ORPHA: 2882; DO: 0060983;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p21 | Sitosterolemia 2 | 618666 | Autosomal recessive | 3 | ABCG5 | 605459 |
A number sign (#) is used with this entry because of evidence that sitosterolemia-2 (STSL2) is caused by homozygous or compound heterozygous mutation in the ABCG5 gene (605459) on chromosome 2p21.
Sitosterolemia, also known as phytosterolemia, is an autosomal recessive metabolic condition characterized by unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules, such as sitosterol. Patients with this disorder have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease (summary by Berge et al., 2000).
For a general phenotypic description and a discussion of genetic heterogeneity of sitosterolemia, see 210250.
Lee et al. (2001) reported patients with sitosterolemia from 9 unrelated families who had mutations in the ABCG5 gene. All probands had typical clinical features of the disorder and elevated plasma sitosterol levels.
Rios et al. (2010) reported an 11-month old Romanian girl in whom sitosterolemia became evident after she was weaned from an exclusive breast milk diet.
By studying 10 well-characterized families with sitosterolemia, Patel et al. (1998) localized the genetic defect to 2p21, between microsatellite markers D2S1788 and D2S1352 (maximum lod score = 4.49 at theta = 0.0).
Lee et al. (2001) studied 30 families which were assembled from around the world and had no evidence of genetic heterogeneity. A maximum multipoint lod score of 11.49 was obtained for marker D2S2998. Using both homozygosity mapping and informative recombination events, the critical interval containing the sitosterolemia gene was narrowed to a region defined by markers D2S2294 and Afm210xe9, a distance of approximately 2 cM. Homozygosity and haplotype sharing was identified in probands from nonconsanguineous marriages from a number of families, strongly supporting the existence of a founder effect among Amish/Mennonite, Finnish/Norwegian, and Japanese populations.
The patient of Rios et al. (2010), who presented with xanthomas of the Achilles tendon and very high plasma cholesterol levels after weaning from breastfeeding, was treated with ezetimibe, a lipid-lowering agent that reduces the absorption of plant sterols as well as cholesterol. The plasma cholesterol level fell progressively into the normal range, but the plant sterol levels remained elevated despite the patient consuming a low cholesterol, low plant sterol diet.
Tada et al. (2020) reported that heterozygous mutation in the ABCG5 or ABCG8 (605460) gene contributed to the elevation of LDL cholesterol. They investigated whether treatment with the drug ezetimibe in addition to statin therapy would be more effective in patients with a mutation in either gene. Ezetimibe is a selective cholesterol absorption inhibitor, which potently inhibits the uptake and absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides, or bile acids (summary by Davis et al., 2008). Tada et al. (2020) identified 10 different mutations in these genes in 26 individuals among 321 hypercholesterolemic study subjects. Baseline LDL cholesterol levels did not differ between the 2 groups nor did the LDL cholesterol levels differ between both groups when treated with atorvastatin. However, LDL cholesterol levels obtained with 10 mg/day atorvastatin and 10 mg/day ezetimibe in patients with an ABCG5 or ABCG8 mutation were significantly lower than those in patients without such mutations (72 +/- 26 mg/dl vs 87 +/- 29 mg/dl, p less than 0.05). Tada et al. (2020) concluded that ezetimibe-atorvastatin combination therapy may be more beneficial in hypercholesterolemic patients with an ABCG5 or ABCG8 mutation.
The transmission pattern of STLS2 in the families reported by Berge et al. (2000) was consistent with autosomal recessive inheritance.
Berge et al. (2000) identified homozygosity or compound heterozygosity for several mutations in 2 adjacent, oppositely oriented genes that encode members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family, ABCG8 (see 605460.0001-605460.0008) and ABCG5 (see 605459.0001), in 9 patients with sitosterolemia. The 2 genes are expressed at highest levels in liver and intestine. In mice, cholesterol feeding upregulates expression of both genes. Based on their data, Berge et al. (2000) concluded 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. Treatment with a low cholesterol diet resulted in a reduction of plasma cholesterol from a high of 800 in some patients to a low of 106.
Lee et al. (2001) identified homozygosity for mutations in the ABCG5 gene (605459.0001-605459.0004) 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).
In studies of a large multiethnic cohort of patients with sitosterolemia, Lu et al. (2001) identified a missense mutation in the ABCG5 gene (R389H; 605459.0005) in 6 of 20 alleles. The mutation was found only in Japanese patients; it was not found in a random sample of 82 normal Japanese subjects.
In 4 affected members of a family with sitosterolemia, Rees et al. (2005) identified a homozygous nonsense mutation in the ABCG5 gene (E77X; 605459.0006). 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).
Rios et al. (2010) reported an 11-month old Romanian girl with xanthomas and marked hypercholesterolemia. She was initially thought to have primary hypercholesterolemia (see 143890), bu 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.
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 (see LXRA, 602423) 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.
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]
Davis, H. R., Jr., Basso, F., Hoos, L. M., Tetzloff, G., Lally, S. M., Altmann, S. W. Cholesterol homeostasis by the intestine: lessons from Niemann-Pick C1 like 1 (NPC1L1) Atheroscler. Suppl. 9: 77-81, 2008. [PubMed: 18585981] [Full Text: https://doi.org/10.1016/j.atherosclerosissup.2008.05.008]
Lee, M.-H., Gordon, D., Ott, J., Lu, K., Ose, L., Miettinen, T., Gylling, H., Stalenhoef, A. F., Pandya, A., Hidaka, H., Brewer, B., Jr., Kojima, H., Sakuma, N., Pegoraro, R., Salen, G., Patel, S. B. Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities. Europ. J. Hum. Genet. 9: 375-384, 2001. [PubMed: 11378826] [Full Text: https://doi.org/10.1038/sj.ejhg.5200628]
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., 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]
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]
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]
Tada, H., Okada, H., Nomura, A., Takamura, M., Kawashiri, M. Beneficial effect of ezetimibe-atorvastatin combination therapy in patients with a mutation in ABCG5 or ABCG8 gene. Lipids Health Dis. 19: 3, 2020. Note: Electronic Article. [PubMed: 31901240] [Full Text: https://doi.org/10.1186/s12944-019-1183-4]
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]