Retinal editome profiling in mice reveals RNA editing in key developmental genes associated with retinitis pigmentosa

Adenosine-to-inosine (A-to-I) RNA editing has been found to function in various neurological disorders; however, the role of A-to-I RNA editing in retinitis pigmentosa (RP) remains unclear.

RNA editing profiles of mouse retinas at different developmental stages, and three RP mouse models that were sampled at the peak of photoreceptor cell death for each model were analyzed to identify significant RNA editing events and genes involved in development and RP pathogenesis. Data from two addtional RP models were used for validation. Key editing sites were validated by Sanger sequencing and dual-luciferase reporter assays.

Global A-to-I editing levels increased during normal retinal development, correlating with Adar/Adarb1 expression. In RP models, significant alterations in editing landscapes were observed, including dysregulated editing of 55 IRD-related genes. Functional enrichment and protein-protein interaction (PPI) analyses highlighted 10 hub genes, including Rgs9bp, which showed extensive editing and elevated expression. Editing at specific sites in Rgs9bp enhanced reporter gene expression, implying a functional impact. Notably, Rgs9bp, traditionally linked to cone-specific bradyopsia, exhibited hyper-editing in rod-dominant RP models, suggesting a broader role in retinal degeneration.

Our study reveals that A-to-I RNA editing is dynamically regulated during retinal development and profoundly altered in RP, implicating RNA editing as a novel layer of gene regulation in inherited retinal diseases.