Fibrinogen Matsumoto III: a variant with gamma 275 Arg -> Cys (CGC -> TGC)- Comparison of fibrin polymerization properties with those of Matsumoto I(gamma 364 Asp -> His) and Matsumoto II (gamma 308 Asn -> Lys)

Fibrinogen Matsumoto III (M-III) is a dysfibrinogen identified in a 66-year -old woman with rectal cancer. The fibrinogen level determined by the throm bin-time method was markedly decreased in preoperative coagulation tests of her plasma. Three fibrinogen polypeptide-chain gene fragments from the pro posita were amplified by the polymerase chain reaction method, then sequenc ed. The triplet CGC encoding the amino acid residue gamma 275 was replaced by TGC, resulting in the substitution of Arg-->Cys. There have been previou s reports of nine families with the same alteration, nine families with an Arg-->His variant and one family with an Arg-->Ser variant in this residue, which has been shown to be one of the most important amino acids in the 'D :D' interaction site. In addition, there are three silent mutations in the A alpha-chain gene and two mutations in the intron of the B beta-chain and the gamma-chain gene. However, none of these mutations is thought to be the cause of the dysfunctional fibrinogen. The thrombin-catalyzed fibrin polym erization in the presence of 1 mM Ca ions was markedly delayed in purified M-III. Its lag period was longer than those of Matsumoto II (M-II; gamma 30 8Asn-->Lys) and Matsumoto 1 (M-I; gamma 364Asp-->His). gamma 364Asp is one of the most important residues in the polymerization pocket of the 'D:E' in teraction site and gamma 308Asn is located in the vicinity of a high affini ty Ca2+ binding site in the D-domain, gamma 311-336. The maximum slope of t he polymerization curve for M-III was about 4-fold steeper than that for M- I but less steep than that for M-II. These results may suggest that the ter tiary structure of the polymerization pocket plays a more important role in the lateral aggregation of protofibrils than that of the 'D:D' interaction site.