Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: 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; Elliott, David; Lindsay, Susan; Ali, Robin; Steel, David; Armstrong, Lyle; Sernagor, Evelyne; Urlaub, Henning; Pierce, Eric; Lührmann, Reinhard; Grellscheid, Sushma-Nagaraja; Johnson, Colin; Lako, Majlinda;
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 19
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06448-y
• Languages: English
• ISSNs: 2041-1723

Abstract

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 asPrpf31 +/− 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 andPrpf31 +/− 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. Mutations in pre-mRNA processing factors cause autosomal dominant retinitis pigmentosa. Here the authors provide insights into the pathophysiological mechanisms underlying non-syndromic retinal disease caused by heterozygous mutations in genes encoding ubiquitously expressed splicing factors.