title: Five novel and four recurrent point mutations in the antithrombin gene causing venous thrombosis.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan. keiring@rr.iij4u.or.jp
authors.forename: Keiko
authors.initials: K
authors.lastname: Nagaizumi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inaba
authors.forename: Kagehiro
authors.initials: K
authors.lastname: Amano
authors.forename: Midori
authors.initials: M
authors.lastname: Suzuki
authors.forename: Morio
authors.initials: M
authors.lastname: Arai
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Fukutake
mesh_terms: D000293:Adolescent; D000328:Adult; D000990:Antithrombin III / Q000737:chemistry / Q000235:genetics*; D020152:Antithrombin III Deficiency / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011487:Protein Conformation; D020246:Venous Thrombosis / Q000209:etiology / Q000235:genetics*
chemical_list: D000990:Antithrombin III