title: Genetic polymorphism of murine tissue plasminogen activator associated with antiphospholipid syndrome.
abstract: In a subset of patients with systemic lupus erythematosus (SLE), antiphospholipid syndrome characterized by thrombocytopenia, thrombosis, recurrent abortion and antiphospholipid antibodies develops. Male (NZW x BXSB) F1 mice are widely used as a model for SLE-associated antiphospholipid syndrome. Our earlier genetic studies showed that one susceptibility allele for thrombocytopenia and associated IgG platelet-binding autoantibodies in male (NZW x BXSB) F1 mice was linked to the BXSB-type polymorphic microsatellite D8Mit96, located in proximity to the gene Plat for tissue-type plasminogen activator (t-PA). In the present studies, sequence analyses for structural and promoter regions of Plat revealed a single nucleotide polymorphism encoding a catalytic domain of t-PA, with an amino acid substitution of anionic Glu366 in NZW for a cationic Lys in BXSB. Progeny studies using NZW x (NZW x BXSB) F1 male backcross mice showed that the BXSB Plat allele was significantly associated with high levels of both platelet-binding antibodies and thrombocytopenia. Furthermore, these two traits appeared to be regulated by a complementary effect of two BXSB alleles; one is linked to Plat and the other to the H-2 complex and the gene for plasminogen. Thus, the BXSB-type Plat may be one susceptibility allele for the multigenic antiphospholipid syndrome seen in (NZW x BXSB) F1 mice. Potential mechanisms are discussed.
authors.affiliation: Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Shirai
authors.forename: A
authors.initials: A
authors.lastname: Ida
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.forename: R
authors.initials: R
authors.lastname: Sanokawa-Akakura
authors.forename: Y
authors.initials: Y
authors.lastname: Miura
authors.forename: K
authors.initials: K
authors.lastname: Yan
authors.forename: Y
authors.initials: Y
authors.lastname: Hamano
authors.forename: S
authors.initials: S
authors.lastname: Hirose
authors.forename: T
authors.initials: T
authors.lastname: Shirai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016736:Antiphospholipid Syndrome / Q000235:genetics*; D001483:Base Sequence; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D013921:Thrombocytopenia / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000235:genetics*
chemical_list: D010959:Tissue Plasminogen Activator