title: Primary antiphospholipid antibody syndrome with mutations in the phospholipid binding domain of beta(2)-glycoprotein I.
abstract: beta(2)-Glycoprotein I, an anionic phospholipid-binding 50-kDa plasma protein, circulates in the plasma at a concentration of 30-200 microg/ml. Its physiological role remains uncertain, but an important clue to this role is suggested by the finding that antibodies to this protein are frequently found in patients with antiphospholipid antibodies and thrombosis. beta(2)-Glycoprotein I belongs to the complement control protein (CCP) superfamily with five CCP domains. The fifth CCP domain of beta(2)-glycoprotein I has a unique structure and contains a stretch of positively charged amino acids that mediates the binding to phospholipids. This interaction may mediate the clearance of anionic phospholipid-containing surfaces from the circulation. Mutations in this domain affect its binding to phospholipids. We have identified a patient with primary antiphospholipid syndrome who is a compound heterozygous 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 mutant 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 pulmonary embolism at age 28 and a thrombotic stroke at age 35, with no other identifiable risk factor for a hypercoagulable state. This report offers some insight into the mechanism of formation of antiphospholipid antibodies and suggests the possible role of the deficiency of beta(2)-glycoprotein I in the pathogenesis of thrombosis.
authors.affiliation: Division of Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA.
authors.forename: F C
authors.initials: FC
authors.lastname: Gushiken
authors.forename: F C
authors.initials: FC
authors.lastname: Arnett
authors.forename: P
authors.initials: P
authors.lastname: Thiagarajan
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D016736:Antiphospholipid Syndrome / Q000150:complications / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D002308:Cardiolipins / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons; D006023:Glycoproteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010743:Phospholipids / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D011655:Pulmonary Embolism / Q000209:etiology; D020521:Stroke / Q000209:etiology; D020246:Venous Thrombosis / Q000209:etiology; D053482:beta 2-Glycoprotein I
chemical_list: D002308:Cardiolipins; D006023:Glycoproteins; D010743:Phospholipids; D053482:beta 2-Glycoprotein I