title: Genetics of apolipoprotein H (beta2-glycoprotein I) and anionic phospholipid binding.
abstract: Apolipoprotein H (apoH; also known as beta2-glycoprotein I), is an essential cofactor for the binding of certain antiphospholipid antibodies (APA) to anionic phospholipid. The gene coding for apoH is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can effect the binding of apoH to anionic phospholipids and consequently the production of APA. Our group has identified two common mutations at codons 306 (Cys-->Gly) and 316 (Trp-->Ser) in the fifth domain of apoH which affect the binding of apoH to anionic phospholipids (phosphatidylserine or cardiolipin). ApoH from serum samples homozygous for each of these mutations or compound heterozygotes for both mutations showed no binding with anionic phospholipids on ELISA. In vitro mutagenesis and transient expression of these mutations in COS-1 cells followed by cardiolipin binding studies confirmed that Gly306 and Ser316 are causative mutations. Our data indicate that the fifth domain of apoH is essential for anionic phospholipid binding and genetically determined variation in this domain can affect the production of apoH-dependent APA.
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pennsylvania 15261, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Kamboh
authors.forename: H
authors.initials: H
authors.lastname: Mehdi
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D000838:Anions; D016736:Antiphospholipid Syndrome / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D019556:COS Cells; D002308:Cardiolipins / Q000378:metabolism; D003062:Codon / Q000235:genetics; D005838:Genotype; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D010718:Phosphatidylserines / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D053482:beta 2-Glycoprotein I
chemical_list: D000838:Anions; D002308:Cardiolipins; D003062:Codon; D006023:Glycoproteins; D010718:Phosphatidylserines; D010743:Phospholipids; D011993:Recombinant Fusion Proteins; D053482:beta 2-Glycoprotein I