Fibrinogen Niigata with impaired fibrin assembly: An inherited dysfibrinogen with a B beta Asn-160 to Ser substitution associated with extra glycosylation at B beta Asn-158

A novel B beta Asn-160 (TAA) to Ser (TGA) substitution has been identified in fibrinogen Niigata derived from a 64-year-old asymptomatic woman, who is heterozygotic for this abnormality. The mutation creates an Asn-X-Ser-type glycosylation sequence, and a partially sialylated biantennary oligosaccha ride was linked to the B beta Asn-158 residue. The functional abnormality w as attributed Po delayed lateral association of normally formed double-stra nded protofibrils based on normal cross-linking of fibrin gamma-chains and tissue-type plasminogen activator-catalyzed plasmin generation by polymeriz ing fibrin monomers. Enzymatic removal of all the N-linked oligosaccharides from fibrinogen Niigata accelerated fibrin monomer polymerization that rea ched the level of untreated normal fibrin monomers, but the thrombin time w as prolonged from 18.2 seconds to 113 seconds (normal: 11.2 seconds to 8.9 seconds). By scanning electron micrographic analysis, Niigata Fibrin fibers were found to be more curvilinear than normal fibrin fibers. After deglyco sylation, Niigata fibers became straight being similar to untreated normal fibrin fibers, whereas normal deglycosylated fibrin appeared to be less-bra nched than untreated normal or deglycosylated Niigata fibrin. Although norm al and Niigata fibrins were similar to each other in permeation and compact ion studies, deglycosylated normal and Niigata fibrins had much higher perm eability and compaction values, indicating that deglycosylation had brought about the formation of more porous networks. The enzymatic deglycosylation necessitates an Asn to Asp change at position B beta-158 that is responsib le for reducing the fiber thickness because of either local repulsive force s or steric hindrance in the coiled-coil region. (C) 1999 by The American S ociety of Hematology.