A novel missense mutation in the human plasmin inhibitor (alpha2-antiplasmin) gene associated with a bleeding tendency.
Heterozygosity for a G --> A mutation converting Val384(GTG) to Met(ATG) associated with plasmin inhibitor (alpha2-antiplasmin) deficiency was identified in three family members with bleeding tendency. The proband had traumatic breast haematoma and per-/postoperative bleeds. An affected daughter required a blood transfusion after a normal delivery and a son had prolonged bleeding after tooth extraction. The plasma plasmin inhibitor activities of the affected family members were reduced to 49-66% of normal. The antigenic concentrations determined by electroimmunoassay were reduced to 57-68% of normal. Crossed immunoelectrophoresis of plasma from the proband showed a normal pattern. The amino acid Val384 is located eight residues C-terminal (P8') of the P1 residue (Arg376) in the reactive site. The P8' residues of bovine and mouse plasmin inhibitor are both Val. Among other serpins the P8' residue is unconserved. The mutation was not present in the non-affected family member or 30 blood donors. In addition to the Val384Met mutation two new polymorphisms Ala-26(GCG)/Val(GTG) and Arg407(AGG)/Lys(AAG) and one previously reported polymorphism Arg6(CGG)/Trp(TGG) were identified in the plasmin inhibitor gene of the family. The allelic frequencies among 30 blood donors with normal values of plasma plasmin inhibitor (functional) were 0.84/0.16 for C/T in codon -26, 0.81/0.19 for C/T in codon 6 and 0.83/0.17 for G/A in codon 407.
Lind
B
B
Section for Haemostasis and Thrombosis, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. rh02440@rh.dk
Thorsen
S
S
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D001941:Breast Diseases / Q000235:genetics; D005260:Female; D006406:Hematoma / Q000235:genetics; D006474:Hemorrhagic Disorders / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D006473:Postpartum Hemorrhage / Q000235:genetics; D011247:Pregnancy; D000979:alpha-2-Antiplasmin / Q000235:genetics*
D000979:alpha-2-Antiplasmin