Disrupted alternative splicing for genes implicated in splicing and 
ciliogenesis causes PRPF31 retinitis pigmentosa.

Buskin, A.; Zhu, L.; Chichagova, V.; Basu, B.; Mozafarri Jovin, S.; Dolan, D.; Droop, A.; Collin, J.; Bronstein, R.; Mehrotra, S.; Farkas, M.; Hilgen, G.; White, K.; Pan, K. T.; Treumann, A.; Hallam, D.; Bialas, K.; Chung, G.; Mellough, C.; Ding, Y.; Krasnogor, N.; Przyborski, S.; Zwolinski, S.; Al-Aama, J.; Alharthi, S.; Xu, Y.; Wheway, G.; Szymanska, K.; McKibbin, M.; Inglehearn, C. F.; Elliott, D. J.; Lindsay, S.; Ali, R. R.; Steel, D. H.; Armstrong, L.; Sernagor, E.; Urlaub, H.; Pierce, Eric; Lührmann, R.; Grellscheid, S. N.; Johnson, C. A.; Lako, M.

doi:10.1038/s41467-018-06448-y

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Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.

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Mozafarri Jovin, S.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Pan, K. T.
Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society;

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Urlaub, H.
Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society;

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Lührmann, R.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Citation

Buskin, A., Zhu, L., Chichagova, V., Basu, B., Mozafarri Jovin, S., Dolan, D., et al. (2018). Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nature Communications, 9: 4234. doi:10.1038/s41467-018-06448-y.

Cite as: https://hdl.handle.net/21.11116/0000-0002-61B2-7

Abstract

Mutations in pre-mRNA processing factors (PRPFs) cause autosomal-dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause non-syndromic retinal disease. Here, we generate transcriptome profiles from RP11 (PRPF31-mutated) patient-derived retinal organoids and retinal pigment epithelium (RPE), as well as Prpf31+/- mouse tissues, which revealed that disrupted alternative splicing occurred for specific splicing programmes. Mis-splicing of genes encoding pre-mRNA splicing proteins was limited to patient-specific retinal cells and Prpf31+/- mouse retinae and RPE. Mis-splicing of genes implicated in ciliogenesis and cellular adhesion was associated with severe RPE defects that include disrupted apical - basal polarity, reduced trans-epithelial resistance and phagocytic capacity, and decreased cilia length and incidence. Disrupted cilia morphology also occurred in patient-derived photoreceptors, associated with progressive degeneration and cellular stress. In situ gene editing of a pathogenic mutation rescued protein expression and key cellular phenotypes in RPE and photoreceptors, providing proof of concept for future therapeutic strategies.