Alternative titles; symbols
HGNC Approved Gene Symbol: ABCG5
Cytogenetic location: 2p21 Genomic coordinates (GRCh38) : 2:43,806,211-43,839,231 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p21 | Sitosterolemia 2 | 618666 | Autosomal recessive | 3 |
Berge et al. (2000) identified 2 members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family, ABCG5 and ABCG8 (605460), which encode deduced proteins of 651 and 673 amino acids, respectively, that share 28% amino sequence identity. Both proteins contain N-terminal ATP-binding motifs (Walker A and B motifs) and an ABC transporter signature motif (C motif), and both are predicted to contain 6 transmembrane segments in the C terminus. Both are expressed at a high level in the liver and at lower levels in the small intestine and colon. Cholesterol feeding induces coordinate increases in levels of Abcg5 and Abcg8 mRNA in mice.
Like the ABCG8 gene, the ABCG5 gene contains 13 exons and spans about 28 kb (Berge et al., 2000).
To elucidate the roles of ABCG5 and ABCG8 in the trafficking of sterols, Yu et al. (2002) disrupted the Abcg5 and Abcg8 genes in mice (G5G8 -/-). The GTG8 -/- mice had a 2- to 3-fold increase in the fractional absorption of dietary plant sterols, which was associated with an approximate 30-fold increase in plasma sitosterol. Biliary cholesterol concentrations were extremely low in the G5G8 -/- mice when compared with wildtype animals, and increased only modestly with cholesterol feeding. Plasma and liver cholesterol levels were reduced by 50% in the chow-fed G5G8 -/- mice and increased 2.4- and 18-fold, respectively, after cholesterol feeding. These data indicated that ABCG5 and ABCG8 are required for efficient secretion of cholesterol into bile and that disruption of these genes increases dramatically the responsiveness of plasma and hepatic cholesterol levels to changes in dietary cholesterol content.
Small (2003) reviewed the role of ABC transporters in secretion of cholesterol from liver into bile, particularly the role of ABCG5/ABCG8.
Crystal Structure
Lee et al. (2016) used crystallization in lipid bilayers to determine the x-ray structure of the human ABCG5/ABCG8 heterodimer in a nucleotide-free state at 3.9-angstrom resolution, generating the first atomic model of an ABC sterol transporter. The structure revealed a novel transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter. Lee et al. (2016) concluded that the ABCG5/ABCG8 structure provides a mechanistic framework for understanding sterol transport and the disruptive effects of mutations causing sitosterolemia.
Berge et al. (2000) identified the ABCG5 and ABCG8 genes on chromosome 2p21 between markers D2S177 and D2S119. The 2 genes are tandemly arrayed in a head-to-head orientation separated by 374 basepairs.
Lu et al. (2002) found that the Abcg5 and Abcg8 genes map to mouse chromosome 17.
Sitosterolemia (see 618666) is a rare autosomal recessive disorder characterized by intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and impaired ability to excrete sterols into bile. Patients frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Berge et al. (2000) identified multiple mutations in the ABCG8 gene (605460.0001-605460.0008) and 1 mutation in the ABCG5 gene (605459.0001) in patients with sitosterolemia. Berge et al. (2000) concluded from their data that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.
The ABCG5 and ABCG8 genes are an example of closely neighboring genes in a head-to-head orientation that, when mutated, cause the same phenotype. Another example is that of the EVC (604831) and EVC2 (607261) genes, which have the same head-to-head orientation and when mutated lead to the same phenotype.
Lee et al. (2001) identified homozygosity for mutations (see, e.g., 605459.0001-605459.0004) in the ABCG5 gene in 9 unrelated patients with sitosterolemia. The authors noted that some of the patients had previously been reported by Patel et al. (1998) and Patel et al. (1998).
