Alternative titles; symbols
HGNC Approved Gene Symbol: APOH
Cytogenetic location: 17q24.2 Genomic coordinates (GRCh38): 17:66,212,033-66,229,415 (from NCBI)
The APOH gene encodes beta-2 glycoprotein I, also known as apolipoprotein H, a single-chain plasma protein of about 50 kD. Beta-2 GPI binds to and neutralizes negatively charged phospholipid macromolecules, thereby diminishing inappropriate activation of the intrinsic blood coagulation cascade. Beta-2 GPI has been implicated in a variety of physiologic pathways, including blood coagulation, hemostasis, and the production of antiphospholipid antibodies characteristic of antiphospholipid syndrome (APS; 107320) (summary by Mehdi et al., 2003).
Lozier et al. (1984) determined the full amino acid sequence of beta-2-glycoprotein (apoH). The deduced 326-amino acid protein contains 5 attached glucosamine-containing oligosaccharides. Computerized analysis of the sequence revealed 5 consecutive homologous segments in which cysteine, proline, and tryptophan appeared to be highly conserved.
Mehdi et al. (1991) cloned and sequenced APOH cDNAs from human liver and from a human hepatoma cell line. Both cDNAs predicted a protein of 345 amino acids, including a 19-amino acid hydrophobic, N-terminal signal sequence that is not present in the mature protein. The level of APOH mRNA expressed by the hepatoma cells was downregulated by incubation with inflammatory mediators, implying that APOH is a negative acute-phase protein.
By Northern blot analysis, Steinkasserer et al. (1992) established that APOH is synthesized in the liver where a transcript of approximately 1.5 kb was identified.
Sanghera et al. (2001) found that the chimpanzee APOH gene encodes a deduced 326-amino acid protein, as in humans. The human and chimpanzee APOH proteins share 99.4% sequence similarity.
Sheng et al. (1997) found that the mouse Apoh gene contains 8 exons and spans approximately 18 kb.
Sanghera et al. (2001) found that the chimpanzee APOH gene, like the human gene, contains 8 exons.
Haagerup et al. (1991) demonstrated RFLPs in the APOH gene and used these in CEPH family studies to locate the gene on 17q. The marker that showed closest linkage was HOX2 (142960), located at 17q21-q22; lod score = 8.83 at theta = 0.05. Linkage to COL1A1 (120150) was indicated by a lod score of 6.18 at theta = 0.12. By hybridizing a cDNA probe for APOH to a panel of somatic cell hybrids, Steinkasserer et al. (1992) showed that the structural locus maps to 17q23-qter.
Nonaka et al. (1992) mapped the mouse Apoh gene to chromosome 11. Nonaka et al. (1992) commented that the mouse Apoh protein is composed of 5 repeating units called short consensus repeats (SCR), which are found mostly in the regulatory proteins of the complement system.
Nakaya et al. (1980) demonstrated beta-2-glycoprotein I activation of lipoprotein lipase and designated this glycoprotein as apolipoprotein H.
Lozier et al. (1984) noted that B2GI is associated with lipoproteins, binds to platelets, interacts with heparin, and may be involved in blood coagulation.
McNeil et al. (1990) identified beta-2-glycoprotein I as a cofactor required for antiphospholipid antibodies (APA) to bind to cardiolipin. These findings suggested that APA are directed against a complex antigen that includes B2GPI. In addition, B2GPI bound to anionic phospholipids in the absence of anticardiolipin antibodies. McNeil et al. (1990) hypothesized that anticardiolipin APA may interfere with the function of apoH in vivo, which may explain the association of these antibodies with thrombotic tendencies.
Sanghera et al. (1997) noted that apoH had been implicated in a variety of physiologic pathways including lipoprotein metabolism, coagulation, and the production of antiphospholipid autoantibodies. They cited reports supporting the conclusion that apoH is a required cofactor for anionic phospholipid binding by the antiphospholipid autoantibodies found in sera of many patients with systemic lupus erythematosus (SLE; 152700) and primary antiphospholipid syndrome (107320), but it does not seem to be required for the reactivity of antiphospholipid autoantibodies associated with infections. These studies suggested that the apoH-phospholipid complex forms the antigen to which the autoantibodies are directed. Sanghera et al. (1997) postulated that genetically determined structural abnormalities in the lipid-binding domain(s) of apoH may affect its ability to bind lipid and consequently the production of the autoantibodies.
