Apolipoprotein H (apoH; also known as beta(2)-glycoprotein I): is an e
ssential cofactor for the binding of certain antiphospholipid antibodi
es (APA) to anionic phospholipid. The gene coding for apoH is polymorp
hic, with the occurrence of several common alleles in the general popu
lation. This genetically determined variation can effect the binding o
f 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 t
he binding of apoH to anionic phospholipids (phosphatidylserine or car
diolipin). ApoH from serum samples homozygous for each of these mutati
ons or compound heterozygotes for both mutations showed no binding wit
h anionic phospholipids on ELISA. In vitro mutagenesis and transient e
xpression of these mutations in COS-1 cells followed by cardiolipin bi
nding studies confirmed that Gly306 and Ser316 are causative mutations
. Our data indicate that the fifth domain of apoH is essential for ani
onic phospholipid binding and genetically determined variation in this
domain can affect the production of apoH-dependent APA.