Genetic polymorphism of murine tissue plasminogen activator associated with antiphospholipid syndrome.
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.
Shirai
J
J
Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Ida
A
A
Jiang
Y
Y
Sanokawa-Akakura
R
R
Miura
Y
Y
Yan
K
K
Hamano
Y
Y
Hirose
S
S
Shirai
T
T
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*
D010959:Tissue Plasminogen Activator