[Clinical and genetic aspects of antithrombin III deficiency and abnormal antithrombin III].

Antithrombin III (AT III) has been confirmed to play an important role as a serine protease inhibitor in the mechanism of blood coagulation, and its deficiency or abnormality is found to cause thromboembolic disorders by reducing the anticoagulant activity. In this paper AT III gene of patient with congenital AT III deficiency, which was suggested to have qualitative abnormality by isoelectric focusing, was investigated. Analysis of the genomic structure by Southern blot hybridization with a cDNA probe (pAT6) revealed no detectable changes indicating any deletions, rearrangements and translocations. Therefore, we focused to analyze the sequence of exon 6 of AT III gene by polymerase chain reaction (PCR) methods followed by direct sequencing analysis. Nucleotide sequencing of exon 6 of AT III gene showed a G to T transitional mutation resulting in the conversion of arginine-406 to methionine coexisted with normal allele which encodes arginine. The mutation is located near the reactive center of AT III molecule, which region has been proved to be highly conserved during the evolution of serine protease inhibitor (serpin) family. From these results, it is concluded that the new type of mutation at amino acid site 407, which is similar to AT III Utah, is important for maintaining the structural and biological function of this inhibitor.