RT Journal Article SR Electronic T1 Mutations in the Drosophila splicing regulator Prp31 as a model for Retinitis pigmentosa 11 JF bioRxiv FD Cold Spring Harbor Laboratory SP 147918 DO 10.1101/147918 A1 Malte Lehmann A1 Sarita Hebbar A1 Holger Brandl A1 Weihua Leng A1 Naharajan Lakshmanaperumal A1 Sylke Winkler A1 Elisabeth Knust YR 2017 UL http://biorxiv.org/content/early/2017/06/09/147918.abstract AB Retinitis pigmentosa is a clinically heterogeneous disease affecting 1.6 million people worldwide. A growing number of identified disease-causing genes are associated with the spliceosome, but the molecular consequences that link defects in splicing factor genes to the aetiology of the disease remain to be elucidated. In this paper, we present a Drosophila model for Retinitis pigmentosa 11, a human disease caused by mutations in the splicing factor PRPF31. Here, we induced mutations in the Drosophila orthologue Prp31. Mutant flies are viable and show a normal eye phenotype when kept under regular light conditions. However, when exposed to constant light, photoreceptors of mutant flies degenerate, thus resembling the human disease phenotype. Degeneration could be shown to be associated with increased oxidative stress. This increase was in agreement with severe dysregulation of genes involved in oxidation/reduction processes, as revealed by high throughput transcriptome sequencing. In fact, light induced photoreceptor cell degeneration could be attenuated by experimentally reducing oxidative stress. A comparable decrease in retinal degeneration was achieved by raising mutant larvae on a vitamin A-depleted medium, thereby reducing rhodopsin levels. Finally, transcriptome data further uncovered an overall retention of introns in mRNAs. Among those, mRNAs of genes involved in synapse assembly, growth and stability were most prominent. These results point to a multifactorial genesis of light induced degeneration in retinae of Prp31 mutant flies, including transcriptional and splicing dysregulation, oxidative stress and defects in vitamin A metabolism.