Mutant PRPF8 Causes Widespread Splicing Changes in Spliceosome Components in Retinitis Pigmentosa Patient iPSC-Derived RPE Cells
Por:
A. ARZALLUZ-LUQUE, J. CABRERA, H. SKOTTMAN, A. BENGURIA, A. BOLINCHES-AMOROS, N. CUENCA, V. LUPO, A. DOPAZO, S. TARAZONA, B. DELAS, M. CARBALLO, B. PASCUAL, I. HERNAN, S. ERCEG and D. LUKOVIC
Publicada:
29 abr 2021
Resumen:
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.
Filiaciones:
:
Univ Politecn Valencia, Dept Appl Stat Operat Res & Qual, Valencia, Spain
J. CABRERA:
Ctr Nacl Invest Cardiovesc CNIC, Genom Unit, Madrid, Spain
H. SKOTTMAN:
Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland
A. BENGURIA:
Ctr Nacl Invest Cardiovesc CNIC, Genom Unit, Madrid, Spain
A. BOLINCHES-AMOROS:
Res Ctr Principe Felipe, Stem Cells Therapies Neurodegenerat Dis Lab, Valencia, Spain
Res Ctr Principe Felipe, Natl Stem Cell Bank Valencia Node, Valencia, Spain
N. CUENCA:
Univ Alicante, Dept Physiol Genet & Microbiol, Alicante, Spain
:
Ctr Invest Principe Felipe CIPF, Unit Genet & Genom Neuromuscular & Neurodegenerat, Valencia, Spain
IIS Fe CIPF Valencia, Rare Dis Joint Units, Valencia, Spain
A. DOPAZO:
Ctr Nacl Invest Cardiovesc CNIC, Genom Unit, Madrid, Spain
:
Univ Politecn Valencia, Dept Appl Stat Operat Res & Qual, Valencia, Spain
B. DELAS:
Hosp Terrassa, Unitat Genet Mol, Terrassa, Spain
M. CARBALLO:
Hosp Terrassa, Unitat Genet Mol, Terrassa, Spain
B. PASCUAL:
Hosp Terrassa, Unitat Genet Mol, Terrassa, Spain
I. HERNAN:
Hosp Terrassa, Unitat Genet Mol, Terrassa, Spain
:
Res Ctr Principe Felipe, Stem Cells Therapies Neurodegenerat Dis Lab, Valencia, Spain
Res Ctr Principe Felipe, Natl Stem Cell Bank Valencia Node, Valencia, Spain
IIS Fe CIPF Valencia, Rare Dis Joint Units, Valencia, Spain
Czech Acad Sci, Inst Expt Med, Dept Neuroregenerat, Prague, Czech Republic
:
IIS Fe CIPF Valencia, Rare Dis Joint Units, Valencia, Spain
Res Ctr Principe Felipe, Retinal Degenerat Lab, Valencia, Spain
Gold, Green Published
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