Hypodysfibrinogenaemia due to production of mutant fibrinogen alpha-chains lacking fibrinopeptide A and polymerisation knob ‘A’

Abstract

Summary Inherited disorders of fibrinogen are rare and affect either the quantity (hypofibrinogenaemia and afibrinogenaemia) or the quality of the circulating fibrinogen (dysfibrinogenaemia) or both (hypodysfibrinogenaemia). Extensive allelic heterogeneity has been found for all these disorders: in congenital afibrinogenaemia for example more than 40 mutations, the majority in FGA, have been identified in homozygosity or in compound heterozygosity. Numerous mutations have also been identified in patients with hypofibrinogenaemia, many of these patients are in fact heterozygous carriers of afibrinogenaemia mutations. Despite the number of genetic analyses performed, the study of additional patients still allows the identification of novel mutations. Here we describe the characterization of a novel FGA intron 2 donor splice-site mutation (Fibrinogen Montpellier II) identified in three siblings with hypodysfibrinogenaemia. Functional analysis of RNA produced by the mutant minigene in COS-7 cells revealed that the mutation led to the in-frame skipping of exon 2. Western blot analysis of COS-7 cells expressing an exon 2 deleted FGA cDNA revealed that an alpha-chain lacking exon 2, which codes in particular for fibrinopeptide A and polymerisation knob ‘A’, has the potential to be assembled into a hexamer and secreted. Analysis of precipitated fibrinogen from patient plasma showed that the defect leads to the presence in the circulation of alpha-chains lacking knob ‘A’ which is essential for the early stages of fibrin polymerisation. Fibrin made from purified patient fibrinogen clotted with thrombin displayed thinner fibers with frequent ends and large pores.

Three cases of congenital dysfibrinogenemia in unrelated Chinese families

“…[31] Fibrils undergo lateral associations to make up the physical meshwork of the coagulum. The initiating event in normal clot formation is the release of FPA, which exposes 1 set of polymerization domains.…”

Enhanced biocompatibility of CD47-functionalized vascular stents

“…Opened stents were fixed with 2% glutaraldehyde in sodium cacodylate buffer with 0.1 M sodium chloride and then rinsed, dehydrated with serial ethanol dilutions followed by hexamethyldisi-lazane (HMDS, EMS), and sputter-coated with gold palladium (Polaron, Williston, VT) as described previously [27]. Ten digital micrographs at random areas were recorded for analysis using SEM (Quanta250, FEI, Hillsboro, OR).…”

De novo 6.9 Mb interstitial deletion on chromosome 4q31.1‐q32.1 in a girl with severe speech delay and dysmorphic features

“…Finally, our patient shows an abnormal coagulation profile (hypofibrinogenemia and increased activation of partial thromboplastin) with no thrombosis or bleeding event reported. This condition could be explained by the deletion of the FGB/A/G genes [Neerman‐Arbez, 2001; Vorjohann et al, 2010], which code for three different protein components of the fibrinogen, a blood‐borne glycoprotein, whose function is related to platelet aggregation. It is well described that mutations in this genes lead to several disorders, including afibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia that give increased risk to develop bleeding disorders or thrombosis events.…”