TY - JOUR
T1 - Mutant PRPF8 Causes Widespread Splicing Changes in Spliceosome Components in Retinitis Pigmentosa Patient iPSC-Derived RPE Cells
AU - Arzalluz-Luque, Ángeles
AU - Cabrera, Jose Luis
AU - Skottman, Heli
AU - Benguria, Alberto
AU - Bolinches-Amorós, Arantxa
AU - Cuenca, Nicolás
AU - Lupo, Vincenzo
AU - Dopazo, Ana
AU - Tarazona, Sonia
AU - Delás, Bárbara
AU - Carballo, Miguel
AU - Pascual, Beatriz
AU - Hernan, Imma
AU - Erceg, Slaven
AU - Lukovic, Dunja
N1 - Funding Information:
We are thankful to the patient and healthy individuals for generously donating skin biopsies and Mrs. Outi Melin and Hanna Pekkanen with help of RPE differentiations. Funding. This work was supported by Institute of Health Carlos III/ERDF (European Regional Development Fund), Spain [PI16/00409 (DL), PI20/01119 (DL), CP18/00033 (DL), PI15/00227 (MC), CPII16/00037 (SE), and PI18-00286 (SE)], Platform for Proteomics, Genotyping and Cell Lines; PRB3 of ISCIII (PT17/0019/0024); National Science Foundation GACR 18-04393S and the project ?Centre of Reconstructive Neuroscience?, registration number CZ.02. 1.01/0.0./0.0/15_003/0000419PI15/00227; Spanish Ministry of Economy and Competitiveness grant BES-2016-076994 (?A-L); and Academy of Finland (HS).
Publisher Copyright:
© Copyright © 2021 Arzalluz-Luque, Cabrera, Skottman, Benguria, Bolinches-Amorós, Cuenca, Lupo, Dopazo, Tarazona, Delás, Carballo, Pascual, Hernan, Erceg and Lukovic.
PY - 2021/4/29
Y1 - 2021/4/29
N2 - 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.
AB - 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.
KW - alternative splicing
KW - iPSC
KW - pre-mRNA splicing
KW - PRPF8
KW - retinitis pigmentosa
KW - RNA-Seq
KW - RPE
U2 - 10.3389/fnins.2021.636969
DO - 10.3389/fnins.2021.636969
M3 - Article
AN - SCOPUS:85105914164
VL - 15
M1 - 636969
ER -