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In vitro modeling and rescue of ciliopathy associated with mutations in IQCB1 (Nephrocystin 5) using patient-derived cells

ABSTRACT: Mutations in IQCB1/NPHP5 gene encoding the ciliary protein Nephrocystin 5 cause early-onset blinding disease Leber congenital amaurosis (LCA), together with kidney dysfunction in Senior-Løken Syndrome. For in vitro disease modeling, we obtained dermal fibroblasts from NPHP5-LCA patients, which were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into retinal pigment epithelium (RPE) and retinal organoids. Patient fibroblasts and RPE demonstrated aberrantly elongated ciliary axonemes. Organoids revealed impaired development of outer segment structures, which are modified primary cilia, and mislocalization of visual pigments to photoreceptor cell soma. All patient-derived cells showed reduced levels of CEP290 protein, a critical cilia transition zone component interacting with NPHP5, providing a plausible mechanism for aberrant ciliary gating and cargo transport. Disease phenotype in NPHP5-LCA retinal organoids could be rescued by AAV-mediated NPHP5 gene augmentation therapy. Our studies thus establish a human disease model and a path for treatment of NPHP5-LCA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200339 | GEO | 2022/08/26

REPOSITORIES: GEO

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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

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2018-08-20 | PXD010821 | Pride

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

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

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2022-06-06 | E-MTAB-11437 | biostudies-arrayexpress

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

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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.

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