TYPE-I ANTITHROMBIN DEFICIENCY - 5 NOVEL MUTATIONS ASSOCIATED WITH THROMBOSIS

The genetic basis of Type I antithrombin deficiency has been investiga ted in six unrelated kindred with positive histories of thrombosis usi ng a PCR amplification/direct sequencing approach. Four frameshift mut ations, all introducing premature translation termination codons were identified. Thus, deletions, of a C at nucleotide position 2599 or 260 0, a G at position 2601-2602 and a CT dinucleotide at position 7428-74 29 were detected in three kindred and confirmed by restriction enzyme analysis. The identical insertion, of a T at nucleotide 2770, was obse rved in two apparently unrelated families. This finding may have been due to a founder effect since antithrombin gene polymorphism analysis showed all affected individuals to share a common haplotype. An in fra me deletion of 6 bp at nucleotide position 2690-26% causing the remova l of codons 76 and 77 encoding Ile 76 and Phe 77 was also detected ind icating that these amino acids are essential for stability of the matu re antithrombin.