Rios et al. (2010) reported an 11-month old Romanian girl with xanthomas and marked hypercholesterolemia. While she was initially thought to have primary hypercholesterolemia, mutations in the candidate genes LDLRAP1 (605747), LDLR (606945), PCSK9 (607786), APOE (107741), and APOB (107730) were excluded. Whole-genome sequencing revealed 2 nonsense mutations in ABCG5: Q16X, 605459.0007 and R446X, 605459.0008. Sitosterolemia became evident after she was weaned from an exclusive breast milk diet.
Role in Familial Hypercholesterolemia
Tada et al. (2019) analyzed 487 patients that met 2 of 3 of the Japanese clinical diagnostic criteria of familial hypercholesterolemia (FH): (1) LDL-C at or above 180 mg/dL; (2) tendon xanthoma; and (3) family history of FH or premature coronary artery disease (CAD) among a patient's second-degree relatives. They identified 276 individuals (57%) with mutations in 1 FH gene (LDLR, 606945; PCSK9, 607786; or APOB, 107730) and no causative mutations in 156 patients (32%). Mutations in ABCG5 or ABCG8 were found in 37 patients (8%) without FH gene mutations; 3 of the 37 patients had sitosterolemia (0.8%) with biallelic mutations. Eighteen patients (4%) had a mutation in an FH gene as well as an ABCG5 or ABCG8 mutation, which was designated as the ABCG5/8 oligogenic FH group. LDL-C was significantly higher in patients with mutations in the ABCG5/8 oligogenic FH group than in patients with only an FH gene mutation (266 vs 234 mg/dl, p less that 0.05). Tada et al. (2019) concluded that mutations in ABCG5 or ABCG8 cause at least a portion of FH and may exacerbate FH due to higher LDL-C.
Reeskamp et al. (2020) used next-generation sequencing of 3,031 patients referred for familial hypercholesterolemia. Multiple genes were sequenced, including LDLR, APOB, PCSK9, ABCG5, and ABCG8. The frequency of likely heterozygous pathogenic mutations in the FH patients varied from 346 patients (11.42%) with LDLR mutations to 48 patients (1.48%) with ABCG8 mutations and 29 patients (0.96%) with ABCG5 mutations. LDL-C levels were significantly lower in heterozygous carriers of a likely pathogenic ABCG5 or ABCG8 mutation compared to LDLR mutation carriers (6.2 +/- 1.7 vs 7.2 +/- 1.7 mmol/L, P less than .001). In contrast to Tada et al. (2019), who found that patients with an ABCG5 or ABCG8 mutation and a mutation in another FH gene had higher LDL-C levels, Reeskamp et al. (2020) found that heterozygosity for ABCG5 or ABCG8 variants with an additional LDLR mutation did not contribute to higher LDL-C levels (p = 0.259).
Repa et al. (2002) presented evidence for the direct control of the ATP-binding cassette sterol transporters Abca1, Abcg5, and Abcg8 by the liver X receptors (LXRA, 602423; LXRB, 600380). By in situ localization of normal mouse sections, they found that expression of Abcg5 and Abcg8 was localized to hepatocytes of the liver and showed a uniform distribution across the hepatic lobule; in jejunal sections, expression was detected exclusively in enterocytes lining the villi. In comparison, expression of Abca1 was found predominantly in lamina propria and occasionally in enterocytes. The intensity of hepatic and jejunal staining for Abcg5/g8 and Abca1 was increased in normal mice fed cholesterol or other Lxr agonists. Cholesterol feeding resulted in upregulation of Abcg5 and Abcg8 in the Lxrb null mice, but not in the Lxra null or double knockout mice, suggesting that Lxra is required for sterol upregulation of Abcg5/g8 in this model. In a rat hepatoma cell line, Lxr-dependent transcription of the Abcg5/g8 genes was cycloheximide-resistant, indicating that these genes are directly regulated by the liver X receptors. Repa et al. (2002) concluded that the data provide evidence that Abca1, Abcg5, and Abcg8 are expressed in absorptive enterocytes and that all 3 ABC transporters have a role in regulating cholesterol flux in the intestine.
