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.

Department of Applied Statistics Operations Research and Quality Universitat Politècnica de València València Spain

Department of Neuroregeneration Institute of Experimental Medicine Czech Academy of Sciences Prague Czechia

Department of Physiology Genetics and Microbiology University of Alicante Alicante Spain

Faculty of Medicine and Health Technology Tampere University Tampere Finland

Genomics Unit Centro Nacional de Investigaciones Cardiovasculares Madrid Spain

National Stem Cell Bank Valencia Node Research Center Principe Felipe Valencia Spain

Rare Diseases Joint Units IIS La Fe CIPF Valencia Spain

Retinal Degeneration Lab Research Centre Principe Felipe Valencia Spain

Stem Cells Therapies in Neurodegenerative Diseases Lab Research Center Principe Felipe Valencia Spain

Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders Centro de Investigación Príncipe Felipe Valencia Spain

Unitat de Genética Molecular Hospital de Terrassa Terrassa Spain

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Retinitis pigmentosa-linked mutations impair the snRNA unwinding activity of SNRNP200 and reduce pre-mRNA binding of PRPF8