Fibrinogen Alès: a homozygous case of dysfibrinogenemia (gamma-Asp(330)-->Val) characterized by a defective fibrin polymerization site "a".
Congenital homozygous dysfibrinogenemia was diagnosed in a man with a history of 2 thrombotic strokes before age 30. His hemostatic profile was characterized by a dramatically prolonged plasma thrombin clotting time, and no clotting was observed with reptilase. Complete clotting of the abnormal fibrinogen occurred after a prolonged incubation of plasma with thrombin. The release of fibrinopeptides A and B by thrombin and of fibrinopeptide A by reptilase were both normal. Thrombin-induced fibrin polymerization was impaired, and no polymerization occurred with reptilase. The polymerization defect was characterized by a defective site "a," resulting in an absence of interaction between sites A and a, indicated by the lack of fragment D(1) (or fibrinogen) binding to normal fibrin monomers depleted in fibrinopeptide A only (Des-AA fm). By SDS-PAGE, the defect was detected on the gamma-chain and in its fragment D(1). The molecular defect determined by analysis of genomic DNA showed a single base change (A-->T) in exon VIII of the gamma-chain. The resulting change in the amino acid structure is gamma 330 aspartic acid (GAT) --> valine (GTT). It is concluded that the residue gamma-Asp(330) is essential for the normal functioning of the polymerization site a on the fibrinogen gamma-chain.
Lounes
K C
KC
Laboratoire Sainte Marie, Laboratoire de Biochimie A, and INSERM E 99-12, Hôtel-Dieu, Paris, France.
Soria
C
C
Mirshahi
S S
SS
Desvignes
P
P
Mirshahi
M
M
Bertrand
O
O
Bonnet
P
P
Koopman
J
J
Soria
J
J
D000328:Adult; D000347:Afibrinogenemia / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D001665:Binding Sites; D001778:Blood Coagulation Disorders / Q000097:blood / Q000150:complications / Q000235:genetics; D020147:Coagulation Protein Disorders / Q000097:blood / Q000150:complications / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005337:Fibrin / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D015241:Fibrinogens, Abnormal / Q000009:adverse effects / Q000235:genetics* / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000378:metabolism; D006490:Hemostatics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D011485:Protein Binding; D021122:Protein Subunits; D020521:Stroke / Q000097:blood / Q000209:etiology; D013917:Thrombin / Q000187:drug effects / Q000378:metabolism; D013918:Thrombin Time; D019851:Thrombophilia / Q000097:blood / Q000150:complications / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000209:etiology
D015241:Fibrinogens, Abnormal; D005343:Fibrinolytic Agents; D006490:Hemostatics; D021122:Protein Subunits; C417662:fibrinogen Ales; D005337:Fibrin; D013917:Thrombin; D005341:Fibrinolysin