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Human iPSC-Derived RPE and Retinal Organoids Reveal Impaired Alternative Splicing of Genes Involved in Pre-mRNA Splicing in PRPF31 Autosomal Dominant Retinitis Pigmentosa Type 11

55 Pages Posted: 12 Apr 2018   Sneak Peek Status: Review Complete

Adriana Buskin

Newcastle University (UK) - Institute of Genetic Medicine

Lili Zhu

Shenandoah University

Valeria Chichagova

Newcastle University (UK) - Institute of Genetic Medicine

Basudha Basu

University of Leeds - Leeds Institute of Biomedical & Clinical Sciences (LIBACS)

Sina Mozaffari‐Jovin

Max Planck Institute for Biophysical Chemistry

David Dolan

Durham University - Department of Biological Sciences

Alastair Droop

University of Leeds - MRC Medical Bioinformatics Centre

Joseph Colli

Newcastle University (UK) - Institute of Genetic Medicine

Revital Bronstei

Harvard University - Department of Ophthalmology

Sudeep Mehrotr

Harvard University - Department of Ophthalmology

Michael Farkas

State University of New York at Buffalo - Department of Ophthalmology

Gerrit Hilgen

Newcastle University (UK) - Institute of Neuroscience

Kathryn White

Newcastle University (UK) - Electron Microscopy Research Services

Dean Hallam

Newcastle University (UK) - Institute of Genetic Medicine

Katarzyna Bialas

Newcastle University (UK) - Institute of Genetic Medicine

Git Chung

Newcastle University (UK) - Institute for Cell and Molecular Biosciences

Carla Mellough

Newcastle University (UK) - Institute of Genetic Medicine

Yuchun Ding

Newcastle University (UK) - Interdisciplinary Computing and Complex BioSystems (ICOS)

Natalio Krasnogor

Newcastle University (UK) - Interdisciplinary Computing and Complex BioSystems (ICOS)

Stefan Przyborski

Durham University - Department of Biological Sciences

Jumana Al‐Aama

King Abdulaziz University - Princess Al Jawhara Al?Brahim Center of Excellence in Research of Hereditary Disorders

Sameer Alharthi

King Abdulaziz University - Princess Al Jawhara Al?Brahim Center of Excellence in Research of Hereditary Disorders

Yaobo Xu

Newcastle University (UK) - Institute of Genetic Medicine

Gabrielle Wheway

University of the West of England (UWE) - Centre for Research in Biosciences

Katarzyna Szymanska

University of Leeds - Leeds Institute of Biomedical & Clinical Sciences (LIBACS)

Martin McKibbin

Newcastle University (UK) - Institute of Genetic Medicine

Chris F Inglehearn

University of Leeds - Leeds Institute of Biomedical & Clinical Sciences (LIBACS)

David J Elliott

Newcastle University (UK) - Institute of Genetic Medicine

Susan Lindsay

Newcastle University (UK) - Institute of Genetic Medicine

Robin R Ali

London's Global University (UCL) - Institute of Opthalmology

David H Steel

Newcastle University (UK) - Institute of Genetic Medicine

Lyle Armstrong

Newcastle University (UK) - Institute of Genetic Medicine

Evelyne Sernagor

Newcastle University (UK) - Institute of Neuroscience

Eric Pierce

Harvard University - Ocular Genomics Institute

Reinhard Lührmann

Max Planck Institute for Biophysical Chemistry

Sushma‐Nagaraja Grellscheid

Durham University - Department of Biological Sciences

Colin A Johnson

University of Leeds - Leeds Institute of Biomedical & Clinical Sciences (LIBACS)

Majlinda Lako

Newcastle University (UK) - Institute of Genetic Medicine

More...

Abstract

Mutations in pre-mRNA processing factors (PRPFs) cause 40% of autosomal dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed PRPFs cause retinal disease. To understand the molecular basis of this phenotype, we have generated RP type 11 (PRPF31-mutated) patient-specific retinal organoids and retinal pigment epithelium (RPE) from induced pluripotent stem cells (iPSC). Impaired alternative splicing of genes encoding pre-mRNA splicing proteins occurred in patient-specific retinal cells and Prpf31 /- mouse retinae, but not fibroblasts and iPSCs, providing mechanistic insights into retinal-specific phenotypes of PRPFs. RPE was the most affected, characterised by loss of apical-basal polarity, reduced trans-epithelial resistance, phagocytic capacity, microvilli, and cilia length and incidence. Disrupted cilia morphology was observed in patient-derived-photoreceptors that displayed progressive features associated with degeneration and cell stress. In situ gene-editing of a pathogenic mutation rescued key structural and functional phenotypes in RPE and photoreceptors, providing proof-of-concept for future therapeutic strategies.

