Ontology highlight
ABSTRACT:
PROVIDER: PRJNA636189 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11885023_1.fastq.gz | Fastqsanger.gz | |||
| SRR11885023_2.fastq.gz | Fastqsanger.gz | |||
| SRR11885024_1.fastq.gz | Fastqsanger.gz | |||
| SRR11885024_2.fastq.gz | Fastqsanger.gz | |||
| SRR11885025_1.fastq.gz | Fastqsanger.gz |
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Project description:Retinitis pigmentosa (RP) represents a heterogeneous group of hereditary eye disorders characterized by a progressive loss of vision. Mutations in thirty different genes have been linked to the autosomal dominant form of RP (adRP), with nearly one-quarter of them encoding the core components of the spliceosome, a macromolecular machine that removes introns from nascent pre-mRNAs, generating mature transcripts. Here we establish the Drosophila melanogaster model for RP13 linked to the mutations in the most conserved protein of the spliceosome, PRPF8/Prp8. We demonstrate negative impact of the nine different RP-associated Prp8 mutant proteins on the developmental timing when expressed in the endocrine cells specialized to produce the major insect molting hormone. In the developing eye primordium, actively cycling cells rather than differentiated photoreceptors showed sensitivity to Prp8 malfunction. The overexpression of the two most toxic RP variants Prp8S>F and Prp8H>R induced apoptosis and disturbances of the adult eye morphology. While the affected tissue mounted the stress and cytoprotective response, the genetic programs underlying neuronal function were attenuated. Importantly, the expressivity and penetrance among the RP-Prp8 mutations differed and increased under prp8 heterozygosity.
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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.
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Project description:Inherited retinal degenerations (IRDs) are a leading cause of blindness among the young population in the developed world. Approximately half of IRDs initially manifest as gradual loss of night vision and visual fields, characteristic of retinitis pigmentosa (RP). Due to challenges in genetic testing, and the large heterogeneity of mutations underlying RP, targeted gene therapies are an impractical largescale solution in the foreseeable future. For this reason, identifying common key pathophysiological pathways in IRDs that could be used as targets for mutation-agnostic and disease-modifying therapies (DMTs) is warranted. In this study, we investigated retinal proteome of three distinct IRD mouse models, comparing to sex- and age-matched wild-type mice. Specifically, we used the Pde6βRd10 (rd10) and RhoP23H/WT (P23H) mouse models of autosomal recessive and autosomal dominant RP, respectively, as well as the Rpe65-/- mouse model of Leber´s congenital amaurosis type 2 (LCA2). The mice were housed at two distinct institutions and analyzed using LC-MS in three separate facilities/instruments following data-dependent and data-independent acquisition modes. This cross-institutional and multi-methodological approach signifies the reliability and reproducibility of the results. The largescale retinal proteome profiling, coupled with in vivo electroretinography recordings, provided us with a reliable basis for comparing the disease phenotypes and severity.
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Project description:Inherited retinal degenerations (IRDs) are a leading cause of blindness among the young population in the developed world. Approximately half of IRDs initially manifest as gradual loss of night vision and visual fields, characteristic of retinitis pigmentosa (RP). Due to challenges in genetic testing, and the large heterogeneity of mutations underlying RP, targeted gene therapies are an impractical largescale solution in the foreseeable future. For this reason, identifying common key pathophysiological pathways in IRDs that could be used as targets for mutation-agnostic and disease-modifying therapies (DMTs) is warranted. In this study, we investigated retinal proteome of three distinct IRD mouse models, comparing to sex- and age-matched wild-type mice. Specifically, we used the Pde6βRd10 (rd10) and RhoP23H/WT (P23H) mouse models of autosomal recessive and autosomal dominant RP, respectively, as well as the Rpe65-/- mouse model of Leber´s congenital amaurosis type 2 (LCA2). The mice were housed at two distinct institutions and analyzed using LC-MS in three separate facilities/instruments following data-dependent and data-independent acquisition modes. This cross-institutional and multi-methodological approach signifies the reliability and reproducibility of the results. The largescale retinal proteome profiling, coupled with in vivo electroretinography recordings, provided us with a reliable basis for comparing the disease phenotypes and severity.
