Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mutant PRPF8 causes widespread splicing changes in spliceosome components in retinitis pigmentosa patient RPE cells

ABSTRACT: Mutant PRPF8 causes widespread splicing changes in spliceosome components in retinitis pigmentosa patient RPE cells

PROVIDER: PRJNA694104 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR13508000.fastq.gz	Fastqsanger.gz
	SRR13508001.fastq.gz	Fastqsanger.gz
	SRR13508002.fastq.gz	Fastqsanger.gz
	SRR13508003.fastq.gz	Fastqsanger.gz
	SRR13508004.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 12

Similar Datasets

Mutant PRPF8 causes widespread splicing changes in spliceosome components in retinitis pigmentosa patient RPE cells

Project description:Retinitis pigmentosa is a rare, progressive disease which 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 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 specific splicing program, and identifies retinal AS events as a framework towards the design of novel therapeutic opportunities.

2021-03-05 | GSE165322 | GEO

PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects

Project description:Mutations in the carboxy terminal of the core spliceosome factor PRPF8 cause autosomal dominant retinitis pigmentosa (RP) 13. Comprehensive cellular, biochemical, and molecular investigations of iPSC-derived retinal organoids, retinal pigment epithelium (RPE) and kidney organoids from four patients carrying the pathogenic PRPF8 RP type 13 c.6926A>C (p.H2309P) heterozygous missense mutation, revealed retinal tissue-specific effects including lower splicing specificity, ciliary abnormalities, altered apical-basal polarity, rod degeneration and loss of photoreceptors. The p.H2309P mutation affected the 5’ splice site recognition by PRPF8 of transcripts encoding ciliary proteins, altered spliceosome kinetics and organisation of nuclear speckles as well as PRPF8 binding to spliceosomal U6 snRNAs and snoRNAs, leading to accumulation of unspliced poly A+ mRNAs specifically in RPE cells and retinal organoids. Together these data provide the most comprehensive characterisation of splicing factor causing RP disease, providing molecular insights into the tissue specificity of pathomechanisms and informing future therapeutic approaches.

2024-02-29 | GSE235866 | GEO

PRPF8 CLIP seq for iPSC, kidney organoid, retinal organoid, and retinal epithelium derived from c.6926A>C RPE with Retinitis Pigmentosa patients and CRISPR/Cas9 corrected

Project description:Retinitis Pigmentosa is a group of inherited eye disorders characterized by progressive degeneration of photoreceptor cells in the retina, leading to vision loss and eventual blindness. One of the known genetic mutations associated with RP is the c.6926A>C mutation in the RPE (retinal pigment epithelium) cells. The dataset involves multiple experimental approaches and cell types, providing a comprehensive understanding of the disease and potential corrective strategies.

2024-03-13 | E-MTAB-13171 | biostudies-arrayexpress

Nrf2 overexpression rescues RPE morphology in mouse models of retinitis pigmentosa

Project description:Nrf2 overexpression rescues RPE morphology in mouse models of retinitis pigmentosa

| PRJNA675578 | ENA

PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5'-splice-site selection causing tissue-specific defects

Project description:The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13, with unclear role in human splicing and tissue-specificity mechanism. We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926A>C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects. Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5’-splice site (5’SS) selection by spliceosomes, for which disruption impaired alternative splicing and weak/suboptimal 5’SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. Altered splicing efficiency, nuclear speckles organisation, and PRPF8 interaction with U6 snRNA, caused accumulation of active spliceosomes and poly(A)+ mRNAs in unique splicing clusters located at the nuclear periphery of photoreceptors. Collectively these elucidate the role of PRPF8/Brr2 regulatory mechanisms in splicing and the molecular basis of retinal disease, informing therapeutic approaches.

2024-02-16 | GSE236702 | GEO

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

Project description: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.

| S-EPMC8116631 | biostudies-literature