Fibrinogen Hershey IV: A novel dysfibrinogen with a γV411I mutation in the integrin αIIbβ3 binding site

Abstract

The carboxyl terminal segment of the fibrinogen gamma chain from gamma408-411 plays a crucial role in platelet aggregation via interactions with the platelet receptor alpha(IIb)beta(3). We describe here the first naturally-occurring fibrinogen point mutation affecting this region and demonstrate its effects on platelet interactions. DNA sequencing was used to sequence the proband DNA, and platelet aggregation and direct binding assays were used to quantitate the biological effects of fibrinogen Hershey IV. The Hershey IV proband was found to be heterozygous for two mutations, gammaV411I and gammaR275C. Little difference in aggregation was seen when fibrinogen Hershey IV was compared to normal fibrinogen. However, less aggregation inhibition was observed using a competing synthetic dodecapeptide containing the V411I mutation as compared to the wild-type dodecapeptide. Purified fibrinogen Hershey IV also bound to purified platelet alpha(IIb)beta(3) with a lower affinity than wild-type fibrinogen. These findings show that the gammaV411I mutation results in a decreased ability to bind platelets. In the heterozygous state, however, the available wild-type fibrinogen appears to be sufficient to support normal platelet aggregation.

Severe bleeding in a woman heterozygous for the fibrinogen γR275C mutation

“…Excessive bleeding was also reported in another patient with the γR275C mutation whose dysfibrinogen, Fibrinogen Hershey IV, was characterized previously by our laboratory [8]. In this case, the proband was a 52-year-old woman who gave a history of frequent, sometimes prolonged epistaxis as a child.…”

“…However, Fibrinogen Hannover IV and Hershey IV are associated with hemorrhage, while Fibrinogens Bellingham, Bologna, Cedar Rapids, and Villajoyosa are associated with thrombosis, although all these dysfibrinogens contain a γR275C mutation. A mechanistic explanation for the hemorrhagic phenotype associated with Fibrinogen Hershey IV is also complicated by the fact that Hershey IV proband is a compound heterozygote with a novel γV411I mutation in the platelet integrin αIIbβ3 binding site [8]. The present report provides evidence that the γR275C mutation alone in Fibrinogen Portland I can result in a hemorrhagic phenotype.…”

Three cases of abnormal fibrinogens: Šumperk (Bβ His67Leu), Uniãov (Bβ Gly414Ser), and Brno (γArg275His)

“…The molecule consists of threedifferent pairs of polypeptide chains -Aα,Bβ,and γ (1).Aclusterofthreegenes (FGA, FGB, and FGG)coding individual chains is situatedatchromosome 4( 4q31.3.4q32.1) (2).Amutation in anyo ft hese genes maylead to congenitalafibrinogenemia, hypofibrinogenemia or dysfibrinogenemia. Among the 454 reported fibrinogen abnormalities are248 mutations in the Aα chain, 66 mutations in the Bβ chain, and 137 mutations in the γ chain (3).Several mutations were described during the last twoyears (4)(5)(6)(7)(8)(9). In this study, we identifiedanovel mutation Bβ His67Leu causing hypofibrinogenemia, and twoc ases of mutations alreadyd escribed -B β Gly414Ser,and γArg275His.…”

Two cases of congenital dysfibrinogenemia associated with thrombosis – Fibrinogen Praha III and Fibrinogen Plzeň

“…Dysfibrinogenemias are associated with low functional fibrinogen level and prolonged thrombin time, and can result from a variety of different mutations. About 454 mutations in fibrinogen have been identified worldwide (4); and several mutations were described during the last two years (5)(6)(7)(8)(9)(10). The majority of cases are asymptomatic.…”