A NEW-TYPE OF CONGENITAL DYSFIBRINOGEN, FIBRINOGEN BREMEN, WITH AN A-ALPHA GLY-17 TO VAL SUBSTITUTION ASSOCIATED WITH HEMORRHAGIC DIATHESISAND DELAYED WOUND-HEALING

We have identified a new type of Aa Gly-17 to Val substitution in a co ngenital dysfibrinogen, fibrinogen Bremen, derived from a 15-year-old boy having manifested easy bruising and delayed wound healing. The fun ctional abnormality was characterized by altered fibrin monomer polyme rization, which became evident by increasing the salt concentration an d pH. A synthetic tetrapeptide with a sequence of the amino-terminal s egment of normal fibrin alpha-chain, Gly-Pro-Arg-Val, substantially in hibited polymerization of both normal and the patient-derived fibrin m onomers. A synthetic tetrapeptide with the Bremen type sequence of Val -Pro-Arg-Val inhibited polymerization of the patient's fibrin monomers partially at a peptide: fibrin monomer molar ratio of 4,000:1, and th at of normal one at a much higher ratio of 10,000:1. Likewise, a synth etic peptide Ala-Pro-Arg-Val with a replacement of the Gly residue by another aliphatic amino acid Ala inhibited similarly the patient's fib rin monomer polymerization. Thus, the hypothetical two-pronged socket- like structure consisting of the a-amino group of the amino-terminal G ly and the guanidino group of an Arg at position 3 of the normal fibri n alpha-chain seems to be restored considerably in the mutant fibrin a lpha-chain at low ionic strengths and pH's, despite the replacement of the amino-terminal Gly by another aliphatic amino acid Val.