Characterization of fibrinogen New York 1. A dysfunctional fibrinogen with a deletion of B beta(9-72) corresponding exactly to exon 2 of the gene

Fibrinogen New York 1 (NY-1) was identified in a family with a thrombotic tendency. Studies on fibrinogen NY-1 and the fibrinogen from her brother, designated NY-1a, showed that both have abnormal thrombin-nonclottable fibrinogen (50% of the total fibrinogen in NY-1 and 35-40% in NY-1a) and that the trait is heterozygous and autosomal codominant. The abnormal fibrinogen polymerizes in the presence of calcium and can be further cross-linked by Factor XIIIa. The release rates of fibrinopeptides A and B by thrombin from both (NY-1 and NY-1a) were slower than those from normal fibrinogen. Two mol of fibrinopeptide A but only 0.6-1.0 (NY-1) or 1.0-1.3 (NY-1a) mol of fibrinopeptide B were released per mol of fibrinogen. Additionally, only 1.0 (NY-1) or 1.3 (NY-1a) mol of the B beta(1-42) peptide were released by plasmin/mol. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the reduced fibrinogen revealed two protein bands in the B beta-chain region (Mr = 54,000 as compared with 57,300 for the normal). When NY-1a fibrinogen was treated with CNBr, two sizes of the NH2-terminal disulfide knot were obtained (Mr = 59,000 and 49,000). The Mr = 49,000 component is consistent with an abnormal NH2-terminal disulfide knot with two defective NH2-terminal B beta-chains. Amino acid sequence analyses demonstrated that the abnormal B beta-chain is the result of a deletion in the sequence from residues 9 to 72. This deletion corresponds exactly to exon 2 of the gene. Since this family has a thrombotic tendency, the defect in the fibrinogen may be important in the pathogenesis of thrombosis in this family.