Primary antiphospholipid antibody syndrome with mutations in the phospholipid binding domain of beta(2)-glycoprotein I

beta(2)-Glycoprotein I, an anionic phospholipid-binding 50-kDa plasma prote in, circulates in the plasma at a concentration of 30-200 mu g/ml. Its phys iological role remains uncertain, but an important clue to this role is sug gested by the finding that antibodies to this protein are frequently found in patients with antiphospholipid antibodies and thrombosis. beta(2)-Glycop rotein I belongs to the complement control protein (CCP) superfamily with f ive CCP domains. The fifth CCP domain of beta(2)-glycoprotein I has a uniqu e structure and contains a stretch of positively charged amino acids that m ediates the binding to phospholipids. This interaction may mediate the clea rance of anionic phospholipid-containing surfaces from the circulation. Mut ations in this domain affect its binding to phospholipids. We have identifi ed a patient with primary antiphospholipid syndrome who is a compound heter ozygous for two mutations in the fifth CCP. One mutation is located in exon 7 (codon 306), and the second mutation is in exon 8 (codon 316), The mutan t beta(2)-glycoprotein I was present in normal quantities in his plasma but did not bind to cardiolipin, He had recurrent deep vein thrombosis and pul monary embolism at age 28 and a thrombotic stroke at age 35, with no other identifiable risk factor for a hypercoagulable state. This report offers so me insight into the mechanism of formation of antiphospholipid antibodies a nd suggests the possible role of the deficiency of beta(2)-glycoprotein I i n the pathogenesis of thrombosis. (C) 2000 Wiley-Liss, Inc.