Alternative titles; symbols
HGNC Approved Gene Symbol: ABCG8
Cytogenetic location: 2p21 Genomic coordinates (GRCh38) : 2:43,838,971-43,882,988 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p21 | {Gallbladder disease 4} | 611465 | 3 | |
| Sitosterolemia 1 | 210250 | Autosomal recessive | 3 |
Berge et al. (2000) identified 2 members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family: ABCG8 and ABCG5 (605459). ABCG8 and ABCG5 encode deduced proteins of 673 and 651 amino acids, respectively, that share 28% sequence identity. ABCG8 is most similar to ABCG1 (603076), which resembles the Drosophila 'white' gene. Both the ABCG8 and ABCG5 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 highly expressed in liver and are also detectable in small intestine and colon. Cholesterol feeding induces coordinate increases in levels of Abcg5 and Abcg8 mRNA in mice (Berge et al., 2000).
Like the ABCG5 gene, the ABCG8 gene contains 13 exons and spans about 28 kb (Berge et al., 2000).
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 (see 615460).
Berge et al. (2000) identified the ABCG8 and ABCG5 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.
Sitosterolemia 1
In patients with sitosterolemia-1 (STSL1; 210250) and STSL2 (618666), Berge et al. (2000) identified multiple mutations in the ABCG8 gene and 1 mutation in the ABCG5 gene, respectively. All mutations in the ABCG8 gene were found in homozygosity or compound heterozygosity, consistent with the autosomal recessive nature of the disorder. Nonsense and missense mutations were identified. 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.
Lu et al. (2001) provided a detailed characterization of the molecular defects in a very large multiethnic cohort of patients with sitosterolemia. All affected individuals in 37 families carried a mutation in either ABCG5 or ABCG8 but not in both. Clinically, there were no readily apparent features that differentiated individuals with mutations in sterolin-1 versus sterolin-2. The authors suggested that these 2 proteins either act as functional heterodimers or are tightly coupled along a pathway that regulates dietary sterol absorption. Thus, complete loss of any of the sterolins will lead to a functional deficiency. An individual who, hypothetically, carries a mutation in 1 copy of ABCG5 and in 1 copy of ABCG8 may not have sitosterolemia, since he or she would be predicted to have 25% or more normally functioning sterolins. Consistent with this interpretation, the obligate heterozygous parents of the probands did not appear to manifest any clinical or biochemical features, although they were predicted to have 50% normally functioning sterolins. All Japanese probands appeared to have mutations in the ABCG5 gene only; however, mutations in ABCG5 were not exclusively limited to the Japanese. Despite the presence of only 1 known consanguineous marriage, there was a very high degree of homozygosity for informative markers around the 2 loci and evidence of linkage disequilibrium.
In a 59-year-old Corsican woman with sitosterolemia with a hematologic presentation, Melenotte et al. (2014) identified homozygosity for a nonsense mutation in the ABCG8 gene (Q302X; 605460.0011).
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).
Susceptibility to Gallstone Disease
Buch et al. (2007) identified a SNP (rs11887534) in the ABCG8 gene (D19H; 605460.0009) that was associated with gallstone disease (see GBD4, 611465) in several patient cohorts.
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.
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 German Swiss patient with sitosterolemia (STSL1; 210250), the first to be described with this disorder (Bhattacharyya and Connor, 1974), Berge et al. (2000) identified a homozygous G-to-A transition at nucleotide 1083 in the ABCG8 gene, resulting in a trp361-to-ter (W361X) substitution. The patient's cholesterol was 195 mg/dl.
In studies of a multiethnic cohort of patients with sitosterolemia, Lu et al. (2001) found that 19 of 49 mutant alleles of the ABCG8 gene carried the trp361-to-ter mutation.
Rees et al. (2005) identified homozygosity for the W361X mutation in 2 unrelated patients with sitosterolemia. One patient presented with postsurgical bleeding tendency and xanthomata. Both had evidence of mild hemolytic anemia with reticulocytosis, as well as increased platelet volume. 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.
In an Amish American patient with sitosterolemia (STSL1; 210250), Berge et al. (2000) identified a G-to-A transition at nucleotide 1720 of the ABCG8 gene, resulting in a gly574-to-arg (G574R) substitution. The patient died of coronary artery disease at 13 years of age. This patient was the proband of the extensive Amish kindred studied by Beaty et al. (1986) and also by Kwiterovich et al., 1981.
In a Swiss woman with sitosterolemia who had typical xanthomas and also mitral and aortic valvular disease, Solca et al. (2005) identified homozygosity for the G574R mutation in the ABCG8 gene. Extended haplotype analysis of this patient and 2 Amish-Mennonite patients with the same mutation revealed that the Swiss patient and 1 Amish-Mennonite patient had identical SNPs, with minor differences between the 2 Amish-Mennonite patients. Solca et al. (2005) concluded that the G574R mutation in the Amish-Mennonite population originated in Europe more than 250 years ago.
