The splicing regulator Prp31 prevents retinal degeneration in Drosophila by regulating Rhodopsin levels

Abstract Retinitis pigmentosa (RP) is a clinically heterogeneous disease affecting 1.6 million people worldwide. The second-largest group of genes causing autosomal dominant RP in human encodes regulators of the splicing machinery, but the molecular consequences that link defects in splicing factor genes to the aetiology of the disease remain to be elucidated. Mutations in PRPF31, one of the splicing factors, are linked to RP11. To get insight into the mechanisms by which mutations in this gene lead to retinal degeneration, we induced mutations in the Drosophila orthologue Prp31 . Flies heterozygous mutant for Prp31 are viable and develop normal eyes and retina. However, photoreceptors degenerate under light stress, thus resembling the human disease phenotype. Prp31 mutant flies show a high degree of phenotypic variability, similar as reported for human RP11 patients. Degeneration is associated with increased accumulation of rhodopsin 1, both in the rhabdomere and in the cell body. In fact, reducing rhodopsin levels by raising animals in a carotenoid-free medium not only suppressed rhodopsin accumulation, but also retinal degeneration. In addition, our results underscore the relevance of eye color mutations on phenotypic traits, in particular whilst studying a complex process such as retinal degeneration. Article Summary Retinitis pigmentosa (RP) is a human disease affecting 1.6 million people worldwide. So far >50 genes have been identified that are causally related to RP. Mutations in the splicing factor PRPF31 are linked to RP11. We induced mutations in the Drosophila orthologue Prp31 and show that flies heterozygous for Prp31 undergo light-dependent retinal degeneration. Degeneration is associated with increased accumulation of the light-sensitive molecule, rhodopsin 1. In fact, reducing rhodopsin levels by dietary intervention suppressed retinal degeneration. We believe that this model will help to better understand the aetiology of the human disease.