Human Molecular Genetics, Vol 6, 311-316, Copyright © 1997 by Oxford University Press
DK Sanghera, DR Wagenknecht, JA McIntyre and MI Kamboh
Apolipoprotein H (apoH), also known as beta 2-glycoprotein-I, is considered
to be a cofactor for the binding of certain antiphospholipid autoantibodies
to negatively charged phospholipids. Genetically determined structural
abnormalities in the lipid binding domain(s) of apoH can affect its ability
to bind lipid and consequently the production of the autoantibodies. In
this study we have identified two common structural mutations at codons 316
and 306 in the fifth domain of apoH which rendered apoH unable to bind to
negatively charged phosphatidylserine (PS). The missense mutation at codon
316 (TGG --> TCG) replaces Trp316 with Ser316 and disrupts the integrity
of four highly conserved hydrophobic amino acids sequence at positions
313-316, which is a potential protein-lipid hydrophobic interaction site.
The missense mutation at codon 306 (TGC --> GGC) involves the
substitution of Cys306 by Gly306 which causes the disruption of a disulfide
bond between Cys281 and Cys306 and affects the normal configuration of the
fifth domain of apoH that appears to be critical for clustering positively
charged amino acids along with four hydrophobic amino acids sequence. ApoH
from the two homozygotes (Ser316/Ser316) and all seven compound
heterozygotes (Ser316/Gly306) failed to bind to PS; all heterozygotes at
one or the other sites and wild type showed normal PS binding. These data
indicate that the fifth domain of apoH harbors the lipid binding region. An
estimated 2 million Caucasians in the United States, who are compound
heterozygotes for the two mutations, may be precluded from producing
apoH-dependent antiphospholipid autoantibodies.
ARTICLES
Identification of structural mutations in the fifth domain of apolipoprotein H (beta 2-glycoprotein I) which affect phospholipid binding
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261, USA.
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