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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 × 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 × 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 × (NZW × 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 × BXSB) F1 mice. Potential mechanisms are discussed.

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Correspondence to T Shirai.

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This work was supported in part by CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation (JST) and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.

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Shirai, J., Ida, A., Jiang, Y. et al. Genetic polymorphism of murine tissue plasminogen activator associated with antiphospholipid syndrome. Genes Immun 1, 130–136 (1999). https://doi.org/10.1038/sj.gene.6363651

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  • DOI: https://doi.org/10.1038/sj.gene.6363651

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