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

Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa
Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa
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.
Buskin, Adriana
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Zhu, Lili
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Dolan, David
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Collin, Joseph
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Mehrotra, Sudeep
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Treumann, Achim
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Al-Aama, Jumana
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Alharthi, Sameer
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Wheway, Gabrielle
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McKibbin, Martin
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Inglehearn, Chris F.
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Steel, David H.
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Armstrong, Lyle
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Sernagor, Evelyne
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Urlaub, Henning
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Pierce, Eric
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Luehrmann, Reinhard
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Grellscheid, Sushma-Nagaraja
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Johnson, Colin A.
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Lako, Majlinda
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Buskin, Adriana
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Zhu, Lili
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Chichagova, Valeria
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Basu, Basudha
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Mozaffari-Jovin, Sina
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Dolan, David
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Droop, Alastair
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Collin, Joseph
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Bronstein, Revital
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Mehrotra, Sudeep
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Farkas, Michael
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Hilgen, Gerrit
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White, Kathryn
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Pan, Kuan-Ting
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Treumann, Achim
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Hallam, Dean
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Chung, Git
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Al-Aama, Jumana
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Wheway, Gabrielle
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Szymanska, Katarzyna
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McKibbin, Martin
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Inglehearn, Chris F.
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Elliott, David J.
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Ali, Robin R.
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Steel, David H.
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Armstrong, Lyle
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Sernagor, Evelyne
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Urlaub, Henning
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Pierce, Eric
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Luehrmann, Reinhard
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Grellscheid, Sushma-Nagaraja
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Johnson, Colin A.
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Lako, Majlinda
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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, Przyborski, 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, Luehrmann, Reinhard, Grellscheid, Sushma-Nagaraja, Johnson, Colin A. and Lako, Majlinda (2018) Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nature Communications, 9 (1), [4234]. (doi:10.1038/s41467-018-06448-y).

Record type: Article

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.

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Accepted/In Press date: 3 September 2018
e-pub ahead of print date: 12 October 2018
Published date: 12 October 2018

Identifiers

Local EPrints ID: 427875
URI: http://eprints.soton.ac.uk/id/eprint/427875
PURE UUID: f0558452-4ee5-42c8-b902-b7f2c0285acf
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783

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Date deposited: 30 Jan 2019 17:31
Last modified: 23 May 2020 00:44

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Contributors

Author: Adriana Buskin
Author: Lili Zhu
Author: Valeria Chichagova
Author: Basudha Basu
Author: Sina Mozaffari-Jovin
Author: David Dolan
Author: Alastair Droop
Author: Joseph Collin
Author: Revital Bronstein
Author: Sudeep Mehrotra
Author: Michael Farkas
Author: Gerrit Hilgen
Author: Kathryn White
Author: Kuan-Ting Pan
Author: Achim Treumann
Author: Dean Hallam
Author: Katarzyna Bialas
Author: Git Chung
Author: Carla Mellough
Author: Yuchun Ding
Author: Natalio Krasnogor
Author: Stefan Przyborski
Author: Simon Zwolinski
Author: Jumana Al-Aama
Author: Sameer Alharthi
Author: Yaobo Xu
Author: Katarzyna Szymanska
Author: Martin McKibbin
Author: Chris F. Inglehearn
Author: David J. Elliott
Author: Susan Lindsay
Author: Robin R. Ali
Author: David H. Steel
Author: Lyle Armstrong
Author: Evelyne Sernagor
Author: Henning Urlaub
Author: Eric Pierce
Author: Reinhard Luehrmann
Author: Sushma-Nagaraja Grellscheid
Author: Colin A. Johnson
Author: Majlinda Lako

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