Other entities represented in this entry:
HGNC Approved Gene Symbol: APOA2
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:161,222,292-161,223,628 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | {Hypercholesterolemia, familial, modifier of} | 143890 | Autosomal dominant; Autosomal recessive | 3 |
| Apolipoprotein A-II deficiency | 3 |
Apolipoprotein A-II, like apolipoprotein A-I (APOA1; 107680), is a major apolipoprotein in high density lipoprotein (HDL).
Sakaguchi et al. (1984) and Lackner et al. (1984) isolated the gene for apolipoprotein A-II from a human cDNA library using synthetic oligonucleotides as probes.
Sakaguchi et al. (1984) and Lackner et al. (1984) isolated a restriction fragment of 300 bp from an apoA-II cDNA clone and used it as a probe in filter hybridization assay of DNA from human-mouse somatic cell hybrids. Restriction digestion was performed with HindIII. They found that apoA-II segregates with chromosome 1. The gene was regionalized to 1p21-qter and may reside in a conserved linkage group with renin and peptidase C.
Moore et al. (1984) confirmed the assignment of the APOA2 gene to chromosome 1. By in situ hybridization, Middleton-Price et al. (1988) mapped the APOA2 gene to 1q21-q23. Southern hybridization to the DNA from somatic cell hybrids made from cells carrying a balanced translocation between X and 1 confirmed the localization as proximal to 1q23. In the course of creating a physical map of human 1q21-q23, Oakey et al. (1992) confirmed this assignment. Using a cDNA probe, Rogne et al. (1989) found tight linkage with Duffy blood group (FY; 110700). No recombination was found in 19 meioses examined, giving a maximal lod score of 4.2 at theta = 0.0. This information, combined with other data, made the most likely distance between FY and APOA2 about 10% recombination, with a combined lod score of 5.6 for both sexes.
In the mouse, the genes for apoA-I and apoA-II are on separate chromosomes (Lusis et al., 1983)--mouse chromosomes 9 and 1, respectively. Thus, in man, apoA-II was presumably not coded by 11q, the site of the APOA1 gene.
Apolipoprotein A-II is the second most abundant protein of high density lipoprotein particles. Warden et al. (1993) showed that in both mice and humans, the APOA2 gene is linked to a gene that controls plasma levels of apoA-II and that the APOA2 gene or its product influences, by an unknown mechanism, plasma levels of free fatty acids (FFA).
Allayee et al. (2003) studied 18 extended families of Dutch Caucasian descent with familial combined hyperlipidemia (FCHL; 144250) and found that, despite having lower levels of HDLC, FCHL subjects had higher apoA-II levels compared with unaffected relatives (p less than 0.00016). Triglyceride and HDL-C levels were significant predictors of apoA-II levels, demonstrating that apoA-II variation is associated with several FCHL-related traits. After adjustment for multiple covariates, there was evidence for the heritability of apoA-II levels (h-squared = 0.15; p less than 0.02) in this sample. A genome scan for apoA-II levels identified significant evidence (lod = 3.1) for linkage to a locus on chromosome 1q41, coincident with a suggestive linkage for triglycerides (lod = 1.4), suggesting that this locus may have pleiotropic effects on apoA-II and FCHL traits. Allayee et al. (2003) concluded that apoA-II is biochemically and genetically associated with FCHL and may serve as a useful marker for understanding the mechanism by which FCHL develops.
Sontag and Reardon (2014) noted that mouse Apoa2 shares only 55% amino acid identity with human APOA2 and exists as a monomer, since it lacks the cysteine residue in human APOA2. They purified the 2 most common polymorphic variants of mouse Apoa2, which differ at 3 amino acid sites, and showed that the polymorphisms altered the physical and functional nature of Apoa2.
Fager et al. (1981) found an inverse relationship between serum apoA-II and a risk of myocardial infarction.
Kessling et al. (1988) studied the high density lipoprotein-cholesterol concentrations (HDLC) along with RFLPs in the APOA2 and APOA1-APOC3-APOA4 gene cluster in 109 men selected from a random sample of 1,910 men aged 45 to 59 years. They found no significant difference in allelic frequencies at either locus between the groups of individuals with high and low HDL-C levels. They did find an association between a PstI RFLP associated with apoA-I and genetic variation determining the plasma concentration of apoA-I. No significant association was found between alleles for the apoA-II MspI RFLP and apoA-II or HDL concentrations.