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Project description:Inherited retinal degenerations (IRDs) are a leading cause of blindness among the young population in the developed world. Approximately half of IRDs initially manifest as gradual loss of night vision and visual fields, characteristic of retinitis pigmentosa (RP). Due to challenges in genetic testing, and the large heterogeneity of mutations underlying RP, targeted gene therapies are an impractical largescale solution in the foreseeable future. For this reason, identifying common key pathophysiological pathways in IRDs that could be used as targets for mutation-agnostic and disease-modifying therapies (DMTs) is warranted. In this study, we investigated retinal proteome of three distinct IRD mouse models, comparing to sex- and age-matched wild-type mice. Specifically, we used the Pde6βRd10 (rd10) and RhoP23H/WT (P23H) mouse models of autosomal recessive and autosomal dominant RP, respectively, as well as the Rpe65-/- mouse model of Leber´s congenital amaurosis type 2 (LCA2). The mice were housed at two distinct institutions and analyzed using LC-MS in three separate facilities/instruments following data-dependent and data-independent acquisition modes. This cross-institutional and multi-methodological approach signifies the reliability and reproducibility of the results. The largescale retinal proteome profiling, coupled with in vivo electroretinography recordings, provided us with a reliable basis for comparing the disease phenotypes and severity.
2024-10-10 | PXD052554 | Pride
Project description:Inherited retinal degenerations (IRDs) are a leading cause of blindness among the young population in the developed world. Approximately half of IRDs initially manifest as gradual loss of night vision and visual fields, characteristic of retinitis pigmentosa (RP). Due to challenges in genetic testing, and the large heterogeneity of mutations underlying RP, targeted gene therapies are an impractical largescale solution in the foreseeable future. For this reason, identifying common key pathophysiological pathways in IRDs that could be used as targets for mutation-agnostic and disease-modifying therapies (DMTs) is warranted. In this study, we investigated retinal proteome of three distinct IRD mouse models, comparing to sex- and age-matched wild-type mice. Specifically, we used the Pde6βRd10 (rd10) and RhoP23H/WT (P23H) mouse models of autosomal recessive and autosomal dominant RP, respectively, as well as the Rpe65-/- mouse model of Leber´s congenital amaurosis type 2 (LCA2). The mice were housed at two distinct institutions and analyzed using LC-MS in three separate facilities/instruments following data-dependent and data-independent acquisition modes. This cross-institutional and multi-methodological approach signifies the reliability and reproducibility of the results. The largescale retinal proteome profiling, coupled with in vivo electroretinography recordings, provided us with a reliable basis for comparing the disease phenotypes and severity.
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Project description:The Affymetrix Human Gene 2.0 ST array was used to measure differential expression of RNA isolated from normal and Diamond Blackfan anemia (DBA) erythroid progenitors after ex vivo expansion of circulating, peripheral blood derived hematopoietic stem cells under erythroid growth conditions. The gene-level probe summaries reported in this series were computed using RMA as implemented in the Bioconductor package Oligo v1.36.1. Diamond Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by erythroid aplasia, usually without perturbation of other hematopoietic lineages. Approximately 65% of DBA patients with autosomal dominant inheritance have heterozygous mutations or deletions in ribosomal protein (RP) genes while <1% of patients with X-linked inheritance have been identified with mutations in the transcription factor, GATA1. Erythroid cells from patients with DBA have not been well characterized and the mechanisms underlying the erythroid specific effects of either RP or GATA1 associated DBA remain unclear. We have developed an in vitro culture system to expand peripheral blood CD34+ progenitor cells from patients with DBA and differentiate them into erythroid cells. Cells from patients with RP or GATA1 mutations showed decreased proliferation and delayed erythroid differentiation compared to controls. RNA transcript analyses of erythroid cells from controls and patients with RP or GATA1 mutations showed distinctive differences, with upregulation of heme biosynthesis genes prominently in RP-mediated DBA and failure to upregulate components of the translational apparatus in GATA1-mediated DBA. Our data show that dysregulation of translational function is a common feature of DBA caused by both RP and GATA1 mutations.
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