Adriana Buskin
Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa
Buskin, Adriana; Zhu, Lili; Chichagova, Valeria; Basu, Basudha; Mozaffari-Jovin, Sina; Dolan, David; Droop, Alastair; Collin, Joseph; Bronstein, Revital; Mehrotra, Sudeep; Farkas, Michael; Hilgen, Gerrit; White, Kathryn; Pan, Kuan Ting; Treumann, Achim; Hallam, Dean; Bialas, Katarzyna; Chung, Git; Mellough, Carla; Ding, Yuchun; Krasnogor, Natalio; Przyborksi, Stefan; Zwolinski, Simon; Al-Aama, Jumana; Alharthi, Sameer; Xu, Yaobo; Wheway, Gabrielle; Szymanska, Katarzyna; McKibbin, Martin; Inglehearn, Chris F; Elliott, David J; Lindsay, Susan; Ali, Robin R; Steel, David H; Armstrong, Lyle; Sernagor, Evelyne; Urlaub, Henning; Pierce, Eric; L�hrmann, Reinhard; Grellscheid, Sushma Nagaraja; Johnson, Colin A; Lako, Majlinda
Authors
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 Przyborksi
Simon Zwolinski
Jumana Al-Aama
Sameer Alharthi
Yaobo Xu
Gabrielle Wheway Gabrielle.Wheway@uwe.ac.uk
Occasional Associate Lecturer - CHSS - DAS
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 L�hrmann
Sushma Nagaraja Grellscheid
Colin A Johnson
Majlinda Lako
Abstract
© 2018, The Author(s). 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.
Journal Article Type | Article |
---|---|
Acceptance Date | Sep 3, 2018 |
Publication Date | Dec 1, 2018 |
Deposit Date | Aug 13, 2018 |
Publicly Available Date | Aug 14, 2018 |
Journal | Nature Communications |
Electronic ISSN | 2041-1723 |
Publisher | Nature Research (part of Springer Nature) |
Peer Reviewed | Peer Reviewed |
Volume | 9 |
Issue | 1 |
Pages | 4234 |
DOI | https://doi.org/10.1038/s41467-018-06448-y |
Keywords | retinitis pigmentosa, splicing, pre-mRNA, PRPF31, RNAseq, cilia, photoreceptor, RPE, retina, blindness |
Public URL | https://uwe-repository.worktribe.com/output/858836 |
Publisher URL | https://doi.org/10.1038/s41467-018-06448-y |
Contract Date | Aug 13, 2018 |
Files
s41467-018-06448-y.pdf
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