To detect variants at the Abcg5/Abcg8 locus, Sehayek et al. (2002) carried out a genetic cross between 2 laboratory mouse strains. Parental C57BL/6J mice had almost twice the campesterol and sitosterol levels compared with parental CASA/Rk mice, and F1 mice had levels halfway between those of the parental mice. The authors performed an intercross between F1 sibs and measured plasma plant sterol levels in 102 male and 99 female F2 mice. Plasma plant sterols in F2 sibs displayed a unimodal distribution, suggesting the effects of several genes rather than a single major gene. In the F2 mice, a full genome scan revealed significant linkages on chromosomes 14 and 2. With regard to chromosome 14, analysis showed a single peak for linkage at 17 cM with a lod score of 9.9, designated plasma plant sterol 14 (Plast14). With regard to chromosome 2, analysis showed 2 significant peaks for linkage at 18 and 65 cM with lod scores of 4.1 and 3.65, respectively, designated Plast2a and Plast2b, respectively. Four interactions between loci, predominantly of an additive nature, were also demonstrated, the most significant between Plast14 and Plast2b (lod = 16.44). No significant linkage or gene interaction was detected for the Abcg5/Abcg8 locus on mouse chromosome 17. Therefore, other genes besides ABCG5/ABCG8 presumably influence plasma plant sterol levels in humans as well.
In Abcg5/Abcg8-deficient mice, Yang et al. (2004) demonstrated that accumulation of plant sterols perturbed cholesterol homeostasis in the adrenal gland, with a 91% reduction in its cholesterol content. Despite very low cholesterol levels, there was no compensatory increase in cholesterol synthesis or in lipoprotein receptor expression. Adrenal cholesterol levels returned to near-normal levels in mice treated with ezetimibe, which blocks phytosterol absorption. In cultured adrenal cells, stigmasterol but not sitosterol inhibited SREBP2 (600481) processing and reduced cholesterol synthesis; stigmasterol also activated the liver X receptor in a cell-based reporter assay. Yang et al. (2004) concluded that selected dietary plant sterols disrupt cholesterol homeostasis by affecting 2 critical regulatory pathways of lipid metabolism.
In a Chinese patient with sitosterolemia (STSL2; 618666), Berge et al. (2000) identified a c.1222C-T transition in the ABCG5 gene, resulting in an arg408-to-ter (R408X) substitution. No mutation was identified on the other allele; however, the patient had a cholesterol of 620 mg/dl.
Lee et al. (2001) identified homozygosity for the R408X mutation in the ABCG5 gene in a Japanese patient (pedigree 3500) with sitosterolemia.
Lee et al. (2001) found that 2 sisters (pedigree 500) with sitosterolemia (STSL2; 618666) were homozygous for a c.867C-T transition in exon 6 of the ABCG5 gene, resulting in an arg243-to-stop (R243X) substitution. Both parents were heterozygous.
In 2 unrelated Japanese families (pedigree 700 and pedigree 3300), Lee et al. (2001) found that patients with sitosterolemia (STSL2; 618666) were homozygous for a c.1396G-A transition in exon 9 of the ABCG5 gene, resulting in an arg419-to-his (R419H) substitution.
In a female patient (pedigree 4000) with sitosterolemia (STSL2; 618666), Lee et al. (2001) found a homozygous c.1396G-C transversion in exon 9 of the ABCG5 gene, resulting in an arg419-to-pro (R419P) substitution. Both parents were heterozygous.
In a large multiethnic cohort of patients with sitosterolemia (STSL2; 618666), Lu et al. (2001) found that an arg389-to-his mutation was present in 6 of 20 alleles and was found only in Japanese patients. The mutation was not found in a random sample of 82 normal Japanese subjects.
