Journal Article

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

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

2018

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/100 / 13/106 / 13/51 / 38/91 / 631/136/142 / 631/532/2064/2158 / Alternative splicing / Alternative Splicing - genetics / Alternative Splicing - physiology / Animals / Cell Adhesion - genetics / Cell Adhesion - physiology / Cell Differentiation - genetics / Cell Differentiation - physiology / Cilia / Cilia - genetics / Cilia - metabolism / Cilia - physiology / Degeneration / Epithelium / Eye Proteins - genetics / Eye Proteins - metabolism / Flow Cytometry / Gene expression / Genes / Genetic modification / Genome editing / Humanities and Social Sciences / Humans / Immunohistochemistry / Induced Pluripotent Stem Cells - metabolism / Mice / Morphology / mRNA processing / multidisciplinary / Mutation / Mutation - genetics / Organoids / Organoids - cytology / Organoids - metabolism / Phagocytes / Phenotypes / Photoreception / Photoreceptors / Polarity / Post-transcription / Proteins / Retina / Retina - cytology / Retina - metabolism / Retinal cells / Retinal pigment epithelium / Retinitis / Retinitis pigmentosa / Retinitis Pigmentosa - etiology / Retinitis Pigmentosa - genetics / Retinitis Pigmentosa - metabolism / RNA Splicing - genetics / RNA Splicing - physiology / Science / Science (multidisciplinary) / Splicing