ANTITHROMBINS SOUTHPORT (LEU 99 TO VAL) AND VIENNA (GIN 118 TO PRO) -2 NOVEL ANTITHROMBIN VARIANTS WITH ABNORMAL HEPARIN-BINDING

We report the characterization of three variant antithrombins with red uced heparin binding as the primary abnormality. Two of these variants , antithrombin Southport (Leu 99 to Val, 2759 C to G) and antithrombin Vienna (Gin 118 to Pro, 5349 A to C) were novel, whereas the third, P ro 41 to Leu, has been previously described as antithrombin Basel. All three variants exhibited reduced binding for heparin on crossed immun oelectrophoresis and in quantitative monoclonal antibody-based assay. The mutations were characterized by direct sequence analysis of enzyma tically amplified genomic DNA and all affected individuals were hetero zygous for the mutations. These three mutations do not occur al the si tes of the basic amino acids directly involved in heparin binding nor do they result in a change in charge of the affected residue, It seems probable that they reduce heparin affinity either by perturbing the i nitial contact site involved in the heparin-binding domain (Arg 47, Ar g 129 and possibly Arg 24), or by preventing the subsequent heparin-in duced conformational change.