In 4 affected members of a family with sitosterolemia (STSL2; 618666), Rees et al. (2005) identified a homozygous 229G-T transversion in the ABCG5 gene, resulting in a glu77-to-ter (E77X) substitution. Laboratory studies showed mild hemolytic anemia with reticulocytosis, decreased platelet counts, and increased platelet volume. All patients also had growth retardation. Rees et al. (2005) noted that the phenotype was reminiscent of so-called Mediterranean stomatocytosis/macrothrombocytopenia (see 210250), and that the results indicated that these hematologic features are part of the manifestation of sitosterolemia, perhaps due to abnormal membrane lipid content in red cells and platelets.
Rios et al. (2010) reported an 11-month old Romanian girl with sitosterolemia (STSL2; 618666) who presented with xanthomas and marked hypercholesterolemia. Sitosterolemia became evident after she was weaned from an exclusive breast milk diet. The patient harbored 2 nonsense mutations in the ABCG5 gene: gln16 to ter (Q16X) and arg446 to ter (R446X; 605459.0008).
Mannucci et al. (2007) reported a mother, daughter, and son with sitosterolemia (STSL2; 618666) who were homozygous for a 1336C-T transition in the ABCG5 gene that was predicted to result in an arg446-to-ter (R446X) substitution.
For discussion of the R446X mutation in the ABCG5 gene that was found in compound heterozygous state in a patient with sitosterolemia by Rios et al. (2010), see 605459.0007.
Berge, K. E., Tian, H., Graf, G. A., Yu, L., Grishin, N. V., Schultz, J., Kwiterovich, P., Shan, B., Barnes, R., Hobbs, H. H. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290: 1771-1775, 2000. [PubMed: 11099417] [Full Text: https://doi.org/10.1126/science.290.5497.1771]
Lee, J.-Y., Kinch, L. N., Borek, D. M., Wang, J., Wang, J., Urbatsch, I. L., Xie, X.-S., Grishin, N. V., Cohen, J. C., Otwinowski, Z., Hobbs, H. H., Rosenbaum, D. M. Crystal structure of the human sterol transporter ABCG5/ABCG8. Nature 533: 561-564, 2016. [PubMed: 27144356] [Full Text: https://doi.org/10.1038/nature17666]
Lee, M.-H., Lu, K., Hazard, S., Yu, H., Shulenin, S., Hidaka, H., Kojima, H., Allikmets, R., Sakuma, N., Pegoraro, R., Srivastava, A. K., Salen, G., Dean, M., Patel, S. B. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nature Genet. 27: 79-83, 2001. [PubMed: 11138003] [Full Text: https://doi.org/10.1038/83799]
Lu, K., Lee, M. H., Yu, H., Zhou, Y., Sandell, S. A., Salen, G., Patel, S. B. Molecular cloning, genomic organization, genetic variations, and characterization of murine sterolin genes Abcg5 and Abcg8. J. Lipid Res. 43: 565-578, 2002. [PubMed: 11907139]
Lu, K., Lee, M.-H., Hazard, S., Brooks-Wilson, A., Hidaka, H., Kojima, H., Ose, L., Stalenhoef, A. F. H., Mietinnen, T., Bjorkhem, I., Bruckert, E., Pandya, A., Brewer, H. B., Jr., Salen, G., Dean, M., Srivastava, A., Patel, S. B. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am. J. Hum. Genet. 69: 278-290, 2001. [PubMed: 11452359] [Full Text: https://doi.org/10.1086/321294]
Mannucci, L., Guardamagna, O., Bertucci, P., Pisciotta, L., Liberatoscioli, L., Bertolini, S., Irace, C., Gnasso, A., Federici, G., Cortese, C. Beta-sitosterolaemia: a new nonsense mutation in the ABCG5 gene. Europ. J. Clin. Invest. 37: 997-1000, 2007. [PubMed: 17976197] [Full Text: https://doi.org/10.1111/j.1365-2362.2007.01880.x]
