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Nat Commun. 2018 Oct 12;9(1):4234. doi: 10.1038/s41467-018-06448-y.

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

Author information

1
Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
2
Leeds Institute of Medical Research, University of Leeds, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
3
Department of Cellular Biochemistry, Max-Planck-Institute of Biophysical Chemistry, Am Fassberg 11, Goettingen, D-37077, Germany.
4
Department of Biological Sciences, Durham University, South Road, Durham, DH1 3LE, UK.
5
MRC Medical Bioinformatics Centre, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK.
6
Ocular Genomics Institute, Mass Eye and Ear and Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA.
7
Departments of Ophthalmology and Biochemistry, Jacobs School of Medicine and Biomedical Science, State University of New York at Buffalo, 955 Main Street, Buffalo, NY, 14203-1121, USA.
8
Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
9
Electron Microscopy Research Services, Medical School, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
10
Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
11
Newcastle University Protein and Proteome Analysis (NUPPA), Devonshire Building, Devonshire Terrace, Newcastle upon Tyne, NE1 7RU, UK.
12
Interdisciplinary Computing and Complex Biosystems (ICOS) Research Group, School of Computing, Newcastle University, Urban Sciences Building, 1 Science Square, Newcastle Helix, Newcastle upon Tyne, NE4 5TG, UK.
13
Princess Al Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, 7393 Al-Malae'b St, Jeddah, 22252, Saudi Arabia.
14
Centre for Research in Biosciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol, BS16 1QY, UK.
15
UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK.
16
Bioanalytical Mass Spectrometry Group, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, Goettingen, D-37077, Germany.
17
Department of Biological Sciences, Durham University, South Road, Durham, DH1 3LE, UK. sushma@cantab.net.
18
Computational Biology Unit, Department of Biological Sciences, University of Bergen, Thormohlensgt 55, Bergen, N-5008, Norway. sushma@cantab.net.
19
Leeds Institute of Medical Research, University of Leeds, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK. c.johnson@leeds.ac.uk.
20
Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. majlinda.lako@ncl.ac.uk.

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.

PMID:
30315276
PMCID:
PMC6185938
DOI:
10.1038/s41467-018-06448-y
[Indexed for MEDLINE]
Free PMC Article

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