BICC1 is a genetic modifier for Polycystic Kidney Disease
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ABSTRACT:
PROVIDER: PRJNA1091688 | ENA |
REPOSITORIES: ENA
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Project description:Autosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants in PKD1 or PKD2. Variable disease expression is incompletely understood with rare very early-onset PKD (VEO-PKD) presentations in utero or infancy. In animal models, the RNA-binding molecule Bicc1 has been shown to play a crucial role in the pathogenesis of PKD. To further investigate this, we first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded by PKD1 and PKD2 via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies in Xenopus and mice. These resulted in more severe disease when Bicc1 was depleted in conjunction with Pkd1, Pkd2 or Pkhd1., Finally, in a large human patient cohort, we identified several VEO-PKD patients that exhibited compound situations of PKD1, PKD2 and PKHD1 in conjunction with BICC1 as well as a sibling pair with a homozygous BICC1 mutation. Together these findings support the hypothesis that BICC1 cooperates with PKD1 and PKD2, and that BICC1 variants may aggravate disease severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.
2025-06-28 | GSE262417 | GEO
Project description:Polycystic Kidney Disease (PKD) is a genetic disease of the kidney characterized by the gradual replacement of normal kidney parenchyma by fluid-filled cysts and fibrotic tissue. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene. Here we present an RNASeq experiment designed to investigate the effect of a kidney specific and Tamoxifen inducible knockout of the Pkd1 gene in mice. The Pkd1cko mice were harvested at different time points 2-weeks, 3-weeks, 5-weeks, 10.5-weeks, 11-weeks and 15-weeks after gene inactivation.
2019-12-24 | E-MTAB-8086 | biostudies-arrayexpress
Project description:Polycystic Kidney Disease (PKD) is a genetic disease of the kidney characterized by the gradual replacement of normal kidney parenchyma by fluid-filled cysts and fibrotic tissue. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene. Here we present an RNASeq experiment designed to investigate the effect of a kidney specific and Tamoxifen inducible knockout of the Pkd1 gene in mice. 7 mice were grouped into two groups, 4 Tamoxifen treated mice which develop an adult onset Polycystic Kidney Disease phenotype and 3 untreated mice which have WT phenotype.
2016-06-01 | E-MTAB-4086 | biostudies-arrayexpress
Project description:MODELLING GENETIC POLYCYSTIC KIDNEY DISEASE USING HUMAN PLURIPOTENT STEM CELL- DERIVED KIDNEY ORGANOIDS
| PRJNA966953 | ENA
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID’s 173900, 601313, 613095) leads to end stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles disrupted using a tamoxifen-inducible Cre recombinase, transcriptomics and metabolomics were applied to follow disease progression in animals induced before P10. Network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. These analyses also predict metabolic pathways, notably those controlled by HNF4α, are key elements in postnatal kidney maturation and early steps of cyst formation. To test this hypothesis, metabolic networks were altered by inactivating Hnf4a and Pkd1. The Pkd1/Hnf4a double knock-out have significantly more cystic kidneys thus indicating that modulating metabolic pathways might be an effective therapeutic approach. We crossed fifth-generation C57/BL6 Pkd1cond mice to fifth-generation C57/BL6 tamoxifen-Cre (B6.Cg-Tg(Cre/Esr1)5Amc/J mice (stock 004682), Jackson Laboratories) and C57/BL6 congenic B6.129S4-Gt(ROSA)26Sortm1Sor/J (stock 003474, Jackson Laboratories) to produce Pkd1 conditional mice with TamCre (mutant) or without TamCre (control). We induced Cre recombinase activity in mice < 10 days of age by intraperitoneally injecting nursing mothers with tamoxifen (10 mg/40 g) , and harvested kidney samples of control and mutant (34 and 36 animals, respectively) between the ages of 11 and 24 days. Postprocessed files (expression p value<0.05; quantile normalized; merged and corrected for batch-effect using COMBAT) linked below as supplementary files.
2012-11-29 | E-GEOD-32586 | biostudies-arrayexpress
Project description:Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by mutations in the gene PKHD1. ARPKD presents with considerably clinical variability which is linked to the type of PKHD1 mutation but not position. Animal models of Polycystic Kidney Disease (PKD) suggest there is a complex genetic landscape with genetic modifiers as a potential cause of disease variability. Transcriptomic analysis identified a considerable number of genes linked to cellular metabolism and development. Amongst these genes were those linked to WNT signalling. Two individuals in this cohort had the same mutations in PKHD1 but different rates of kidney disease progression. Amongst the transcriptomic differences of these two individuals were differences in the expression changes of WNT genes.
2024-09-06 | GSE242476 | GEO
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID’s 173900, 601313, 613095) leads to end stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles disrupted using a tamoxifen-inducible Cre recombinase, transcriptomics and metabolomics were applied to follow disease progression in animals induced before P10. Network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. These analyses also predict metabolic pathways, notably those controlled by HNF4α, are key elements in postnatal kidney maturation and early steps of cyst formation. To test this hypothesis, metabolic networks were altered by inactivating Hnf4a and Pkd1. The Pkd1/Hnf4a double knock-out have significantly more cystic kidneys thus indicating that modulating metabolic pathways might be an effective therapeutic approach.
2012-11-29 | GSE32586 | GEO
Project description:Polycystic Kidney Disease Progression Expression Analysis
| PRJEB35921 | ENA
Project description:ADPKD (Autosomal dominant polycystic kidney disease) is the most common inherited disorders and is characterized by growth of numerous cysts filled with fluid in the kidneys. Ultimately, it leads to kidney failure. The mutations of PKD1 and PKD2 account for approximately 85 and 15 percent of ADPKD, respectively. However, the mechanisms related to genetic mutation of PKD1 and PKD2 are still unclear. To investigate altered gene expression levels, Affymetrix microarray was performed using the kidney tissue from normal and ADPKD patients.
2012-02-16 | GSE35831 | GEO
Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.
2021-07-15 | GSE179947 | GEO