A new type of congenital dysfibrinogen, fibrinogen Bremen, with an A alpha Gly-17 to Val substitution associated with hemorrhagic diathesis and delayed wound healing.
We have identified a new type of A alpha Gly-17 to Val substitution in a congenital dysfibrinogen, fibrinogen Bremen, derived from a 15-year-old boy having manifested easy bruising and delayed wound healing. The functional abnormality was characterized by altered fibrin monomer polymerization, which became evident by increasing the salt concentration and pH. A synthetic tetrapeptide with a sequence of the amino-terminal segment of normal fibrin alpha-chain, Gly-Pro-Arg-Val, substantially inhibited polymerization of both normal and the patient-derived fibrin monomers. 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 that of normal one at a much higher ratio of 10,000:1. Likewise, a synthetic peptide Ala-Pro-Arg-Val with a replacement of the Gly residue by another aliphatic amino acid Ala inhibited similarly the patient's fibrin monomer polymerization. Thus, the hypothetical two-pronged socket-like structure consisting of the alpha-amino group of the amino-terminal Gly and the guanidino group of an Arg at position 3 of the normal fibrin alpha-chain seems to be restored considerably in the mutant fibrin alpha-chain at low ionic strengths and pH's, despite the replacement of the amino-terminal Gly by another aliphatic amino acid Val.
Wada
Y
Y
Division of Hemostasis and Thrombosis Research, Jichi Medical School, Tochigi, Japan.
Niwa
K
K
Maekawa
H
H
Asakura
S
S
Sugo
T
T
Nakanishi
M
M
Auerswald
G
G
Popp
M
M
Matsuda
M
M
D000293:Adolescent; D000595:Amino Acid Sequence; D001704:Biopolymers; D015241:Fibrinogens, Abnormal / Q000235:genetics / Q000494:pharmacology*; D005998:Glycine / Q000235:genetics*; D006474:Hemorrhagic Disorders / Q000097:blood*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics*; D013997:Time Factors; D014633:Valine / Q000235:genetics*; D014945:Wound Healing / Q000502:physiology*
D001704:Biopolymers; D015241:Fibrinogens, Abnormal; D010446:Peptide Fragments; C084844:fibrinogen Bremen; D014633:Valine; D005998:Glycine