Abstract
Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are manifested mainly in bleeding and thrombotic disorders. Clinically relevant mutations of fibrinogen are listed in the Human Fibrinogen Database. For the αC-connector (amino acids Aα240–410, nascent chain numbering), we have extended this database, with detailed descriptions of the clinical manifestations among members of reported families. This includes the specification of bleeding and thrombotic events and results of coagulation assays. Where available, the impact of a mutation on clotting and fibrinolysis is reported. The collected data show that the Human Fibrinogen Database reports considerably fewer missense and synonymous mutations than the general COSMIC and dbSNP databases. Homozygous nonsense or frameshift mutations in the αC-connector are responsible for most clinically relevant symptoms, while heterozygous mutations are often asymptomatic. Symptomatic subjects suffer from bleeding and, less frequently, from thrombotic events. Miscarriages within the first trimester and prolonged wound healing were reported in a few subjects. All mutations inducing thrombotic phenotypes are located at the identical positions within the consensus sequence of the tandem repeats.
Highlights
Heterozygous carriers of the Champagne au Mont d’Or compound mutation and AαP289T are diagnosed with dysfibrinogenemia due to the presence of abnormal fibrinogen in the blood, the values of functional and antigenic fibrinogen in these subjects are within the normal range
We reviewed mutations in the αC-connector of fibrinogen and cataloged as much clinically and structurally relevant information about each item as possible
Our work revealed that the general COSMIC and dbSNP databases contain considerably more missense and synonymous mutations than the Human Fibrinogen Database (HFD), the database focused on clinically relevant mutations in fibrinogen
Summary
Sci. 2022, 23, 132 hepatic parenchymal cells, with the Bβ chain considered the rate-limiting chain [7] During assembly these chains form heterotrimers and two such trimers consecutively interlink in a centrosymmetric manner with their N-termini oriented towards each other [5]. The fibrin monomer is formed by the thrombin cleavage of fibrinopeptides A and B from the N-termini of the fibrinogen Aα and Bβ chains. The Bβ and γ chains further form a globular fibrinogen-related domain; its structure is described, e.g., in works [9,10]. The Aα chain loops back, making a short α-helix of 17 AAs that is anti-parallel to the coiled-coil domain with which it interacts in a hydrophobic manner. The αC-domain interacts with the N-termini of fibrinogen but not of fibrin [12].
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