ABCG5 – Familial Hypercholesterolemia

ABCG5 has been implicated as a minor locus influencing hypercholesterolemia in individuals meeting clinical criteria for familial hypercholesterolemia (FH). In a cohort of 487 FH subjects, 37 (8%) carried deleterious ABCG5 or ABCG8 variants in the absence of mutations in LDLR, APOB, or PCSK9, including three with bi-allelic mutations consistent with sitosterolemia; heterozygous ABCG5 variant carriers had significantly higher LDL-C and altered sterol ratios, suggesting a mimicking or exacerbating role in the FH phenotype (PMID:31327807). However, these variants did not exhibit clear autosomal dominant segregation in family studies.

Functional assays of ABCG5 missense and truncating variants demonstrate impaired sterol efflux and heterodimer trafficking in vitro, confirming a loss-of-function effect on sterol transport (PMID:15054092). Population-level data reveal heterozygous ABCG5 loss-of-function carriers have modest LDL-C elevations and approximately two-fold increased risk of coronary artery disease, but the evidence for ABCG5 as an independent autosomal dominant FH gene remains limited (PMID:32862661).

Key Take-home: ABCG5 variants can mimic and worsen hypercholesterolemia phenotypes in FH-like individuals, but current genetic and functional data support only a limited autosomal dominant association.

References

• Circulation journal : official journal of the Japanese Circulation Society • 2019 • Rare and Deleterious Mutations in ABCG5/ABCG8 Genes Contribute to Mimicking and Worsening of Familial Hypercholesterolemia Phenotype PMID:31327807
• The Journal of biological chemistry • 2004 • Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking PMID:15054092
• Circulation. Genomic and precision medicine • 2020 • Heterozygous ABCG5 Gene Deficiency and Risk of Coronary Artery Disease PMID:32862661

Evidence Based Scoring (AI generated)