Polymerization defect of fibrinogen Baltimore III due to a γAsn³⁰⁸ → Ile mutation

Fibrinogen Baltimore III, a congenital abnormal fibrinogen with impaired fibrin monomer polymerization, displays a normal γ-chain and a γ-variant that has an apparently lower relative molecular weight (mol wt) than normal on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Reverse phase high-performance liquid chromatography (HPLC) analysis of the lysyl endopeptidase digest of the purified 7-chains of fibrinogen Baltimore III revealed the presence of a peptide that is not found in the digest of the normal fibrinogen γ-chain. Amino acid sequence analysis of this peptide indicated that the γ-chain residue 308, asparagine. is replaced by isoleucine. Concanavalin A bound both normal and variant 7-chains of fibrinogen Baltimore III, indicating that the carbohydrate moiety is not altered and is not responsible for the increase in electrophoretic mobility of the Baltimore III 7-chain. This study suggests that the integrity of γAsn³⁰⁸ is critical for fibrin monomer polymerization, since alteration to either a basic (fibrinogen Kyoto I, Asn → Lys) or hydrophobic (Asn → Ile) residue results in significantly delayed polymerization of fibrinogen to fibrin.