Sitosterolemia is a rare, autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations, caused by mutations in the adenosine triphosphate-bind-ing cassette (ABC) transporter ABCG5 or ABCG8 genes.
Sitosterolemia induced in Abcg5- and Abcg8-deficient mice fed a high plant sterol diet resulted in accumulation of free sterols in platelet plasma membranes, leading to hyperactivatable platelets characterized by constitutive binding of fibrinogen to its αIIbβ3 integrin receptor, internalization of the αIIbβ3 complex, generation of platelet-derived microparticles, and changes in the quantity and subcellular localization of filamin.
A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia.
Although not sufficient evidence exists to regard this sequence variation as a mutation, this previously unreleased sequence variation occurred in a "hot spot" area for sitosterolemia of the ABCG5 gene (exon 9) and the similar increased plasma plant sterol concentrations of the heterozygous mother contribute to the notion, that this very likely presents an inactivating mutation.
Based on the third variant, a stop variant in ABCG5 (p.(Arg446*)), we established a diagnosis of sitosterolemia, confirmed by elevated blood plant sterol levels and successfully initiated targeted lipid-lowering treatment.
In this regard, ABC transporters, such as ABCA1, ABCG5 and ABCG8, were initially found to be responsible for genetically-inherited syndromes like Tangier diseases and sitosterolemia.
Interestingly, mutation of ABCG5 and or ABCG8 genes in man causes sitosterolemia, a rare genetic disease characterized by massive absorption of plant sterols and premature arteriosclerosis.