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Mutant PRPF8 Causes Widespread Splicing Changes in Spliceosome Components in Retinitis Pigmentosa Patient iPSC-Derived RPE Cells

Authors :
Ángeles Arzalluz-Luque
Jose Luis Cabrera
Heli Skottman
Alberto Benguria
Arantxa Bolinches-Amorós
Nicolás Cuenca
Vincenzo Lupo
Ana Dopazo
Sonia Tarazona
Bárbara Delás
Miguel Carballo
Beatriz Pascual
Imma Hernan
Slaven Erceg
Dunja Lukovic
Source :
Frontiers in Neuroscience, Vol 15 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

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.

Details

Language :
English
ISSN :
1662453X
Volume :
15
Database :
Directory of Open Access Journals
Journal :
Frontiers in Neuroscience
Publication Type :
Academic Journal
Accession number :
edsdoj.347373adf3fd4a898beb0087c33bbc18
Document Type :
article
Full Text :
https://doi.org/10.3389/fnins.2021.636969