Fibrinogen Lima: a homozygous dysfibrinogen with an A alpha-arginine-141 to serine substitution associated with extra N-glycosylation at A alpha-asparagine-139. Impaired fibrin gel formation but normal fibrin-facilitated plasminogen activation catalyzed by tissue-type plasminogen activator.

Abstract

An Aa-arginine-141 to serine substitution has been identified in a homozygous dysfibrinogen, fibrinogen Lima, associated with impaired fibrin polymerization. The point mutation created an asparagine-X-serine-type glycosylation sequence, and indeed, extra, mainly disialylated biantennary oligosaccharides have been isolated from Aa asparagine-139 of the patient's fibrinogen. This type of glycosylation sequence is unique for human fibrinogen, because the sequences shown for normal and abnormal fibrinogens are all asparagine-X-threonine types. The terminal sialic acids of the extra oligosaccharides seem to have largely contributed to the impaired fibrin gel formation, as evidenced by its correction to a near normal level by desialylation. Nevertheless, the polymerizing fibrin facilitated tissuetype plasminogen activator-catalyzed plasmin formation in a normal fashion, indicating that the initial two-stranded fibrin protofibrils had been constructed normally. Thus the impaired fibrin gel formation could be attributed to the delay in their subsequent lateral association, most probably because of the repulsive forces generated by the negative electric charge of the extra sialic acids. The substitution of a basic residue arginine to a noncharged residue serine may also have contributed to the impaired function in a similar manner or by steric hindrance in association with bulky extra oligosaccharide chains. (J. Clin. Invest. 1992. 90:67-76.) Key words: amino acid substitutioncongenital homozygous dysfibrinogen * extra asparagine-linked oligosaccharide * fibrin-facilitated plasminogen activation * lateral association of fibrin protofibrils

Elucidating the role of carbohydrate determinants in regulating hemostasis: insights and opportunities

“…A number of different amino acid substitutions that introduce additional N-linked glycosylation sites have also been described in patients with congenital dysfibrinogenemia. These include fibrinogens Lima (Aa Arg141Ser), 80 Caracas II (Aa Ser434Asn), 81 Asahi (g Met310Thr), 82 and Kaiserslauten (g Lys380Asn). In each of these cases, the attachment of an extra N-linked glycan causes impaired functional activity and a consequent bleeding tendency.…”

Gain-of-glycosylation mutations

“…These novel glycans have frequently been identified as pathogenic, or at least as being involved in pathogenesis [28,29,32,33,35,37,43,47]. However, the biochemical documentation of this phenomenon was in all cases incomplete, and the novel glycans were thus never definitively demonstrated to be pathogenic.…”

Molecular characterization of 7 patients affected by dys- or hypo-dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation

“…Such phenomena were observed in other hyperglycosylated fibrinogens (affecting the Aα or γ chains; e.g. Caracas II, Lima, and Kaiserslautern), for which a complete desialylation was able to normalize the prolonged thrombin time [27][28][29]. Alternatively, as described for fibrinogen Niigata, in which the desialylation further prolonged the thrombin time [26], the amino acid substitution itself could profoundly affect the process of fibrin assembly.…”