNAallowed walking to discover experiments that all three allowed genes to map discover on thatthe same all three chromosomal genes map region, on the even same though chromosomal they show region, an opposite even though transcription they show orientation an opposite [15]. transcriptionThe fibrinogen orientation genes cluster [15]. on The human fibrinogen chromosome genes cluster4, in a region on human of approximately chromosome 50 4, kb. ina The region gene of approximatelycoding for the 50fibrinogen kb. The alpha gene codingchain (gene for the symbol, fibrinogen FGA alphaapproved chain by (gene HUGO symbol, Gene NomenclatureFGA approved byCommittee) HUGO Gene has Nomenclaturea 7.6 kb size and Committee) consists of 6 has exon a 7.6s [16], kb while size and the consistsfibrinogen of 6beta exons chain [16 gene], while (gene the fibrinogensymbol, FGB beta) occupies chain gene an 8 (gene kb sized symbol, regionFGB and) occupies presents an 8 exons. 8 kb sized Finally, region the andgene presents coding for 8 exons. the Finally,fibrinogen the genegamma coding chain for (gene the fibrinogensymbol, FGG gamma) encompasses chain (gene an 8.5 symbol, kb regionFGG )and encompasses presents 10 an exons. 8.5 kb regionCongenital and presents fibrinogen 10 exons.disorders Congenital are uncommon fibrinogen and disorders can be associated are uncommon with an and altered can be synthesis, associated withassembly, an altered protein synthesis, stability assembly, and/or with protein dysfunctional stability and/or fibrinogen with dysfunctional molecules. Afibrinogenemia fibrinogen molecules. and Afibrinogenemiahypofibrinogenemia and indicate hypofibrinogenemia quantitative fibrinogen indicate disorders. quantitative They fibrinogen are mostly disorders. caused by They genetic are mostlyvariations caused affecting by genetic plasma variations amounts of affecting fibrinogen plasma. On the amounts other hand, of fibrinogen. dysfibrinogenemia On the other indicates hand, dysfibrinogenemiaqualitative fibrinogen indicates disorders, qualitative which fibrinogen are mostly disorders, determined which by are genetic mostly variations determined modifying by genetic variationsfibrinogen modifyingfunctionality. fibrinogen An extensive functionality. review Anof laboratory extensive reviewissues ofand laboratory an update issues of genetic and an updatediagnosis of geneticconcerning diagnosis the fibrinogen concerning disorders the fibrinogen has been disorders made by has Neerman-Arbez been made by Neerman-Arbezand colleagues [17]. Because congenital fibrinogen disorders are rare, to not duplicate available articles reviewing and colleagues [17]. Because congenital fibrinogen disorders are rare, to not duplicate available the literature, we attempt to provide an update, focusing on molecular aspects and articles reviewing the literature, we attempt to provide an update, focusing on molecular aspects genotype-phenotype correlations in quantitative (afibrinogenemia, hypofibrinogenemia) and and genotype-phenotype correlations in quantitative (afibrinogenemia, hypofibrinogenemia) and functional disorders (dysfibrinogenemia). functional disorders (dysfibrinogenemia). Figure 1. A sketch representing the physiologic role of fibrinogen in the clot formation. The fibrinogen Figure 1. A sketch representing the physiologic role of fibrinogen in the clot formation. The molecule links activated platelets together (white clot) through the alphaIIb–beta3integrin that serves fibrinogen molecule links activated platelets together
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