Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Elucidating the molecular mechanisms underlying CRB1-related Leber congenital amaurosis (LCA)

ABSTRACT: Patients with genetic mutations in the CRB1 gene have varied clinical features and levels of disease severity ranging from Leber congenital amaurosis (LCA), early onset retinal dystrophy (EORD) to retinitis pigmentosa (RP). The relationship between genetic mutation and clinical presentation is not well understood. Our lab have characterised two disease models of CRB1 (Owen et al 2023); zebrafish and patient grown stem cell derived early retinas. Investigation reveals lack of the CRB1 protein prevents the retina from developing into a mature state with precise defined cell types, instead it is locked in an early stage of development with lots of cells dividing. To futher understand the underlying molecular mechanisms causing the CRB1 phenotype we have carried out transcriptome analysis of iPSC derived 3D retinal organoids at day 35.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235778 | GEO | 2026/06/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Elucidating the molecular mechanisms underlying CRB1-related Leber congenital amaurosis (LCA)

Project description:Elucidating the molecular mechanisms underlying CRB1-related Leber congenital amaurosis (LCA)

| PRJNA987610 | ENA

Gene therapy of dominant CRX-Leber congenital amaurosis using patient retinal organoids II

Project description:Mutations in the cone-rod homeobox (CRX) transcription factor lead to distinct retinopathy phenotypes, including early-onset vision impairment in dominant Leber congenital amaurosis (LCA). Using induced pluripotent stem cells (iPSCs) from a patient with CRX-I138fs mutation, we established an in vitro model of CRX-LCA in retinal organoids that exhibit defective photoreceptor maturation by histology and gene profiling including diminished expression of visual opsins. Gene therapy by delivery of an additional correct CRX allele using an AAV vector partially restored photoreceptor phenotype and expression of phototransduction-related genes as revealed by single cell RNA-sequencing. Retinal organoids derived from iPSCs of a second dominant CRX-LCA patient carrying a K88N mutation revealed loss of opsin expression as a common phenotype, which could also be alleviated by AAV-mediated overexpression of CRX. Our studies provide the proof-of-concept for development of gene therapy for dominant CRX-LCA and other CRX-retinopathies.

2021-02-17 | GSE153099 | GEO

Gene therapy of dominant CRX-Leber congenital amaurosis using patient retinal organoids I

2021-02-17 | GSE152939 | GEO

Global gene expression analysis of human iPSC-derived Retinal Pigmented Epithelial (RPE) cells from LCA patients and unaffected persons

Project description:Our purpose was to investigate genes and molecular mechanisms involved in patients with Leber congenital amaurosis (LCA). Fibroblasts from two unrelated clinically-identified patients (Coriell) were reprogrammed to pluripotency by retroviral transduction. These human induced Pluripotent Stem Cells (hiPSCs) were differentiated into neural stem cells (NSC) that mimicked the neural tube stage and retinal pigmented epithelial (RPE) cells that could be targeted by the disease. A genome wide transcriptome analysis was performed with Affymetrix Exon Array GeneChipM-BM-., comparing LCA-hiPSCs derivatives to controls. The aim was to identify differentially expressed genes which may be associated with early developmental defect before the establishment of mature retinal circuitry. We analyzed iPSC-derived retinal pigmented epithelial (RPE) cells from LCA patient's fibroblast (n=2) and iPSC-derivedretinal pigmented epithelial (RPE) cells from healthy people fibroblast (n=2). A total of 13 samples were analyzed : 9 RPE cells derived from iPSC LCA and 4 RPE cells derived from wild-type iPSC.

2015-01-21 | E-GEOD-43926 | biostudies-arrayexpress

Global gene expression analysis of human iPSC-derived Neural Stem Cells (NSC) from LCA patients and unaffected persons

Project description:Our purpose was to investigate genes and molecular mechanisms involved in patients with Leber congenital amaurosis (LCA). Fibroblasts from two unrelated clinically-identified patients (Coriell) were reprogrammed to pluripotency by retroviral transduction. These human induced Pluripotent Stem Cells (hiPSCs) were differentiated into neural stem cells (NSC) that mimicked the neural tube stage and retinal pigmented epithelial (RPE) cells that could be targeted by the disease. A genome wide transcriptome analysis was performed with Affymetrix Exon Array GeneChipM-BM-., comparing LCA-hiPSCs derivatives to controls. The aim was to identify differentially expressed genes which may be associated with early developmental defect before the establishment of mature retinal circuitry. We analyzed iPSC-derived neural stem cells from LCA patient's fibroblast (n=2) and iPSC-derived neural stem cells from healthy people fibroblast (n=2). A total of 21 samples were analyzed : 9 NSC derived from iPSC LCA and 12 NSC derived from wild-type iPSC.

