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Sitosterolemia is a rare autosomal recessive lipid disorder characterized by the accumulation of dietary plant sterols in blood and tissues, leading to cutaneous xanthomas, accelerated atherosclerosis, and hematologic abnormalities. The disease is caused by biallelic loss-of-function variants in the ATP-binding cassette transporter ABCG8, which pairs with ABCG5 to efflux sterols from enterocytes into the gut lumen and from hepatocytes into bile. In healthy individuals, this heterodimer restricts plant sterol absorption and promotes biliary excretion; disruption causes hyperabsorption, impaired excretion, and toxic sterol deposition.
Genetic evidence for ABCG8’s role in sitosterolemia began with linkage of the sitosterolemia locus to chromosome 2p21 in 10 families (PMID:9727073). Subsequent studies identified ABCG8 mutations in 9 of 34 mapped pedigrees, alongside 6 ABCG5 families, establishing allelic heterogeneity (PMID:11099417; PMID:11452359). Over 110 probands from more than 34 unrelated families, including founder cohorts (Amish-Mennonite, Mediterranean), harbor homozygous or compound heterozygous ABCG8 variants that segregate perfectly with disease (PMID:29984642).
The ABCG8 variant spectrum encompasses missense, nonsense, splice-site, frameshift, and intronic mutations. A recurrent missense allele, c.1720G>A (p.Gly574Arg), appears in diverse populations and is associated with severe phytosterolemia, xanthomatosis, and premature coronary disease. Other reported variants include c.490C>T (p.Arg164Ter), c.1083G>A (p.Trp361Ter), and c.965-1G>C. Many patients also carry concurrent ABCG5 mutations, reflecting the obligate heterodimeric function of the transporter.
Functional assays demonstrate that missense mutations disrupt ABCG5/ABCG8 heterodimerization, glycosylation, and trafficking to the apical membrane, abolishing ATPase-coupled sterol export (PMID:15054092). Mouse models harboring Abcg5/8 deficiency recapitulate macrothrombocytopenia, hemolytic anemia, and sterol overload, confirming the physiological necessity of the transporter in sterol homeostasis (PMID:19846887). Structural studies reveal a transmembrane polar relay critical for allosteric ATP hydrolysis; mutations in this network markedly impair sterol-stimulated ATPase activity (PMID:33228147).
No substantive conflicting evidence has challenged ABCG8’s causative role; heterozygous carriers exhibit mildly elevated plant sterols without clinical disease, consistent with autosomal recessive inheritance. However, ABCG5 and ABCG8 heterozygous loss-of-function variants have been linked to modest LDL-cholesterol elevation and increased coronary artery disease risk in large cohorts (PMID:32862661).
In summary, definitive genetic and functional data over two decades establish ABCG8 loss-of-function as the molecular basis of sitosterolemia. Early molecular diagnosis via targeted sequencing and phytosterol measurement enables prompt dietary modification and ezetimibe therapy, preventing xanthomas and atherosclerotic complications. Key Take-home: Screening for ABCG8 variants is critical in patients with hypercholesterolemia and xanthomas to distinguish sitosterolemia from familial hypercholesterolemia and guide life-saving interventions.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong
Functional EvidenceStrongMouse models and cellular assays show loss-of-function disrupts heterodimer trafficking and efflux activity |