MOLECULAR-BASIS FOR FIBRINOGEN DUSART (A-ALPHA 554 ARG -] CYS) AND ITS ASSOCIATION WITH ABNORMAL FIBRIN POLYMERIZATION AND THROMBOPHILIA

The molecular defect in the abnormal fibrinogen Dusart (Paris V) that is associated with thrombophilia was determined by sequence analysis o f genomic DNA that had been amplified using the polymerase chain react ion. The propositus was heterozygous for a single base change (C --> T ) in the Aalpha-chain gene, resulting in the amino acid substitution A alpha 554 Arg --> Cys. Restriction analysis of the amplified DNA deriv ed from the family members showed that his father and his two sons wer e also heterozygous. Electron microscopic studies on fibrin formed fro m purified fibrinogen Dusart demonstrated fibers that were much thinne r than in normal fibrin. In contrast to the previously observed defect ive binding of plasminogen, the binding of thrombospondin to immobiliz ed fibrinogen Dusart was similar to that of normal fibrinogen. Immunob lot 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-al bumin complexes. Furthermore, small amounts of high molecular weight c omplexes containing fibrinogen were detected in all the heterozygous i ndividuals. These data indicate that the molecular abnormality in fibr inogen Dusart (Aalpha 554 Arg --> Cys) results in defective lateral as sociation of the fibrin fibers and disulfide-linked complex formation with albumin, and is associated with a family history of recurrent thr ombosis in the affected individuals.