Submission Details

Autosomal recessive

04/12/2019

The ABCG8 gene is located on chromosome 2 at 2p21 and encodes the ATP binding cassette subfamily G member 8 protein. This protein, which is also referred to as sterolin-2, forms a heterodimer transporter with sterolin-1, which is encoded by the ABCG5 gene. The heterodimeric transporter functions in the elimination of plant sterols, particularly sterol excretion by the liver into bile. ABCG8 was first reported in relation to autosomal recessive sitosterolemia in 2000 (11099417: Berge et al. 2000). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Six cases with variants in this gene were evaluated to support this curation (11099417: Berge et al. 2000; 11452359: Lu et al. 2001; 16029460: Rees et al. 2005). Six unique variants in this gene (homozygous or compound heterozygous) were identified in these cases and included one missense and five predicted null (four stop-gained and one splice). Variants in this gene were confirmed to segregate with the disease in one additional family member, and the missense variant was identified as a founder in the Amish population. More evidence is available in the literature. Genetic and experimental data indicate the mechanism for disease is homozygous loss of function. This gene-disease association is supported by strong expression in the liver and small intestine, protein interaction data, in vitro functional assays of patient-identified variants, and recapitulation of key disease features in homozygous knockout mice (15054092: Graf et al. 2004; 11099417: Berge et al. 2000; 11901146: Repa et al. 2002; 15040800: Klett et al. 2004). In summary, ABCG8 is definitively associated with autosomal recessive sitosterolemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

11099417 11452359 16029460 15054092 11901146 15040800 12208867