In a brother and sister with apolipoprotein A-II deficiency, Deeb et al. (1990) identified homozygosity for a mutation in the APOA2 gene (107670.0001).
Through molecular study of a 1,135-member American Caucasian familial hypercholesterolemia (143890) kindred, Takada et al. (2002) demonstrated that a SNP of the promoter of the APOA2 gene, -265T-C (107670.0002), influenced the level of total cholesterol and low density lipoprotein (LDL) cholesterol in members with a mutation in the LDLR gene causing hypercholesterolemia (606945.0063).
In the first known case of familial apolipoprotein A-II deficiency, discovered in Hiroshima, Japan, and designated apoA-II(Hiroshima), Deeb et al. (1990) found that the proband and her sister were homozygous for a G-to-A transition at position 1 of intron 3 of the APOA2 gene. The proband had no immunologically detectable apolipoprotein A-II in her plasma but the deficiency had little influence either on lipid and lipoprotein profiles or, so it seemed, on the occurrence of coronary artery disease.
Through molecular study of a 1,135-member American Caucasian familial hypercholesterolemia (143890) kindred, Takada et al. (2002) demonstrated that a SNP of the promoter of the APOA2 gene, -265T-C, influenced the level of total cholesterol and low density lipoprotein (LDL) cholesterol in members with a mutation in the LDLR gene causing hypercholesterolemia (606945.0063). Strikingly lower total cholesterol and LDL cholesterol values were observed among most of the LDLR mutation carriers who were simultaneously homozygous for the -265C allele of the APOA2 gene. In vitro transfection assays showed that transcriptional activity of the APOA2 promoter was reduced by 30% in the -265C allele as compared with the -265T allele. Takada et al. (2002) stated this was the largest familial hypercholesterolemia kindred, with more than 60,000 estimated members descending from a common ancestor in the 18th century.
Allayee, H., Castellani, L. W., Cantor, R. M., de Bruin, T. W. A., Lusis, A. J. Biochemical and genetic association of plasma apolipoprotein A-II levels with familial combined hyperlipidemia. Circ. Res. 92: 1262-1267, 2003. [PubMed: 12738753] [Full Text: https://doi.org/10.1161/01.RES.0000075600.87675.16]
Deeb, S. S., Takata, K., Peng, R., Kajiyama, G., Albers, J. J. A splice-junction mutation responsible for familial apolipoprotein A-II deficiency. Am. J. Hum. Genet. 46: 822-827, 1990. [PubMed: 2107739]
Fager, G., Wiklund, O., Olofsson, S.-O., Norfeldt, P.-I., Vedin, A., Bondjers, G. Multivariate analyses of serum apolipoproteins and risk factors in relation to acute myocardial infarction. Arteriosclerosis 1: 273-279, 1981. [PubMed: 7295199] [Full Text: https://doi.org/10.1161/01.atv.1.4.273]
Kessling, A. M., Rajput-Wiliams, J., Bainton, D., Scott, J., Miller, N. E., Baker, I., Humphries, S. E. DNA polymorphisms of the apolipoprotein AII and AI-CIII-AIV genes: a study in men selected for differences in high-density-lipoprotein cholesterol concentration. Am. J. Hum. Genet. 42: 458-467, 1988. [PubMed: 2894758]
Knott, T. J., Eddy, R. L., Robertson, M. E., Priestley, L. M., Scott, J., Shows, T. B. Chromosomal localization of the human apoprotein CI gene and of a polymorphic apoprotein AII gene. Biochem. Biophys. Res. Commun. 125: 299-306, 1984. [PubMed: 6095840] [Full Text: https://doi.org/10.1016/s0006-291x(84)80368-x]
Knott, T. J., Wallis, S. C., Robertson, M. E., Priestley, L. M., Urdea, M., Rall, L. B., Scott, J. The human apolipoprotein AII gene: structural organization and sites of expression. Nucleic Acids Res. 13: 6387-6398, 1985. [PubMed: 2995928] [Full Text: https://doi.org/10.1093/nar/13.17.6387]
