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

Buskin, Adriana and Zhu, Lili and Chichagova, Valeria and Basu, Basudha and Mozaffari-Jovin, Sina and Dolan, David and Droop, Alastair and Collin, Joseph and Bronstein, Revital and Mehrotra, Sudeep and Farkas, Michael and Hilgen, Gerrit and White, Kathryn and Pan, Kuan-Ting and Treumann, Achim and Hallam, Dean and Bialas, Katarzyna and Chung, Git and Mellough, Carla and Ding, Yuchun and Krasnogor, Natalio and Przyborski, Stefan and Zwolinski, Simon and Al-Aama, Jumana and Alharthi, Sameer and Xu, Yaobo and Wheway, Gabrielle and Szymanska, Katarzyna and McKibbin, Martin and Inglehearn, Chris F. and Elliott, David J. and Lindsay, Susan and Ali, Robin R. and Steel, David H. and Armstrong, Lyle and Sernagor, Evelyne and Urlaub, Henning and Pierce, Eric and Lührmann, Reinhard and Grellscheid, Sushma-Nagaraja and Johnson, Colin A. and Lako, Majlinda (2018) 'Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.', Nature communications., 9 (1). p. 4234.


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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Publisher statement:Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
Date accepted:03 September 2018
Date deposited:25 October 2018
Date of first online publication:12 October 2018
Date first made open access:25 October 2018

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