A γ methionine-310 to threonine substitution and consequent N-glycosylation at γ asparagine-308 identified in a congenital dysfibrinogenemia associated with posttraumatic bleeding, fibrinogen asahi

Abstract

In an abnormal fibrinogen with severely impaired polymerization of fibrin monomers, we identified a methionine-to-threonine substitution at position 310 of the γ chain. Furthermore, asparagine at position 308 was found to be N-glycosylated due to a newly formed consensus sequence, asparagine(308)-glycine(309)-threonine(310). The two structural defects in the mutant γ chain may well perturb the conformation required for fibrin monomer polymerization that is specifically assigned to the D domain of fibrinogen. This alteration also seems to affect the intermolecular γ chain cross-linking of fibrin and fibrinogen, although the amine acceptor γ glutamine-398 was found to function normally. These functional abnormalities may well be related to posttraumatic hemorrhage as observed in a 33-yr-old man with moderate hemorrhagic diathesis related to injuries since his early adolescence. The structure of the extra carbohydrate moiety attached to asparagine-308 was found to be identical with those derived from the normal Bβ and γ chains as evidenced by HPLC.