In an 8-month-old Caucasian American with sitosterolemia (STSL1; 210250), Berge et al. (2000) identified a C-to-G transversion at nucleotide 1974 of the ABCG8 gene, resulting in a tyr658-to-ter substitution. The child was compound heterozygous for the W361X mutation (605460.0001). The cholesterol fell from 800 to 151 mg/dl on a low cholesterol diet.
In a Chinese child with sitosterolemia (STSL1; 210250), Berge et al. (2000) identified a G-to-A transition at nucleotide 788 of the ABCG8 gene, resulting in an arg263-to-gln substitution. The other allele had a deletion of C at nucleotide 547 resulting in termination at codon 191 (605460.0005). The child's cholesterol was 556 mg/dl.
For discussion of the 1-bp deletion in the ABCG8 gene (547delC) that was found in compound heterozygous state in a patient with sitosterolemia (STSL1; 210250) by Berge et al. (2000), see 605460.0004.
In a Caucasian American child with sitosterolemia (STSL1; 210250), Berge et al. (2000) identified a C-to-T transition at nucleotide 1234 of the ABCG8 gene, resulting in an arg412-to-ter substitution. The child was a compound heterozygote for the W361X mutation (605460.0001). The child's cholesterol fell from 375 to 201 mg/dl on a low cholesterol diet.
In a Caucasian American child with sitosterolemia (STSL1; 210250), Berge et al. (2000) identified a T-to-G transversion at nucleotide 1787 of the ABCG8 gene, resulting in a leu596-to-arg substitution. A mutation was not identified on the other allele. The child's cholesterol fell from 753 to 106 mg/dl on a low cholesterol diet.
In a Mexican American patient with sitosterolemia (STSL1; 210250), Berge et al. (2000) identified an A-to-C transversion at nucleotide 691 of the ABCG8 gene, resulting in a pro231-to-thr substitution. The patient was a compound heterozygote for the arg412-to-ter mutation (R412X; 605460.0006). The patient's LDL cholesterol fell from 380 to 280 mg/dl.
Buch et al. (2007) identified a SNP (rs11887534) in the ABCG8 gene, a G-to-C transversion corresponding to an asp19-to-his (D19H) substitution, that was significantly associated with gallstones (GBD4; 611465) in 3 replication studies. In an initial genomewide screening panel among 280 affected individuals and 360 controls, the authors identified 235 significant SNPs, including D19H. A follow-up study in 1,105 additional affected individuals replicated the disease association of D19H (p = 4.1 x 10(-9), 1.1 x 10(-4) after Bonferroni correction). Additional significant replication was achieved in 728 Germans (p = 2.8 x 10(-7)). The overall odds ratio in the full German sample was 2.2 and 7.1 for heterozygous and homozygous H allele carriers, respectively, corresponding to a population risk of about 11%. The association was stronger in those with cholesterol gallstones, suggesting that his19 may be associated with increased efficiency of cholesterol transport into the bile lumen, causing cholesterol hypersaturation of bile and promoting the formation of gallstones.
In 4 Schmiedeleut (S-leut) Hutterite individuals with sitosterolemia (STSL1; 210250), Chong et al. (2012) identified a homozygous C-to-G transition at nucleotide 320 of the ABCG8 gene, resulting in a ser-to-ter substitution at codon 107 (S107X). All 4 individuals (2 teenaged sibs and 2 adult sibs) had elevated sitosterol levels (4.29-19.0 mg/100ml). The mutation was identified in a carrier screening for mutations resulting in autosomal recessive disorders among 1,644 S-leut Hutterites in the United States. The mutation, private to the Hutterite population, was found in heterozygosity in 127 individuals and homozygosity in 4 among 1,515 screened, giving a carrier frequency among the Hutterites of 0.084, or 1 in 12.
In a 59-year-old Corsican woman with sitosterolemia-1 (STSL1; 210250) who had premature atherosclerotic disease and hemolytic anemia with macrothrombocytopenia, Melenotte et al. (2014) identified a homozygous c.904C-T transition (c.904C-T, NM_022437.2) in the ABCG8 gene, resulting in a gln302-to-ter (Q302X) substitution.
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Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. A population-based study of autosomal-recessive disease-causing mutations in a founder population. Am. J. Hum. Genet. 91: 608-620, 2012. [PubMed: 22981120] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.007]
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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]
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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]
Solca, C., Stanga, Z., Pandit, B., Diem, P., Greeve, J., Patel, S. B. Sitosterolaemia in Switzerland: molecular genetics links the US Amish-Mennonites to their European roots. Clin. Genet. 68: 174-178, 2005. [PubMed: 15996216] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00472.x]
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]