A gamma Gly-268 to Glu substitution is responsible for impaired fibrin assembly in a homozygous dysfibrinogen Kurashiki I

Abstract

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.

Electrospray ionization mass spectrometry identification of fibrinogen Banks Peninsula (γ280Tyr→Cys): a new variant with defective polymerization

“…Recent interest has centred on the role of γ chain C‐terminal residues in promoting D:D interactions. Based on other recent studies ( Mosesson et al , 1995a ; Niwa et al , 1996 ), it seems likely that the mutation at γ280 perturbs the end to end association (D:D interaction) of adjacent fibrin monomers prior to factor XIIIa crosslinking, rather than having an effect on the initial polymerization event (D:E interaction). Evidence supporting this conclusion comes from recently published crystallographic data ( Yee et al , 1997 ; Pratt et al , 1997 ; Spraggon et al , 1997 ).…”

“…Here the authors concluded that both fibrin D:E interaction and factor XIIIa fibrinogen crosslinking occur normally. Factor XIIIa crosslinking experiments on the recently described homozygous variant fibrinogen Kurashiki I (γ268 Gly→Glu) ( Niwa et al , 1996 ) contrast with Tokyo II and Banks Peninsula. In Kurashiki I, factor XIIIa crosslinking of fibrinogen γ chains was delayed.…”

“…It has been suggested that the ability of D domains to self associate can be measured in isolation from D:E interactions by examining the rate of factor XIIIa catalysed fibrinogen (as opposed to fibrin) crosslinking ( Niwa et al , 1996 ). When factor XIIIa crosslinking was performed on fibrinogen Banks Peninsula, the rate of crosslink formation was indistinguishable from normal.…”

A novel fibrinogen variant – Liberec: dysfibrinogenaemia associated with γ Tyr262Cys substitution

“…Niwa et al. described mutation γ G268E (fibrinogen Kurashiki I) causing dysfibrinogenaemia (18). The patient manifested no major bleeding or thrombosis.…”

Dysfibrinogenemia and Thrombosis

“…58,59 The interface for this site lies be tween γ275R and 7300S, 43 but other nearby 7 chain residues contribute to the site, as evidenced by impaired D:D interactions in dysfibrinogenemic molecules such as fibrinogen Kurashiki I (7G268E). 61 The so-called γ XL assembly site is situated in the Cterminal region of each 7 chain. It contains the factor XIIIa cross-linking sequence between γ398 Gln and 7406 Lys and overlaps the platelet fibrinogen receptor α IIb β 3 binding site at γ400-411 of γA chains.…”