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

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 nonsyndromic 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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Item Type:	Article
Authors/Creators:	Buskin, A Zhu, L Chichagova, V Basu, B https://orcid.org/0000-0002-5434-5202 Mozaffari-Jovin, S Dolan, D Droop, A https://orcid.org/0000-0001-7695-7480 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 https://orcid.org/0000-0001-7736-5225 McKibbin, M Inglehearn, CF https://orcid.org/0000-0002-5143-2562 Elliott, DJ Lindsay, S Ali, RR Steel, DH Armstrong, L Sernagor, E Urlaub, H Pierce, E Lührmann, R Grellscheid, S-N Johnson, CA https://orcid.org/0000-0002-2979-8234 Lako, M
Copyright, Publisher and Additional Information:	© The Author(s) 2018. 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 http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 12 October 2018 Accepted: 3 September 2018
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > Medicine & Health Faculty Office (Leeds) > Leeds Inst for Data Analytics (LIDA)
Funding Information:	Funder Grant number EU - European Union HEALTH-F5-2010-241955 MRC (Medical Research Council) MR/m000532/1 BBSRC (Biotechnology & Biological Sciences Research Council) BB/P007791/1 Fight for Sight GR586
Depositing User:	Symplectic Publications
Date Deposited:	14 Aug 2018 10:34
Last Modified:	25 Jun 2023 21:28
Status:	Published
Publisher:	Springer Nature
Identification Number:	10.1038/s41467-018-06448-y
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:134518

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

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