Mutant PRPF8 Causes Widespread Splicing Changes in Spliceosome Components in Retinitis Pigmentosa Patient iPSC-Derived RPE Cells.
PRPF8
RNA-Seq
RPE
alternative splicing
iPSC
pre-mRNA splicing
retinitis pigmentosa
Journal
Frontiers in neuroscience
ISSN: 1662-4548
Titre abrégé: Front Neurosci
Pays: Switzerland
ID NLM: 101478481
Informations de publication
Date de publication:
2021
2021
Historique:
received:
02
12
2020
accepted:
25
02
2021
entrez:
17
5
2021
pubmed:
18
5
2021
medline:
18
5
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33994920
doi: 10.3389/fnins.2021.636969
pmc: PMC8116631
doi:
Types de publication
Journal Article
Langues
eng
Pagination
636969Informations de copyright
Copyright © 2021 Arzalluz-Luque, Cabrera, Skottman, Benguria, Bolinches-Amorós, Cuenca, Lupo, Dopazo, Tarazona, Delás, Carballo, Pascual, Hernan, Erceg and Lukovic.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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