Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-06448-y
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Funding
- Fight for Sight [1456/1457]
- ERC [CoG_614620, 2012-ADG_20120314]
- RP Fighting Blindness [GR584]
- CRACKIT23 challenge phase 1 award [NC/CO16206/1]
- CiC [MC_PC_15030]
- SFB [860]
- Medical Research Council [MR/K011154/1, MR/M000532/1, MR/N005872/1]
- NIH [RO1 EY020902]
- Rosanne Silbermann Foundation
- European Community's Seventh Framework Programme FP7/2009 [241955 SYSCILIA]
- Bergens forskningsstiftelse [BFS2017TMT01]
- Biotechnology and Biological Sciences Research Council [BB/P007791/1] Funding Source: researchfish
- Medical Research Council [MR/M000532/1, MR/K011154/1, MR/N005872/1] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [09JTA] Funding Source: researchfish
- BBSRC [BB/P007791/1, BB/E012841/1, BB/M012093/1] Funding Source: UKRI
- MRC [MR/J004553/1, MR/L01629X/1, MR/R011338/1, MR/N005872/1, MR/M000532/1, MR/K011154/1] Funding Source: UKRI
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Mutations in pre-mRNA processing factors (PRPFs) cause autosomal-dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause nonsyndromic 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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