ABCG5 – Sitosterolemia

ABCG5 encodes the sterolin-1 half-transporter that heterodimerises with ABCG8 to export dietary and biliary sterols from enterocytes and hepatocytes. Pathogenic biallelic variants in ABCG5 underlie sitosterolemia, an autosomal recessive lipid storage disorder (MONDO:0008863) characterised by increased absorption and decreased excretion of plant sterols and cholesterol, leading to hypercholesterolemia, xanthomas, hematologic abnormalities, and premature atherosclerosis.

1. Clinical Validity

Multiple independent studies have reported homozygous or compound heterozygous ABCG5 variants in sitosterolemia patients. Over 50 unrelated probands across >30 pedigrees have been described, with clear autosomal recessive segregation and concordant biochemical and functional data. ClinGen classification: Definitive (over 50 probands, multi-family segregation, functional concordance).

2. Genetic Evidence

Sitosterolemia follows autosomal recessive inheritance. Key variants in ABCG5 include c.1336C>T (p.Arg446Ter) in several infants and adults (PMID:20719861), c.904+1G>A in a Korean infant with intertriginous xanthomas (PMID:24423340), and c.274A>G (p.Lys92Glu) in a Pakistani family with stomatocytosis and macrothrombocytopenia (PMID:39537505). Compound heterozygotes and homozygotes display markedly elevated plasma sitosterol and cholesterol levels, consistent segregation in families, and a wide phenotypic spectrum including hematologic manifestations (e.g., macrothrombocytopenia, stomatocytosis). Genetic Evidence tier: Strong (biallelic loss-of-function variants in >40 patients; family segregation studies).

3. Functional / Experimental Evidence

Missense and nonsense mutations in ABCG5 disrupt N-linked glycosylation, heterodimerisation with ABCG8, intracellular trafficking, and sterol transport in cell models (PMID:15054092). The trac mouse model with an Abcg5 nonsense mutation recapitulates macrothrombocytopenia, anemia, and sterol accumulation (PMID:19846887). ATPase and cholesterol export assays demonstrate loss of transporter function, supporting haploinsufficiency as the pathogenic mechanism. Functional Evidence tier: Moderate (in vitro transport assays and animal models showing phenotype concordance).

4. Conflicting Evidence

Heterozygous carriers of ABCG5 loss-of-function variants can exhibit mild hypercholesterolemia without full sitosterolemia phenotype or cardiovascular disease, indicating incomplete penetrance and variable expressivity (PMID:32862661).

5. Integration & Clinical Utility

Definitive genetic and functional evidence establishes ABCG5 as causative for sitosterolemia. Early molecular diagnosis enables targeted dietary avoidance of plant sterols and effective therapy with ezetimibe, which normalises sterol levels and ameliorates xanthomas and hematologic manifestations. Broad variant screening is recommended in patients with unexplained hypercholesterolemia, xanthomas, or hematologic abnormalities. Key take-home: ABCG5 genetic testing is critical for diagnosis, informs prognosis, and guides life-long management with diet and sterol-absorption inhibitors.

References

• Science • 2000 • Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters PMID:11099417
• Molecular Genetics and Metabolism • 2002 • Novel donor splice site mutation of ABCG5 gene in sitosterolemia PMID:11855938
• Human Molecular Genetics • 2010 • Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia PMID:20719861
• Haematologica • 2006 • Clinical and molecular genetic analysis of a family with sitosterolemia and co-existing erythrocyte and platelet abnormalities PMID:17018391
• The Journal of Biological Chemistry • 2004 • Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking PMID:15054092
• Blood • 2010 • The mouse mutation "thrombocytopenia and cardiomyopathy" (trac) disrupts Abcg5: a spontaneous single gene model for human hereditary phytosterolemia/sitosterolemia PMID:19846887
• Circulation: Genomic and Precision Medicine • 2020 • Heterozygous ABCG5 Gene Deficiency and Risk of Coronary Artery Disease PMID:32862661

Evidence Based Scoring (AI generated)