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• W2017403407 abstract "Afibrinogenemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous inheritance of fibrinogen mutations. It is characterized by an absence of clottable plasma fibrinogen, although sensitive immunoassays can often detect trace amounts of the molecule. Common symptoms include joint and mucosal bleeding, but gastrointestinal and central nervous system bleeding have also been described [1]. While seeming contradictory, thrombosis is also a rare manifestation of afibrinogenemia [2]. The proband in this report, a 41-year-old man of Sri Lankan descent, first presented at the age of 29 with hematemesis and melena from a Mallory–Weiss tear. Coagulation studies revealed a functional (Clauss) fibrinogen concentration of <0.1 g L−1 [normal range (NR): 1.5–4.0 g L−1], a thrombin time of >300 s (NR: 18–26 s) and an international normalized ratio of >8.5 (NR: 0.8–1.2). No fibrinogen was detected by radial immunodiffusion, heat precipitation or plasma protein electrophoresis. A diagnosis of afibrinogenemia was made, and the hematemesis managed with cryoprecipitate. He remained well until age 34 when he presented with a cerebral transient ischemic attack. Further investigations suggested a prior apical myocardial infarction with a left ventricular mural thrombus. From age 35–40, the proband experienced recurrent bilateral weakness because of transient ischemic attack and an echocardiogram revealed a persistent mural thrombus. A coagulation screen showed a normal plasminogen radial immunodiffusion assay with a low functional (chromogenic) plasminogen of 39% (NR: 80–120%), most likely because of low fibrin levels causing diminished tissue plasminogen activator activity. All other tests, including antithrombin III, protein C, protein S, activated protein C resistance ratio, lupus anticoagulant, and anticardiolipin antibodies, were normal. Treatment with low-dose warfarin was ineffective and therapeutic dose low-molecular weight heparin (enoxaparin) resulted in bleeding complications, including melena that required transfusion, as did antiplatelet therapy in combination with low-dose enoxaparin. The reason for the bleeding is obvious, as no significant fibrin clot can be formed. The thromboembolic events are probably because of fibrin being a cofactor of platelet aggregation, such that large, loosely packed and unstable platelet thrombi form in the absence of fibrin. It was concluded that the proband was best managed on low-dose (20 mg) enoxaparin twice daily, which he has taken for 8 months without any further bleeding or thrombotic episodes. Quantitative Western blot of purified fibrinogen revealed a normal pattern of Aα, Bβ, and γ chains, and indicated a fibrinogen concentration approximately one 50th of normal levels, or ∼0.05 g L−1 (Fig. 1). It was concluded that the proband had very severe hypofibrinogenemia and that his three-fibrinogen chains were of normal size. Western blot of 7.5% reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis of purified fibrinogen. Citrate plasma was collected at a time when cryoprecipitate had not recently been transfused. Fibrinogen was purified from plasma by precipitation with 35% saturated ammonium sulfate [3]. The purified proteins were diluted appropriately and analyzed by Western blot with rabbit polyclonal antibody to human fibrinogen (DakoCytomation, Glostrup, Denmark). Lane 1, 1 μL normal control with plasma fibrinogen concentration of 2.5 g L−1 (equivalent to 1:125 final dilution of plasma); Lane 2, 1 μL proband (1:2.5 final dilution; thus, 50× normal control loading). Densitometry of fibrinogen bands revealed that the proband had a fibrinogen concentration approximately one 50th of normal levels, or ∼0.05 g L−1 (Quantity One software; Bio-Rad, Hercules, CA, USA). In order to determine the underlying genetic abnormality, all exons, intron–exon boundaries and promoters of all three-fibrinogen genes were sequenced using standard methods. Surprisingly, no mutation was detected, and long-range polymerase chain reactions coupled with restriction endonuclease digestions ruled out any large-scale rearrangement within a fibrinogen gene. Furthermore, no gross chromosomal translocations or deletions could be detected by karyotype analysis or fluorescent in situ hybridization of the fibrinogen gene cluster. However, the proband was homozygous at every polymorphic locus in the fibrinogen cluster, most likely because of his two chromosomes being identical by descent. His parents in Sri Lanka were consanguineous, as in ∼50% of all afibrinogenemia cases [4]. The implication of this was that the proband would probably be homozygous for an intronic mutation that was leaky enough to produce a small amount of normal fibrinogen. Indeed, when all introns were sequenced, a single homozygous a→g substitution was found within intron 1 of the Bβ gene (FGB), 2076 nucleotides from exon 1 and 600 nucleotides from exon 2: FGB IVS1+2076 a→g. This was not found in 50 normal controls from the Christchurch population and no other fibrinogen mutation was identified in any exon, intron or promoter. The proband's two children, a 7-year-old girl and 6-year-old boy, were heterozygous for FGB IVS1+2076 a→g. Both had low functional fibrinogen concentrations (1.6 and 1.4 g L−1, respectively). All stages of thrombin-catalyzed fibrin polymerization were normal in each child and it was concluded that they had inherited hypofibrinogenemia. The fact that the variant affects FGB is consistent with the hypofibrinogenemic phenotype of this family, as production of Bβ chains is rate-limiting [5]. Furthermore, heterozygous point mutations within the Bβ and γ chains, but not the Aα chains, are able to cause hypofibrinogenemia [6]. Afibrinogenemia (or severe hypofibrinogenemia) is usually caused by large deletions or missense, splice site (reviewed in Neerman-Arbez [7]), frameshift or nonsense mutations (Aα [8], Bβ [9], γ [10]). None of these was detected here. Instead, only a single nucleotide change was identified after all three-fibrinogen genes had been sequenced in their entirety: FGB IVS1+2076 a→g. The question remained as to whether this variant, located deep within an intron, affects plasma fibrinogen levels. The computer program SpliceView [11] predicted that the mutation should not affect pre-mRNA splicing, arguing against the possibility that it creates a cryptic exon boundary. However, it may result in expression of an aberrant mRNA by affecting: (i) binding of a silencer or enhancer, preventing authentic splice sites being distinguished from pseudo sites with identical signal sequences; (ii) RNA secondary structure; (iii) splicing at the correct sites [12, 13]. There is a precedent for this type of deep intronic mutation causing disease: a mutation at a similar intronic location, approximately 2000 nucleotides from exon 20 and 600 nucleotides from exon 21 of the ATM gene, affects splicing by activation of a cryptic exon [14]. Cases such as these illustrate the importance of investigating non-coding regions for pathological mutations and emphasize the care that is needed when assessing the significance of a sequence variant. While we were unable to carry out the functional splicing assays that might shed light on the mechanism involved, we hope that this report will stimulate others to look for this mutation in cases where there is no easily identifiable cause for hypo- or afibrinogenemia. Ethical approval was granted for this work and the patients involved gave informed consent. We wish to thank all family members for their participation in this study." @default.
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• W2017403407 title "An intronic mutation within FGB (IVS1+2076 a→g) is associated with afibrinogenemia and recurrent transient ischemic attacks" @default.
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