Five Novel and Four Recurrent Point Mutations in the Antithrombin Gene Causing Venous Thrombosis

• Published in: International journal of hematology Vol. 78; no. 1; pp. 79 - 83
• Main Authors: Nagaizumi, Keiko, Inaba, Hiroshi, Amano, Kagehiro, Suzuki, Midori, Arai, Morio, Fukutake, Katsuyuki
• Format: Journal Article
• Language: English
• Published: Tokyo Springer 01.07.2003; Springer Nature B.V
• Subjects: Abnormalities; Adolescent; Adult; Anticoagulants; Antigens; Antithrombin; Antithrombin III - chemistry; Antithrombin III - genetics; Antithrombin III Deficiency - genetics; AT deficiency; Biological and medical sciences; Direct sequence; DNA Mutational Analysis; Exons; Female; Genotype; Hematologic and hematopoietic diseases; Humans; Japan; Kinases; Male; Medical sciences; Middle Aged; Missense mutation; Mutation; Mutation, Missense; Pedigree; Phenotype; Platelet diseases and coagulopathies; Point Mutation; Polymerase chain reaction; Protein Conformation; Serine proteinase inhibitors; Splice junctions; Thromboembolism; Thrombosis; Venous thrombosis; Venous Thrombosis - etiology; Venous Thrombosis - genetics; Asia; Japan; Human; Hypercoagulability; Cardiovascular disease; Hemopathy; Antithrombin; Thrombosis; Vascular disease; Thrombophilia; Missense mutation; Gene; Point mutation; Gene rearrangement; Genetics; Vein; Coagulopathy
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/bf02983246

We analyzed the antithrombin (AT) gene in 9 unrelated Japanese patients with thrombotic disease. All 7 exons, the splice junctions, and the 5'-flanking region of the AT gene were amplified by polymerase chain reaction and sequenced directly. Nine different point mutations, all in the heterozygous state, were identified. Five novel (M-32T, M89K, L146H, Q159X, and L409P) and 2 previously reported (R132X and R359X) point mutations were identified in patients with type 1 deficiency. Two different missense mutations, R393C and R393H, located in the protease reactive site were detected in patients with type 2 deficiency. No other sequence abnormalities in the AT gene were detected by direct sequencing. None of the mutations was present in 100 alleles from 50 unrelated Japanese control subjects Although type 1 deficiency was diagnosed in patient 7 on the basis of approximately 50% AT antigen and activity levels, the data indicated that the novel L409P mutation is a type 2 pleiotropic effects (PE) deficiency because its location in the C-terminal portion of the reactive site is similar to the locations of reported PE type mutations, and it is highly conserved among other serpins.