Title
Molecular basis for fibrinogen Dusart (Aα 554 Arg → Cys) and its association with abnormal fibrin polymerization and thrombophilia
Author
Koopman, J.
Haverkate, F.
Grimbergen, J.
Lord, S.T.
Mosesson, M.W.
DiOrio, J.P.
Siebenlist, K.S.
Legrand, C.
Soria, J.
Soria, C.
Caen, J.P.
Instituut voor verouderings- en vaatziekten onderzoek TNO
Publication year
1993
Abstract
The molecular defect in the abnormal fibrinogen Dusart (Paris V) that is associated with thrombophilia was determined by sequence analysis of genomic DNA that had been amplified using the polymerase chain reaction. The propositus was heterozygous for a single base change (C → T) in the Aα- chain gene, resulting in the amino acid substitution Aα 554 Arg → Cys. Restriction analysis of the amplified DNA derived from the family members showed that his father and his two sons were also heterozygous. Electron microscopic studies on fibrin formed from purified fibrinogen Dusart demonstrated fibers that were much thinner than in normal fibrin. In contrast to the previously observed defective binding of plasminogen, the binding of thrombospondin to immobilized fibrinogen Dusart was similar to that of normal fibrinogen. Immunoblot analysis of plasma fibrinogen demonstrated that a substantial part of the fibrinogen Dusart molecules were disulfide-linked to albumin. The plasma of the affected family members also contained fibrinogen- albumin complexes. Furthermore, small amounts of high molecular weight complexes containing fibrinogen were detected in all the heterozygous individuals. These data indicate that the molecular abnormality in fibrinogen Dusart (Aα 554 Arg → Cys) results in defective lateral association of the fibrin fibers and disulfide-linked complex formation with albumin, and is associated with a family history of recurrent thrombosis in the affected individuals. Chemicals/CAS: antithrombin III, 90170-80-2; fibrinogen, 9001-32-5; plasminogen, 9001-91-6; protein C, 60202-16-6; thrombin, 9002-04-4; Fibrin, 9001-31-4; fibrinogen Dusard; Fibrinogen, 9001-32-5; Fibrinogens, Abnormal; Platelet Membrane Glycoproteins; Sulfhydryl Compounds; Thrombospondins
Subject
Health
Aα chain
albumin, disulfide-linked
dysfibrogenemia
gene analysis
albumin
antithrombin iii
fibrinogen
plasminogen
protein c
protein s
thrombin
amino acid substitution
blood clotting
complex formation
controlled study
disulfide bond
dna sequence
dysfibrinogenemia
female
fibrin polymerization
gene amplification
genetic analysis
heterozygote
nucleic acid base substitution
polymerase chain reaction
priority journal
thrombosis
Adult
Base Sequence
Blood Coagulation Disorders
Case Report
Fibrin
Fibrinogen
Fibrinogens, Abnormal
Gene Amplification
Human
Immunoblotting
Male
Microscopy, Electron
Molecular Sequence Data
Mutation
Platelet Membrane Glycoproteins
Protein Binding
Sequence Analysis, DNA
Structure-Activity Relationship
Sulfhydryl Compounds
Support, Non-U.S. Gov't
Support, U.S. Gov't, P.H.S.
Thrombosis
Thrombospondins
To reference this document use:
http://resolver.tudelft.nl/uuid:a3b8666c-b984-4bc1-93de-02b10de684b9
TNO identifier
232204
ISSN
0021-9738
Source
Journal of Clinical Investigation, 91 (4), 1637-1643
Document type
article