Lackner, K. J., Law, S. W., Brewer, H. B., Jr., Sakaguchi, A. Y., Naylor, S. L. The human apolipoprotein A-II gene is located on chromosome 1. Biochem. Biophys. Res. Commun. 122: 877-883, 1984. [PubMed: 6433912] [Full Text: https://doi.org/10.1016/0006-291x(84)91172-0]
Lackner, K. J., Law, S. W., Brewer, H. B., Jr. The human apolipoprotein A-II gene: complete nucleic acid sequence and genomic organization. Nucleic Acids Res. 13: 4597-4608, 1985. [PubMed: 2989800] [Full Text: https://doi.org/10.1093/nar/13.12.4597]
Lusis, A. J., Taylor, B. A., Wangenstein, R. W., LeBoeuf, R. C. Genetic control of lipid transport in mice. II. Genes controlling structure of high density lipoproteins. J. Biol. Chem. 258: 5071-5078, 1983. [PubMed: 6403543] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(18)32539-0]
Middleton-Price, H. R., van den Berghe, J. A., Scott, T., Knott, T. J., Malcolm, S. Regional chromosomal localisation of APOA2 to 1q21-1q23. Hum. Genet. 79: 283-285, 1988. [PubMed: 3136074] [Full Text: https://doi.org/10.1007/BF00366253]
Moore, M. N., Kao, F.-T., Tsao, Y.-K., Chan, L. Human apolipoprotein A-II: nucleotide sequence of a cloned cDNA, and localization of its structural gene on human chromosome 1. Biochem. Biophys. Res. Commun. 123: 1-7, 1984. [PubMed: 6089788] [Full Text: https://doi.org/10.1016/0006-291x(84)90371-1]
Oakey, R. J., Watson, M. L., Seldin, M. F. Construction of a physical map on mouse and human chromosome 1: comparison of 13 Mb of mouse and 11 Mb of human DNA. Hum. Molec. Genet. 1: 613-620, 1992. [PubMed: 1301170] [Full Text: https://doi.org/10.1093/hmg/1.8.613]
Rogne, S., Myklebost, O., Hoyheim, B., Olaisen, B., Gedde-Dahl, T., Jr. The genes for apolipoprotein AII (APOA2) and the Duffy blood group (FY) are linked on chromosome 1 in man. Genomics 4: 169-173, 1989. [PubMed: 2500391] [Full Text: https://doi.org/10.1016/0888-7543(89)90296-6]
Sakaguchi, A. Y., Naylor, S. L., Fojo, S., Lackner, K. J., Law, S., Brewer, H. B., Jr. Chromosomal array of apolipoprotein genes in man. (Abstract) Am. J. Hum. Genet. 36: 207S only, 1984.
Scott, J., Knott, T. J., Priestley, L. M., Robertson, M. E., Mann, D. V., Kostner, G., Miller, G. J., Miller, N. E. High-density lipoprotein composition is altered by a common DNA polymorphism adjacent to apoprotein AII gene in man. Lancet 326: 771-773, 1985. Note: Originally Volume I. [PubMed: 2858663] [Full Text: https://doi.org/10.1016/s0140-6736(85)91443-6]
Sontag, T. J., Reardon, C. A. Polymorphisms of mouse apolipoprotein A-II alter its physical and functional nature. PLoS One 9: e88705, 2014. Note: Electronic Article. [PubMed: 24520415] [Full Text: https://doi.org/10.1371/journal.pone.0088705]
Takada, D., Emi, M., Ezura, Y., Nobe, Y., Kawamura, K., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred. J. Hum. Genet. 47: 656-664, 2002. [PubMed: 12522687] [Full Text: https://doi.org/10.1007/s100380200101]
Tsao, Y.-K., Wei, C.-F., Robberson, D. L., Gotto, A. M., Jr., Chan, L. Isolation and characterization of the human apolipoprotein A-II gene: electron microscopic analysis of RNA:DNA hybrids, nucleotide sequence, identification of a polymorphic MspI site, and general structural organization of apolipoprotein genes. J. Biol. Chem. 260: 15222-15231, 1985. [PubMed: 2415515]
Warden, C. H., Daluiski, A., Bu, X., Purcell-Huynh, D. A., De Meester, C., Shieh, B.-H., Puppione, D. L., Gray, R. M., Reaven, G. M., Chen, Y.-D. I., Rotter, J. I., Lusis, A. J. Evidence for linkage of the apolipoprotein A-II locus to plasma apolipoprotein A-II and free fatty acid levels in mice and humans. Proc. Nat. Acad. Sci. 90: 10886-10890, 1993. [PubMed: 8248186] [Full Text: https://doi.org/10.1073/pnas.90.22.10886]