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

doi:10.1038/s41467-018-06448-y

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

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 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.

Citation

Buskin, A., Zhu, L., Chichagova, V., Basu, B., Mozaffari-Jovin, S., Dolan, D., …Lako, M. (2018). Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nature Communications, 9(1), 4234. https://doi.org/10.1038/s41467-018-06448-y

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