A gamma Gly-268 to Glu substitution is responsible for impaired fibrin assembly in a homozygous dysfibrinogen Kurashiki I.
A new type of gamma Gly-268 (GGA) to Glu (GAA) substitution has been identified in a homozygous dysfibrinogen by analyses of the affected polypeptide and its encoding gene derived from a 58 year-old man manifesting no major bleeding or thrombosis. The functional abnormality was characterized by impaired fibrin assembly most likely due to failure to construct properly aligned double-stranded fibrin protofibrils. This presumption was deduced from the following findings: (1) Factor XIIIa-catalyzed cross-linking of the fibrin gamma-chains progressed in a normal fashion, indicating that the contact between the central E domain of one fibrin monomer and the D domain of another took place normally; (2) Nevertheless, factor XIIIa-catalyzed cross-linking of the fibrinogen gamma-chains was obviously delayed, suggesting that longitudinal association of D domains of different fibrin monomers, ie, D:D association was perturbed; (3) Plasminogen activation catalyzed by tissue-type plasminogen activator was not as efficiently facilitated by polymerizing fibrin monomer derived from the patient as by the normal counterpart. Therefore, gamma Gly-268 would not be involved in the 'a' site residing in the D domain, which functions as a complementary binding site with the thrombin-activated 'A' site in the central E domain, but would be rather involved in the D:D self association sites recently proposed for human fibrinogen. Thus, the gamma Glu-268 substitution newly identified in this homozygous dysfibrinogen seems to impair proper alignment of adjacent D domains of neighboring fibrin molecules in the double-stranded fibrin protofibril, resulting in delayed fibrin gel formation.
Niwa
K
K
Division of Hemostasis and Thrombosis Research, Institute of Hematology, Jichi Medical School, Tochigi, Japan.
Takebe
M
M
Sugo
T
T
Kawata
Y
Y
Mimuro
J
J
Asakura
S
S
Sakata
Y
Y
Mizushima
J
J
Maeda
A
A
Endo
H
H
Matsuda
M
M
D000347:Afibrinogenemia / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001780:Blood Coagulation Tests; D016466:CHO Cells; D002122:Calcium Chloride / Q000494:pharmacology; D006224:Cricetinae; D004789:Enzyme Activation; D005337:Fibrin / Q000378:metabolism*; D005340:Fibrinogen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010958:Plasminogen / Q000378:metabolism; D017354:Point Mutation; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism
D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen; D011503:Transglutaminases; D010959:Tissue Plasminogen Activator; D002122:Calcium Chloride