Agar et al. (2010) used electron microscopy to demonstrate that B2GPI exists in at least 2 different conformations: a closed circular plasma conformation and an activated open conformation. The closed circular conformation is maintained by interaction between the first (DI) and fifth (DV) domains. In the activated open conformation, a cryptic epitope in the first domain becomes exposed that enables antibodies to bind and form an antibody-B2GPI complex. The open conformation prolonged the activated partial thromboplastin time (APTT) when added to normal plasma, and the APTT was further prolonged by addition of anti-B2GPI antibodies, consistent with an anticoagulant effect. The conformations could be converted into each other by changing pH and salt concentrations.
In a review, Giannakopoulos et al. (2011) noted that B2GPI contains multiple cysteine residues that mediate platelet and endothelial cell adhesion via thiol exchange reactions. Evidence also suggests that B2GPI may play a role in apoptosis by binding to blebs on apoptotic cells.
Richter and Cleve (1988) demonstrated genetic variation of APOH by means of isoelectric focusing, and data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Using thin-layer polyacrylamide isoelectric focusing gels and immunologic identification, Kamboh et al. (1988) demonstrated genetically determined polymorphism of apolipoprotein H. Three common alleles were identified in U.S. whites and blacks. A fourth allele was observed in individuals of African descent. Family data confirmed autosomal codominant inheritance of 4 alleles at a single APOH locus.
Sepehrnia et al. (1988) provided data on the distribution of apolipoprotein polymorphisms in Nigeria, including polymorphism of APOH. The observations supported the conclusion that the APOH*4 is a marker allele unique to blacks and one that may be widely distributed among African populations, whereas the APOH*1 allele may be a unique Caucasian allele that was introduced into the black population of the U.S. by admixture.
Eiberg et al. (1989) reported linkage data suggesting that the structural and quantitative polymorphisms associated with serum beta-2-glycoprotein I were very tightly linked (maximum lod score = 3.28 at theta = 0.0, male and female data combined). Sepehrnia et al. (1989) found specific associations between particular APOH alleles and the level of triglycerides in females.
In a population of black Africans from the Ivory Coast, Cleve et al. (1992) found that the gene frequencies of APOH*1, APOH*2, APOH*3, and APOH*4 were 0.012, 0.921, 0.047, and 0.020, respectively. In a tabular review of reported frequencies in different populations, APOH*4 was found only in individuals of African descent. The most common allele in all populations, including African, Caucasian, European, and East Asian descent, was APOH*2.
Among 661 non-Hispanic whites, Sanghera et al. (1997) found that the frequency of the APOH*1, APOH*2, and APOH*3 alleles were 0.059, 0.868, and 0.073, respectively. Sanghera et al. (1997) determined that the APOH*1 allele is due to a ser88-to-asn (S88N) substitution in exon 3 of the APOH gene. The frequency of the asn88 allele was 0.011, 0.043, and 0.056 in blacks, Hispanics, and non-Hispanic whites, respectively. Based upon reactivity with a certain monoclonal apoH antibody, the APOH*3 allele could be subdivided into APOH*3(W) (reactive) and APOH*3(B) (non-reactive). The APOH*3(W) allele was found to result from a trp316-to-ser (W316S) substitution in the APOH gene. White had a significantly higher frequency of APOH*3(W) (0.059) compared to blacks (0.008).
Sanghera et al. (1997) found that the W316S substitution in the APOH gene occurs in the fifth domain (domain V) of the protein, which affects phospholipid binding. Another structural substitution in this domain, cys306-to-gly (C306G), was also shown to disrupt binding of APOH to phospholipid. These data indicated that domain V of APOH harbors the lipid-binding region.
