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Extension of the Human Fibrinogen Database with Detailed Clinical Information-The αC-Connector Segment
Zofie Sovova1, Klara Pecankova1, Pavel Majek1
1Department of Biochemistry, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 12800 Prague, Czech Republic.
Insights
Fibrinogen mutations in the αC-connector cause bleeding and thrombotic disorders. Homozygous mutations are typically symptomatic, while heterozygous ones are often not, impacting coagulation and fibrinolysis.
Area of Science:
- Biochemistry
- Genetics
- Hematology
Background:
- Fibrinogen is a key plasma glycoprotein in blood coagulation.
- Mutations in fibrinogen can lead to bleeding and thrombotic disorders.
- The Human Fibrinogen Database catalogs clinically relevant mutations.
Purpose of the Study:
- To extend the Human Fibrinogen Database for the αC-connector region (amino acids Aα240-410).
- To detail clinical manifestations, bleeding/thrombotic events, and coagulation assay results for family members with mutations.
- To report the impact of mutations on clotting and fibrinolysis.
Main Methods:
- Database extension with clinical data.
- Analysis of mutation types (missense, synonymous, nonsense, frameshift).
- Correlation of mutation location and type with clinical phenotypes.
Main Results:
- Homozygous nonsense or frameshift mutations in the αC-connector cause most clinically relevant symptoms.
- Heterozygous mutations are frequently asymptomatic.
- Symptomatic individuals experience bleeding, less commonly thrombotic events, miscarriages, and prolonged wound healing.
- Thrombotic phenotypes arise from mutations at specific tandem repeat positions.
Conclusions:
- The αC-connector region harbors clinically significant fibrinogen mutations.
- Mutation type (homozygous vs. heterozygous) and location dictate clinical presentation.
- Understanding these mutations aids in diagnosing and managing coagulation disorders.
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.
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