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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3806-3813
Fibrinogen Niigata With Impaired Fibrin Assembly: An Inherited
Dysfibrinogen With a B Asn-160 to Ser Substitution Associated
With Extra Glycosylation at B Asn-158
Teruko Sugo,
Chizuko Nakamikawa,
Hiroshi Takano,
Jun Mimuro,
Shu-ichi Yamaguchi,
Michael W. Mosesson,
David A. Meh,
James P. DiOrio,
Noriko Takahashi,
Hoyu Takahashi,
Koichi Nagai, and
Michio Matsuda
From the Institute of Hematology, Jichi Medical School, Tochigi,
Japan; Sinai Samaritan Medical Center, University of Wisconsin Medical
School, Milwaukee Clinical Campus, Milwaukee, WI; Baxter Healthcare,
Round Lake, IL; GlycoLab, Nakano Vinegar Co, Handa, Aichi,
Japan; Katahigashi-Keyaki Hospital, Katahigashimura, Niigata, Japan;
and Niigata Prefectural Central Hospital, Joetsu, Niigata, Japan.
A novel B 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 oligosaccharide was
linked to the BAsn-158 residue. The functional abnormality was
attributed to delayed lateral association of normally formed
double-stranded protofibrils based on normal cross-linking of fibrin
 -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 B-158 that is responsible for reducing the
fiber thickness because of either local repulsive forces or steric
hindrance in the coiled-coil region.
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