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Mutations in the Drosophila splicing regulator Prp31 as a model for Retinitis pigmentosa 11

Malte Lehmann, Sarita Hebbar, Holger Brandl, Weihua Leng, Naharajan Lakshmanaperumal, Sylke Winkler, Elisabeth Knust
doi: https://doi.org/10.1101/147918
Malte Lehmann
Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108 01307-Dresden, Germany
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Sarita Hebbar
Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108 01307-Dresden, Germany
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Holger Brandl
Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108 01307-Dresden, Germany
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Weihua Leng
Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108 01307-Dresden, Germany
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Naharajan Lakshmanaperumal
Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108 01307-Dresden, Germany
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Sylke Winkler
Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108 01307-Dresden, Germany
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Elisabeth Knust
Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108 01307-Dresden, Germany
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  • For correspondence: knust@mpi-cbg.de
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Abstract

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.

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Posted June 09, 2017.
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Mutations in the Drosophila splicing regulator Prp31 as a model for Retinitis pigmentosa 11
Malte Lehmann, Sarita Hebbar, Holger Brandl, Weihua Leng, Naharajan Lakshmanaperumal, Sylke Winkler, Elisabeth Knust
bioRxiv 147918; doi: https://doi.org/10.1101/147918
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Mutations in the Drosophila splicing regulator Prp31 as a model for Retinitis pigmentosa 11
Malte Lehmann, Sarita Hebbar, Holger Brandl, Weihua Leng, Naharajan Lakshmanaperumal, Sylke Winkler, Elisabeth Knust
bioRxiv 147918; doi: https://doi.org/10.1101/147918

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