Cystic Kidney Disease: Disease Spectrum and Genotype-Phenotype Correlations
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PROVIDER: PRJNA1274053 | ENA |
REPOSITORIES: ENA
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Project description:Cystic Kidney Disease: Disease Spectrum and Genotype-Phenotype Correlations
| PRJNA1274054 | ENA
Project description:Unravelling Stargardt Disease (STGD1): Modelling Genotype-Phenotype Correlations and Unresolved Genetic Variants in iPSC-Derived Retinal Organoids
| PRJNA988887 | ENA
Project description:Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis - LDN 6716
| PRJNA449799 | ENA
Project description:Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis - LDN 6716
| PRJNA449798 | ENA
Project description:Stargardt disease (STGD1) is an inherited retinopathy affecting approximately 1:8,000 individuals. It is characterised by biallelic mutations in ABCA4, and encodes a vital protein for the recycling of retinaldehyde in the retina. Despite its prevalence and impact, there are currently no treatments available for this condition. Furthermore, 35% of STGD1 cases remain genetically unsolved. Efforts have been directed towards comprehending the fundamental disease mechanisms and identifying all disease-causing variants in the extensive 150kb gene, to better aid with the development of effective therapeutic strategies. In this study, we generated iPSC lines from two monoallelic (PT1 & PT2), late onset STGD1 cases with the heterozygous complex allele - c.[5461-10T>C;5603A>T]. We differentiated these cells alongside a biallelic affected control (AC) - c.4892T>C, and c.4539+2001G>A, to retinal organoids (ROs) allowing us to investigate cellular and molecular characteristics associated with STGD1. We hypothesized that the missing inheritance in our monoallelic cases is due to an RNA defect. Consequently, we utilised a myriad of sequencing strategies including WGS, single-cell RNA sequencing (scRNAseq) and long-read RNA sequencing (LRS) to address this. ROs were grown for 230 days and developed all key retinal neurons with photoreceptor outer segments capable of ABCA4 expression. We observed patient-specific disruption to lamination with OPN1MW/LW+ cone photoreceptor retention in the RO centre during differentiation. Retention was more severe in the AC case affecting both cones and rods, suggesting a genotype/phenotype correlation. scRNAseq suggests retention may be due to the induction of apoptosis in photoreceptors. WGS successfully identified the missing alleles in both cases; PT1 reported c. 5603A>T in homozygous state and PT2 uncovered a rare hypomorph - c.4865T>C. Furthermore, ROs were able to recapitulate the retina-specific splicing defect in PT1 as shown by LRS data. Collectively, these results highlight the suitability of ROs in STGD1 modelling. Their ability to display genotype-phenotype correlations enhances their utility as a platform for therapeutic development. Importantly, both PT1 and PT2 cases were genetically resolved in this study, providing two more individuals their confirmed genetic diagnosis.
2025-02-07 | GSE236097 | GEO
Project description:We show that resident macrophages accumulate in cilia mutant mice prior to cyst formation and that inhibition of resident macrophage accumulation reduces cystic kidney disease.
2019-07-04 | GSE131896 | GEO
Project description:Tissue resident macrophages promote renal cystic disease
| PRJNA545273 | ENA
Project description:Background For many complex diseases, including Parkinson’s disease, regulatory elements located in intergenic regions have been putatively associated with disease risk and development. However, the biological mechanisms linking these intergenic loci to disease pathogenesis remain largely unknown. Fundamentally, this is because these intergenic loci are non-coding, and bespoke approaches to in-depth functional characterisation are required. Here we utilised an integrative, functional approach to identify the genotype-specific impacts of Parkinson’s disease-associated variant rs11610045, located within a complex region on chromosome 12. Methods & Results We utilised CRISPR-Cas9 editing (and reversal) to generate isogenic iPSC clones from the KOLF2.1J line containing either the A|A (WT) or G|G (edited) rs11610045 genotype. We also reverted the G|G genotype back to the A|A genotype in two clones to control for off-target effects. Functional profiling of these clones demonstrated allele-specific regulation of both nearby and distal genes, including THBS1 and PDGFB. Further, affinity purification followed by mass spectrometry identified the differential binding of potential regulatory proteins to the G|G genotype compared to the WT A|A genotype, including the transcription factor TCF7L1. Conclusions Our findings support a model in which non-coding variants, such as rs11610045, impact the expression and downstream activity of multiple genes predominantly through trans-acting mechanisms. In so doing, this study demonstrates a pipeline to delineate SNP-specific impacts in an iPSC model. Finally, we highlight the challenge of aligning genotype dependent expectations of the impact of expression quantitative loci on genes as part of the exploration of how inherited genetic variation contributes to complex genetic disease.
2026-04-07 | PXD065108 | Pride
Project description:Cystic fibrosis (CF) intestinal disease is characterized by alterations in processes such as proliferation and apoptosis which are known to be regulated in part by microRNA’s. Herein, we completed microRNA expression profiling of the intestinal tissue from the cystic fibrosis mouse model of cystic fibrosis transmembrane conductance regulator (Cftr) deficient mice (BALBc/J Cftrtm1UNC), relative to that of wildtype littermates, to determine whether changes in microRNA expression level are part of this phenotype. We identified 24 microRNA's to be significantly differentially expressed in tissue from CF mice compared to wildtype, with the higher expression in tissue from CF mice. These data were confirmed with real time PCR measurements. A comparison of the list of genes previously reported to have decreased expression in the BALB x C57BL/6J F2 CF intestine to that of genes putatively targeted by the 24 microRNA’s, determined from target prediction software, revealed 20% of the gene expression profile to overlap with predicted targets. Pathway analysis identified these common genes to function in phosphatase and tensin homolog-, protein kinase A-, phosphoinositide-3 kinase/Akt- and peroxisome proliferator-activated receptor alpha/retinoid X receptor alpha signaling pathways, among others, and through real time PCR experiments genes of these pathways were demonstrated to have lower expression in the BALB CF intestine. We conclude that altered microRNA expression is a feature which putatively influences both metabolic abnormalities and the altered tissue homeostasis component of CF intestinal disease. Two condition experiment, Balbc/J Cftrtm1UNC -/- (Cystic Fibrosis (CF) Mice) and Balbc/J Cftrtm1UNC +/+ (Wild Type (WT) Mice). Biological Replicates: 7 WT, 8CF. Ileum Tissue.
2011-06-01 | E-GEOD-19621 | biostudies-arrayexpress
Project description:It is widely accepted that injuries to cilia mutant mice accelerate the rate of cystic kidney disease; however, cellular factors that drive the accelerated rate of cystic disease are unknown. By performing single cell RNA sequencing of all CD45+ immune cells, we find that the subtype and gene expression of adaptive immune cells is significantly altered between non-injured, aged cystic mice, injury-accelerated cystic mice, and non-cystic controls. Deletion of all adaptive immune cells reduced cystic disease in the injury-accelerated model but had no effect on cystic disease in the non-injured model. This differential rescue may be due to unique adaptive immune cell subtypes and ligands that are only present in the injury accelerated model of cystic disease.
2022-01-19 | GSE193528 | GEO