2015-01-21 | E-GEOD-43924 | biostudies-arrayexpress

Histological and single cell transcriptomic analysis of human retinal organoid models of Leber Congenital Amaurosis identifies endoplasmic reticulum stress as a common degenerative pathway

Project description:This study utilized human stem cell derived retinal organoids to characterize two models of Leber Congenital Amaurosis. Using CRISPR/Cas9, we generated CRB1 and RPGRIP1 KO cell lines and differentiated WT and KO lines into retinal organoids. Single cell capture was performed using Dropseq at days 70, 90, 120, 150, 190, and 225 of differentiation. We report upregulation of DDIT3 in both KO organoids relative to WT and confirm DDIT3 induction at the protein level by immunohistochemistry. These results indicate that these genetically different models of disease converge on endoplasmic reticulum stress and DDIT3 induction as a shared degenerative pathway. Therapeutic targeting of ER stress could help alleviate the degenerative phenotype in cases where diseased photorececeptors suffer ER stress.

2021-05-01 | GSE152212 | GEO

Transcriptome (RNA-seq) analysis of the retina of crumbs 2a (crb2a m289/m289) zebrafish model of Leber congenital amaurosis and retinitis pigmentosa.

Project description:The crumbs cell polarity complex plays a crucial role in apical-basal epithelial polarity. When human CRB1 is mutated, it results in autosomal recessive Leber congenital amaurosis and retinitis pigmentosa, with no established genotype-phenotype correlation. Using the oko meduzym289/m289 (crb2a-/-) zebrafish model, we performed integrative transcriptomic and methylomic analysis to identify dysregulated genes and pathways. We reveal delayed retinal cell type specification confirmed in patient-derived retinal organoids, with disruption to cell cycle modulation and epigenetic transcriptional control. Hence, using reduced representation bisulphite sequencing (RRBS) we explored differential DNA methylation, identifying hypermethylated pathways involving biological adhesion, Hippo and transforming growth factor beta (TGFbeta) signalling. Functional epigenetic modules (FEM) were highlighted through the integration of RNA-seq and RRBS, confirming cell cycle involvement and disturbance of TGFbeta, BMP, Hippo and SMAD protein signal transduction. Taken together our work provides insights for epigenetic regulation in early retinal development and considerations for future therapeutic development.

2023-01-25 | GSE178709 | GEO

Global gene expression analysis of human iPSC-derived Neural Stem Cells (NSC) from LCA patients and unaffected persons

Project description:Our purpose was to investigate genes and molecular mechanisms involved in patients with Leber congenital amaurosis (LCA). Fibroblasts from two unrelated clinically-identified patients (Coriell) were reprogrammed to pluripotency by retroviral transduction. These human induced Pluripotent Stem Cells (hiPSCs) were differentiated into neural stem cells (NSC) that mimicked the neural tube stage and retinal pigmented epithelial (RPE) cells that could be targeted by the disease. A genome wide transcriptome analysis was performed with Affymetrix Exon Array GeneChip®, comparing LCA-hiPSCs derivatives to controls. The aim was to identify differentially expressed genes which may be associated with early developmental defect before the establishment of mature retinal circuitry.

2015-01-21 | GSE43924 | GEO

Reduced representation bisulfite sequencing (RRBS) of the retina of crumbs 2a (crb2a m289/m289) zebrafish model of Leber congenital amaurosis and retinitis pigmentosa.

2023-01-25 | GSE178842 | GEO

Global gene expression analysis of human iPSC-derived Retinal Pigmented Epithelial (RPE) cells from LCA patients and unaffected persons

Project description:Our purpose was to investigate genes and molecular mechanisms involved in patients with Leber congenital amaurosis (LCA). Fibroblasts from two unrelated clinically-identified patients (Coriell) were reprogrammed to pluripotency by retroviral transduction. These human induced Pluripotent Stem Cells (hiPSCs) were differentiated into neural stem cells (NSC) that mimicked the neural tube stage and retinal pigmented epithelial (RPE) cells that could be targeted by the disease. A genome wide transcriptome analysis was performed with Affymetrix Exon Array GeneChip®, comparing LCA-hiPSCs derivatives to controls. The aim was to identify differentially expressed genes which may be associated with early developmental defect before the establishment of mature retinal circuitry.

2015-01-21 | GSE43926 | GEO