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

Lookup NU author(s): Dr Adriana BuskinORCiD, Dr Lili Zhu, Dr Valeria Chichagova, Dr David Dolan, Dr Joseph Collin, Dr Gerrit HilgenORCiD, Dr Kathryn White, Dr Dean Hallam, Katarzyna Bialas, Dr Git Chung, Dr Carla Mellough, Dr Yuchun Ding, Professor Natalio KrasnogorORCiD, Dr Simon Zwolinski, Dr Yaobo Xu, Professor David Elliott, Emerita Professor Susan Lindsay, Professor David SteelORCiD, Professor Lyle Armstrong, Professor Evelyne SernagorORCiD, Dr Sushma Grellscheid, Professor Majlinda LakoORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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. We have generated 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.

Publication metadata

Author(s): Buskin A, Zhu L, Chichagova V, Basu B, Mozaffari-Jovin S, Dolan D, Droop A, Collin J, Bronstein V, Mehrotra S, Farkas M, Hilgen G, White K, Pan KT, Treumann A, Hallam D, Bialas K, Chung G, Mellough C, Ding Y, Krasnogor N, Pryzborski S, Zwolinski S, Alharthi S, Al-Aama J, Xu Y, Wheway G, Szymanska K, McKibbin M, Inglehearn CF, Elliott DJ, Lindsay S, Ali R, Steel DH, Armstrong L, Sernagor E, Urlaub H, Pierce E, Luehrmann R, Grellscheid SN, Johnson CA, Lako M

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2018

Volume: 9

Online publication date: 12/10/2018

Acceptance date: 03/09/2018

Date deposited: 10/08/2018

ISSN (electronic): 2041-1723

Publisher: Nature


DOI: 10.1038/s41467-018-06448-y


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Funder referenceFunder name
European Community’s Seventh Framework Programme
Medical Research Council