Among 455 non-Hispanic individuals, Mehdi et al. (1999) found that the APOH*3(W) allele was associated with decreased plasma levels of apoH and was estimated to account for about 10% of the phenotypic variation in plasma levels in both men and women. However, Mehdi et al. (2003) found that the W316S allele was in linkage disequilibrium with a promoter polymorphism in the APOH gene, which explained the variation in plasma apoH levels.
Hirose et al. (1999) found that the val247 allele (138700.0001) was significantly associated with the presence of anti-B2GPI antibodies in Asian patients with antiphospholipid syndrome (APS; 107320) in a study of 370 healthy controls from different racial backgrounds and 149 patients with APS. The V allele and the VV genotype occurred most often among Caucasians, less among African Americans, and least among Asians. Conversely, the V allele and the VV genotype were found more frequently among Asian patients with antiphospholipid syndrome than among controls (p = 0.0028 and p = 0.0023, respectively). There were no significant differences in allele or genotype frequencies when comparing Caucasian or African American APS patients with appropriate controls. The differences in allele and genotype frequencies seen in Asian APS patients were restricted to those with anti-B2GPI antibodies.
Haupt et al. (1968) described a family in which 2 brothers had complete absence of what they termed beta-2-glycoprotein I (Bg) in the serum. Both parents, a sister, and both children of 1 of the brothers had half-normal levels of the protein. Cleve and Rittner (1969) found 9 families out of 88 in which 1 parent and about half the children had intermediate concentrations of beta-2-glycoprotein I, presumed to be heterozygous for a deficiency ('null') gene.
Hoeg et al. (1985) observed the rare occurrence of total lack of detectable apoH protein in less than 0.3% of clinic patients. A study of family members of 5 such patients demonstrated autosomal codominant inheritance pattern for plasma levels. The authors were impressed by the lack of consistent effects on other plasma lipoproteins, and concluded that the lack of apolipoprotein H does not result in a significant perturbation of normal lipoprotein metabolism, suggesting that the finding may not have clinical relevance.
Bancsi et al. (1992) concluded that deficiency of plasma B2GPI is not a risk factor for thrombosis. In a comparison of healthy volunteers and 4 different groups of patients with familial thrombophilia, the prevalence of B2GPI deficiency (plasma levels less than 77%) was found to be very similar (6.8-12.5%) and not statistically significant between the groups. One thrombophilic patient was found to be homozygous-deficient for B2GPI and this transmission of the defect in his family followed autosomal inheritance. However, 1 of his brothers was also homozygous-deficient and was free of thromboembolic complications at the age of 35 years.
Using isoelectric focusing and immunoblotting, Sanghera et al. (2001) screened 155 chimpanzees (128 unrelated captured parents and 27 captive-born offspring) for the apoH protein polymorphism. The most common IEF pattern in chimpanzees was identical to a previously described APOH*3 allele in humans. In addition, they identified in chimpanzees an allele designated APOH*4, resulting from a lys210-to-glu missense change in exon 6. They found that the prevalence of anti-apoH antibodies in chimpanzees (64%) was unusually high compared to that in humans. No association was found between the lys210-to-glu mutation and the occurrence of anti-apoH antibodies. The authors suggested that the chimpanzee may serve as a useful animal model for human antiphospholipid syndrome (107320).
Sheng et al. (2001) found that B2ghi-null mice were born at lower than expected frequencies, suggesting that B2gpi may play a role in implantation. However, B2gpi-null mice themselves did not show reproductive abnormalities: the number of pregnancies, litter size, and birth weight was similar to that of heterozygotes and controls. B2gpi-null mice had no detectable organ pathology, and in vivo coagulation profiles were also similar to controls. However, in vitro studies of blood derived from the B2gpi-null mice showed less thrombin generation compared to heterozygotes or controls.
Steinkasserer et al. (1993) described a 2-allele RsaI restriction fragment length polymorphism (RFLP) in the APOH gene and demonstrated that it led to a val247-to-leu (V247L) substitution. In studies of 34 unrelated parents in the CEPH family panel, allele frequencies were found to be 0.76 for valine and 0.23 for leucine. The val-leu polymorphism did not correlate with the 4 isoelectric focusing alleles previously described.
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