Patel, S. B., Honda, A., Salen, G. Sitosterolemia: exclusion of genes involved in reduced cholesterol biosynthesis. J. Lipid Res. 39: 1055-1061, 1998. [PubMed: 9610773]
Patel, S. B., Salen, G., Hidaka, H., Kwiterovich, P. O., Jr., Stalenhoef, A. F. H., Miettinen, T. A., Grundy, S. M., Lee, M.-H., Rubenstein, J. S., Polymeropoulos, M. H., Brownstein, M. J. Mapping a gene involved in regulating dietary cholesterol absorption: the sitosterolemia locus is found at chromosome 2p21. J. Clin. Invest. 102: 1041-1044, 1998. [PubMed: 9727073] [Full Text: https://doi.org/10.1172/JCI3963]
Rees, D. C., Iolascon, A., Carella, M., O'Marcaigh, A. S., Kendra, J. R., Jowitt, S. N., Wales, J. K., Vora, A., Makris, M., Manning, N., Nicolaou, A., Fisher, J., Mann, A., Machin, S. J., Clayton, P. T., Gasparini, P., Stewart, G. W. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Brit. J. Haemat. 130: 297-309, 2005. [PubMed: 16029460] [Full Text: https://doi.org/10.1111/j.1365-2141.2005.05599.x]
Reeskamp, L. F., Volta, A., Zuurbier, L., Defesche, J. C., Kees Hovingh, G., Grefhorst, A. ABCG5 and ABCG8 genetic variants in familial hypercholesterolemia. J. Clin. Lipid. 14: 207-217, 2020. [PubMed: 32088153] [Full Text: https://doi.org/10.1016/j.jacl.2020.01.007]
Repa, J. J., Berge, K. E., Pomajzl, C., Richardson, J. A., Hobbs, H., Mangelsdorf, D. J. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J. Biol. Chem. 277: 18793-18800, 2002. [PubMed: 11901146] [Full Text: https://doi.org/10.1074/jbc.M109927200]
Rios, J., Stein, E., . Shendure, J., Hobbs, H. H., Cohen, J. C. Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. Hum. Molec. Genet. 19: 4313-4318, 2010. [PubMed: 20719861] [Full Text: https://doi.org/10.1093/hmg/ddq352]
Sehayek, E., Duncan, E. M., Lutjohann, D., von Bergmann, K., Ono, J. G., Batta, A. K., Salen, G., Breslow, J. L. Loci on chromosomes 14 and 2, distinct from ABCG5/ABCG8, regulate plasma plant sterol levels in a C57BL/6J x CASA/Rk intercross. Proc. Nat. Acad. Sci. 99: 16215-16219, 2002. [PubMed: 12446833] [Full Text: https://doi.org/10.1073/pnas.212640599]
Small, D. M. Role of ABC transporters in secretion of cholesterol from liver into bile. (Commentary) Proc. Nat. Acad. Sci. 100: 4-6, 2003. [PubMed: 12509503] [Full Text: https://doi.org/10.1073/pnas.0237205100]
Tada, H., Okada, H., Nomura, A., Yashiro, S., Nohara, A., Ishigaki, Y., Takamura, M., Kawashiri, M. Rare and deleterious mutations in ABCG5/ABCG8 genes contribute to mimicking and worsening of familial hypercholesterolemia phenotype. Circ. J. 83: 1917-1924, 2019. [PubMed: 31327807] [Full Text: https://doi.org/10.1253/circj.CJ-19-0317]
Yang, C., Yu, L., Li, W., Xu, F., Cohen, J. C., Hobbs, H. H. Disruption of cholesterol homeostasis by plant sterols. J. Clin. Invest. 114: 813-822, 2004. [PubMed: 15372105] [Full Text: https://doi.org/10.1172/JCI22186]
Yu, L., Hammer, R. E., Li-Hawkins, J., von Bergmann, K., Lutjohann, D., Cohen, J. C., Hobbs, H. H. Disruption of Abcg5/Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc. Nat. Acad. Sci. 99: 16237-16242, 2002. [PubMed: 12444248] [Full Text: https://doi.org/10.1073/pnas.252582399]