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

Adriana Buskin, Lili Zhu, Valeria Chichagova, Basudha Basu, Sina Mozaffari-Jovin, David Dolan, Alastair Droop, Joseph Collin, Revital Bronstein, Sudeep Mehrotra, Michael Farkas, Gerrit Hilgen, Kathryn White, Kuan-Ting Pan, Achim Treumann, Dean Hallam, Katarzyna Bialas, Git Chung, Carla Mellough, Yuchun Ding, Natalio Krasnogor, Stefan Przyborski, Simon Zwolinski, Jumana Al-Aama, Sameer Alharthi, Yaobo Xu, Gabrielle Wheway, Katarzyna Szymanska, Martin McKibbin, Chris F. Inglehearn, David J. Elliott, Susan Lindsay, Robin R. Ali, David H. Steel, Lyle Armstrong, Evelyne Sernagor, Henning Urlaub, Eric Pierce, Reinhard Lührmann, Sushma-Nagaraja Grellscheid (), Colin A. Johnson () and Majlinda Lako ()
Additional contact information
Adriana Buskin: Newcastle University
Lili Zhu: Newcastle University
Valeria Chichagova: Newcastle University
Basudha Basu: St James’s University Hospital
Sina Mozaffari-Jovin: Max-Planck-Institute of Biophysical Chemistry
David Dolan: Durham University
Alastair Droop: University of Leeds
Joseph Collin: Newcastle University
Revital Bronstein: Mass Eye and Ear and Harvard Medical School
Sudeep Mehrotra: Mass Eye and Ear and Harvard Medical School
Michael Farkas: State University of New York at Buffalo
Gerrit Hilgen: Newcastle University
Kathryn White: Newcastle University
Kuan-Ting Pan: Max-Planck-Institute of Biophysical Chemistry
Achim Treumann: Newcastle University
Dean Hallam: Newcastle University
Katarzyna Bialas: Newcastle University
Git Chung: Newcastle University Protein and Proteome Analysis (NUPPA)
Carla Mellough: Newcastle University
Yuchun Ding: Newcastle University
Natalio Krasnogor: Newcastle University
Stefan Przyborski: Durham University
Simon Zwolinski: Newcastle University
Jumana Al-Aama: King Abdulaziz University
Sameer Alharthi: King Abdulaziz University
Yaobo Xu: Newcastle University
Gabrielle Wheway: University of the West of England
Katarzyna Szymanska: St James’s University Hospital
Martin McKibbin: St James’s University Hospital
Chris F. Inglehearn: St James’s University Hospital
David J. Elliott: Newcastle University
Susan Lindsay: Newcastle University
Robin R. Ali: UCL Institute of Ophthalmology
David H. Steel: Newcastle University
Lyle Armstrong: Newcastle University
Evelyne Sernagor: Newcastle University
Henning Urlaub: Max-Planck-Institute for Biophysical Chemistry
Eric Pierce: Mass Eye and Ear and Harvard Medical School
Reinhard Lührmann: Max-Planck-Institute of Biophysical Chemistry
Sushma-Nagaraja Grellscheid: Durham University
Colin A. Johnson: St James’s University Hospital
Majlinda Lako: Newcastle University

Nature Communications, 2018, vol. 9, issue 1, 1-19

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06448-y

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