Fibrinogen Niigata With Impaired Fibrin Assembly: An Inherited Dysfibrinogen With a Bβ Asn-160 to Ser Substitution Associated With Extra Glycosylation at Bβ Asn-158

• Published in: Blood Vol. 94; no. 11; pp. 3806 - 3813
• Main Authors: Sugo, Teruko, Nakamikawa, Chizuko, Takano, Hiroshi, Mimuro, Jun, Yamaguchi, Shu-ichi, Mosesson, Michael W., Meh, David A., DiOrio, James P., Takahashi, Noriko, Takahashi, Hoyu, Nagai, Koichi, Matsuda, Michio
• Format: Journal Article
• Language: English
• Published: 01.12.1999
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.11.3806.423a17_3806_3813

A novel BβAsn-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 oligosaccharide was linked to the BβAsn-158 residue. The functional abnormality was attributed to delayed lateral association of normally formed double-stranded protofibrils based on normal cross-linking of fibrin γ-chains and tissue-type plasminogen activator-catalyzed plasmin generation by polymerizing fibrin monomers. Enzymatic removal of all the N-linked oligosaccharides from fibrinogen Niigata accelerated fibrin monomer polymerization that reached the level of untreated normal fibrin monomers, but the thrombin time was 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 deglycosylation, Niigata fibers became straight being similar to untreated normal fibrin fibers, whereas normal deglycosylated fibrin appeared to be less-branched than untreated normal or deglycosylated Niigata fibrin. Although normal and Niigata fibrins were similar to each other in permeation and compaction studies, deglycosylated normal and Niigata fibrins had much higher permeability 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 Bβ-158 that is responsible for reducing the fiber thickness because of either local repulsive forces or steric hindrance in the coiled-coil region.