Structural and Pathogenic Impacts of ABCA4 Variants in Retinal Degenerations—An In-Silico Study

Abstract

The retina-specific ATP-binding cassette transporter protein ABCA4 is responsible for properly continuing the visual cycle by removing toxic retinoid byproducts of phototransduction. Functional impairment caused by ABCA4 sequence variations is the leading cause of autosomal recessive inherited retinal disorders, including Stargardt disease, retinitis pigmentosa, and cone-rod dystrophy. To date, more than 3000 ABCA4 genetic variants have been identified, approximately 40 percent of which have not been able to be classified for pathogenicity assessments. This study examined 30 missense ABCA4 variants using AlphaFold2 protein modeling and computational structure analysis for pathogenicity prediction. All variants classified as pathogenic (n = 10) were found to have deleterious structural consequences. Eight of the ten benign variants were structurally neutral, while the remaining two resulted in mild structural changes. This study’s results provided multiple lines of computational pathogenicity evidence for eight ABCA4 variants of uncertain clinical significance. Overall, in silico analyses of ABCA4 can provide a valuable tool for understanding the molecular mechanisms of retinal degeneration and their pathogenic impact.

How to Set Up Genetic Counselling for Inherited Macular Dystrophies: Focus on Genetic Characterization

“…Unsurprisingly, we often encounter hypomorphic variants in the milder phenotypes. This is particularly true for ABCA4-related conditions, which are characterized by allelic heterogeneity, where the combination of different degrees of severity of the two variants (and the residual ABCA4 protein function) influence the resulting phenotype [63].…”