Fibrinogen Matsumoto III: a Variant with γ275 Arg→Cys (CGC→TGC) – Comparison of Fibrin Polymerization Properties with those of Matsumoto I (γ364 Asp→His) and Matsumoto II (γ308 Asn→Lys)

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Abstract
Fibrinogen Matsumoto III (M-III) is a dysfibrinogen identified in a 66-year-old woman with rectal cancer. The fibrinogen level determined by the thrombin-time method was markedly decreased in preoperative coagulation tests of her plasma. Three fibrinogen polypeptide-chain gene fragments from the proposita were amplified by the polymerase chain reaction method, then sequenced. The triplet CGC encoding the amino acid residue γ275 was replaced by TGC, resulting in the substitution of Arg→Cys. There have been previous 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 Aα-chain gene and two mutations in the intron of the Bβ-chain and the γ-chain gene. However, none of these mutations is thought to be the cause of the dysfunctional fibrinogen. The thrombin-catalyzed fibrin polymerization 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; γ308Asn→Lys) and Matsumoto I (M-I; γ364Asp→His). γ364Asp is one of the most important residues in the polymerization pocket of the ’D:E’ interaction site and γ308Asn is located in the vicinity of a high affinity Ca2+ binding site in the D-domain, γ311-336. The maximum slope of the 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 tertiary structure of the polymerization pocket plays a more important role in the lateral aggregation of protofibrils than that of the ’D:D’ interaction site.