Suggested Citation

Buskin, Adriana and Zhu, Lili and Chichagova, Valeria and Basu, Basudha and Mozaffari‐Jovin, Sina and Dolan, David and Droop, Alastair and Colli, Joseph and Bronstei, Revital and Mehrotr, Sudeep and Farkas, Michael and Hilgen, Gerrit and White, Kathryn and Hallam, Dean and Bialas, Katarzyna and Chung, Git and Mellough, Carla and Ding, Yuchun and Krasnogor, Natalio and Przyborski, Stefan and Al‐Aama, Jumana and Alharthi, Sameer and Xu, Yaobo and Wheway, Gabrielle and Szymanska, Katarzyna and McKibbin, Martin and Inglehearn, Chris F and Elliott, David J and Lindsay, Susan and Ali, Robin R and Steel, David H and Armstrong, Lyle and Sernagor, Evelyne and Pierce, Eric and Lührmann, Reinhard and Grellscheid, Sushma‐Nagaraja and Johnson, Colin A and Lako, Majlinda, Human iPSC-Derived RPE and Retinal Organoids Reveal Impaired Alternative Splicing of Genes Involved in Pre-mRNA Splicing in PRPF31 Autosomal Dominant Retinitis Pigmentosa Type 11 (2018). Available at SSRN: https://ssrn.com/abstract=3155753 or http://dx.doi.org/10.2139/ssrn.3155753
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Adriana Buskin

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Lili Zhu

Shenandoah University ( email )

Harry Byrd School of Business
1460 University Drive
Winchester, VA 22601
United States

Valeria Chichagova

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Basudha Basu

University of Leeds - Leeds Institute of Biomedical & Clinical Sciences (LIBACS)

Leeds, LS2 9JT
United Kingdom

Sina Mozaffari‐Jovin

Max Planck Institute for Biophysical Chemistry

Am Faßberg 11
Göttingen, 37077
Germany

David Dolan

Durham University - Department of Biological Sciences

Old Elvet
Mill Hill Lane
Durham, Durham DH1 3HP
United Kingdom

Alastair Droop

University of Leeds - MRC Medical Bioinformatics Centre

Leeds, LS2 9JT
United Kingdom

Joseph Colli

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Revital Bronstei

Harvard University - Department of Ophthalmology

250 Longwood Avenue
Boston, MA 02115
United States

Sudeep Mehrotr

Harvard University - Department of Ophthalmology

250 Longwood Avenue
Boston, MA 02115
United States

Michael Farkas

State University of New York at Buffalo - Department of Ophthalmology

Amherst, NY 14260
United States

Gerrit Hilgen

Newcastle University (UK) - Institute of Neuroscience

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Kathryn White

Newcastle University (UK) - Electron Microscopy Research Services

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Dean Hallam

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Katarzyna Bialas

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Git Chung

Newcastle University (UK) - Institute for Cell and Molecular Biosciences

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Carla Mellough

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Yuchun Ding

Newcastle University (UK) - Interdisciplinary Computing and Complex BioSystems (ICOS)

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Natalio Krasnogor

Newcastle University (UK) - Interdisciplinary Computing and Complex BioSystems (ICOS)

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Stefan Przyborski

Durham University - Department of Biological Sciences

Old Elvet
Mill Hill Lane
Durham, Durham DH1 3HP
United Kingdom

Jumana Al‐Aama

King Abdulaziz University - Princess Al Jawhara Al?Brahim Center of Excellence in Research of Hereditary Disorders

P.O.Box 80200
Jeddah, 21589
Saudi Arabia

Sameer Alharthi

King Abdulaziz University - Princess Al Jawhara Al?Brahim Center of Excellence in Research of Hereditary Disorders

P.O.Box 80200
Jeddah, 21589
Saudi Arabia

Yaobo Xu

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Gabrielle Wheway

University of the West of England (UWE) - Centre for Research in Biosciences

Blackberry Hill Bristol
Bristol, Avon BS16 1QY
United Kingdom

Katarzyna Szymanska

University of Leeds - Leeds Institute of Biomedical & Clinical Sciences (LIBACS)

Leeds, LS2 9JT
United Kingdom

Martin McKibbin

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Chris F Inglehearn

University of Leeds - Leeds Institute of Biomedical & Clinical Sciences (LIBACS)

Leeds, LS2 9JT
United Kingdom

David J Elliott

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Susan Lindsay

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Robin R Ali

London's Global University (UCL) - Institute of Opthalmology

Gower Street
London, WC1E 6BT
United Kingdom

David H Steel

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Lyle Armstrong

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Evelyne Sernagor

Newcastle University (UK) - Institute of Neuroscience

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Eric Pierce

Harvard University - Ocular Genomics Institute

250 Longwood Avenue
Boston, MA 02115
United States

Reinhard Lührmann

Max Planck Institute for Biophysical Chemistry

Am Faßberg 11
Göttingen, 37077
Germany

Sushma‐Nagaraja Grellscheid

Durham University - Department of Biological Sciences

Old Elvet
Mill Hill Lane
Durham, Durham DH1 3HP
United Kingdom

Colin A Johnson

University of Leeds - Leeds Institute of Biomedical & Clinical Sciences (LIBACS)

Leeds, LS2 9JT
United Kingdom

Majlinda Lako (Contact Author)

Newcastle University (UK) - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom