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  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., 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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-61B2-7 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-B425-8
Genre: Journal Article

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 Creators:
Buskin, A., Author
Zhu, L., Author
Chichagova, V., Author
Basu, B., Author
Mozafarri Jovin, S.1, Author              
Dolan, D., Author
Droop, A., Author
Collin, J., Author
Bronstein, R., Author
Mehrotra, S., Author
Farkas, M., Author
Hilgen, G., Author
White, K., Author
Pan, K. T.2, Author              
Treumann, A., Author
Hallam, D., Author
Bialas, K., Author
Chung, G., Author
Mellough, C., Author
Ding, Y., Author
Krasnogor, N., AuthorPrzyborski, S., AuthorZwolinski, S., AuthorAl-Aama, J., AuthorAlharthi, S., AuthorXu, Y., AuthorWheway, G., AuthorSzymanska, K., AuthorMcKibbin, M., AuthorInglehearn, C. F., AuthorElliott, D. J., AuthorLindsay, S., AuthorAli, R. R., AuthorSteel, D. H., AuthorArmstrong, L., AuthorSernagor, E., AuthorUrlaub, H.2, Author              Pierce, Eric, AuthorLührmann, R.1, Author              Grellscheid, S. N., AuthorJohnson, C. A., AuthorLako, M., Author more..
Affiliations:
1Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              
2Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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 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.

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Language(s): eng - English
 Dates: 2018-10-12
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/s41467-018-06448-y
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Title: Nature Communications
Source Genre: Journal
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Pages: 19 Volume / Issue: 9 Sequence Number: 4234 Start / End Page: - Identifier: -