Molecular genetic basis and clinical heterogeneity of sitosterolemia: focusing on the mutation spectrum and pathogenic mechanisms of ABCG5/ABCG8 genes

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Sitosterolemia represents a rare autosomal recessive disorder of lipid metabolism, defined by the pathological accumulation of phytosterols—notably sitosterol and campesterol—in both plasma and tissues. This biochemical aberration precipitates severe clinical sequelae, including premature atherosclerosis, hemolytic anemia, and arthritis. The etiology is firmly established as loss-of-function mutations in ABCG5 and ABCG8 , which encode critical sterol efflux transporters. This review systematically dissects the molecular genetic architecture of sitosterolemia, offering a comprehensive evaluation of the ABCG5/ABCG8 mutation spectrum. Our analysis encompasses canonical homozygous and compound heterozygous variants, while also addressing the emerging significance of monoallelic heterozygous mutations. We further examine how specific genotypic alterations impair transporter function and correlate with phenotypic severity. Moreover, by synthesizing recent findings, we investigate whether heterozygous carriers manifest subclinical traits characterized by incomplete penetrance and assess their associated pathogenic risks. Ultimately, this work establishes a robust theoretical framework to advance precise diagnosis, refine genetic counseling strategies, and facilitate personalized clinical management of sitosterolemia.