Molecular basis for antithrombin III type I deficiency: three novel mutations located in exon IV

Antithrombin III (AT III) type I deficiencies are characterized by a 50% decrease of both immunoreactive and functional protein and carry a high risk of thrombotic complication. We have studied the molecular basis for such deficiencies by asymmetric polymerase chain reaction amplification and direct sequencing of the seven exons and of the intron-exon junction of the AT III gene. Three different mutations were observed in the exon IV: a 4-bp deletion, a 2-bp deletion, and a nucleotide insertion. Each of these mutations results in a frameshift introducing premature stop codons at positions 313, 309, and 232, respectively. These results were confirmed by dot-blot analysis with allele-specific oligonucleotide probes. Furthermore, no mutation was observed in the other six exons. The comparison of the type of mutations observed by our group in six cases of type I deficiencies and in 16 cases of type II heparin binding site variants deficiencies suggests that the former are caused by heterogeneous molecular abnormalities while the latter are caused by recurrent missense mutations.