Elucidating the pathogenicity of missense variants in the nucleotide-binding and transmembrane protein domains of ABCG5 associated with sitosterolemia

Consuming vegetables poses a challenge for individuals with sitosterolemia, a rare autosomal recessive genetic disorder characterized by heightened intestinal absorption and decreased biliary excretion of plant sterols. Pathogenic mutations in the ATP Binding Cassette Subfamily G Member 5 (ABCG5) and ATP Binding Cassette Subfamily G Member 8 (ABCG8) genes result in sitosterolemia. ABCG5 and ABCG8 form the ATP-binding cassette transporter protein ABCG5/ABCG8 that functions to efflux plant sterols and cholesterol from the liver and small intestine. This study seeks to predict the pathogenicity of the missense swaps G91E, F399C, R419C, and R419G. These variants were selected based on specific placement within the functional domains of ABCG5. Pathogenicity scores were compared to two pathogenic variants using Mutation Assessor, MetaLR, REVEL, CADD, PolyPhen, and SIFT. ConSurf predicted the amino acid position of each missense swap to be conserved, buried, structural, or exposed. Molecular dynamics simulations revealed differences in movement between the variants and the WT. Our results predict that these variants are pathogenic regarding sitosterolemia. These findings contribute to the understanding of genetic factors influencing sitosterolemia and underscore the importance of further investigations to elucidate the clinical implications of these variants for improved diagnostic and therapeutic strategies in managing this rare genetic disorder.