Mutant PRPF8 Causes Widespread Splicing Changes in Spliceosome Components in Retinitis Pigmentosa Patient iPSC-Derived RPE Cells
Year: 2021
Type: article
Abstract: Retinitis pigmentosa (RP) is a rare, progressive disease that affects photoreceptors and retinal pigment epithelial (RPE) cells with blindness as a final outcome. Despite high medical and social impact, there is currently no therapeutic options to slow down the progression of or cure the disease. The development of effective therapies was largely hindered by high genetic heterogeneity, inaccessible disease tissue, and unfaithful model organisms. The fact that components of ubiquitously expressed splicing factors lead to the retina-specific disease is an additional intriguing question. Herein, we sought to correlate the retinal cell-type-specific disease phenotype with the splicing profile shown by a patient with autosomal recessive RP, caused by a mutation in pre-mRNA splicing factor 8 (PRPF8). In order to get insight into the role of PRPF8 in homeostasis and disease, we capitalize on the ability to generate patient-specific RPE cells and reveal differentially expressed genes unique to RPE cells. We found that spliceosomal complex and ribosomal functions are crucial in determining cell-type specificity through differential expression and alternative splicing (AS) and that PRPF8 mutation causes global changes in splice site selection and exon inclusion that particularly affect genes involved in these cellular functions. This finding corroborates the hypothesis that retinal tissue identity is conferred by a specific splicing program and identifies retinal AS events as a framework toward the design of novel therapeutic opportunities.
Source: Frontiers in Neuroscience
Institutions: Universitat Politècnica de València, Spanish National Centre for Cardiovascular Research, Tampere University, University of Tampere, Centro de Investigacion Principe Felipe, University of Alicante, Instituto de Investigación Sanitaria La Fe, Hospital Terrassa, Czech Academy of Sciences, Czech Academy of Sciences, Institute of Experimental Medicine
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,950
Awards: G1075404386, G12500569, G1414410013, G159882715, G1923619493, G2007293007, Modelos de enfermedad específicos de paciente como herramienta clave para encontrar terápias para enfermedades hereditarias de la retina, G2529116721, G2708544407, G291036901, G302461029, G3490171961, G4131035492, G4280972364, G5350179487, G6031194983, G6372545043, G6909851448, G7656437770, G7745212298, Caracterización de nuevos genes asociados a Retinosis Pigmentaria (adRP) mediante NGS del exoma completo (WES). Transcriptoma de células derivadas de retina con mutación en PRPF8, G8539522561, 3D retinas derivadas de células iPS como herramienta para encontrar terapias eficaces para enfermedades hereditarias de la retina
OpenAlex ID: W3157635384