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Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression [Pkd2]

ABSTRACT: We report the findings of deletion of the miR17 binding motif from Pkd2 mRNA

ORGANISM(S): Mus musculus

PROVIDER: GSE196589 | GEO | 2022/02/11

REPOSITORIES: GEO

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Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression [Pkd1]

Project description:We report the findings of deletion of the miR17 binding motif from Pkd1 mRNA

2022-02-11 | GSE196588 | GEO

Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression

Project description:We report the findings of deletion of the miR17 binding motif from Pkd1 mRNA

2022-02-11 | GSE196237 | GEO

PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression.

Project description:Autosomal dominant polycystic kidney disease (ADPKD), among the most common human genetic conditions and a frequent etiology of kidney failure, is primarily caused by heterozygous PKD1 mutations. Kidney cyst formation occurs when PKD1 dosage falls below a critical threshold. However, no framework exists to harness the remaining allele or reverse PKD1 decline. Here, we show that mRNAs produced by the noninactivated PKD1 allele are repressed via their 3'-UTR miR-17 binding element. Eliminating this motif (Pkd1∆17) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also inhibited via its 3'-UTR miR-17 motif, and Pkd2∆17-induced Polycystin-2 derepression retards cyst growth in Pkd1-mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, modeling PKD1∆17 or PKD2∆17 alleles in patient-derived primary ADPKD cultures leads to smaller cysts, reduced proliferation, lower pCreb1 expression, and improved mitochondrial membrane potential. Thus, evading 3'-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach.

| S-EPMC9376183 | biostudies-literature

Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression [Pkd2]

Project description:Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression [Pkd2]

| PRJNA805547 | ENA

Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression [Pkd1]

Project description:Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression [Pkd1]

| PRJNA805542 | ENA

Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression

Project description:Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression

| PRJNA805541 | ENA

Epigenetic silencing of PKD1 in autosomal dominant polycystic kidney disease

2012-02-16 | GSE35831 | GEO

Epigenetic silencing of PKD1 in autosomal dominant polycystic kidney disease

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. Total RNAs were isolated from kidney of human normal (49 years old/ male) and ADPKD patients (62 years old/ male, 67 years old/ male) using NucleoSpin® RNA Kit (MACHEREY-NAGEL) according to the manufacturer’s instructions. We used tha Affymetrix GeneChip Human Gene 1.0 ST Array. Per RNA sample, 300 ng was used as the input into the Affymetrix procedure as recommended by the manufacturer's protocol.

2012-02-16 | E-GEOD-35831 | biostudies-arrayexpress

PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease.

Project description:BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. METHODS: We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2) and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423). Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31-46 and PKD2 . RESULTS: Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed). We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. CONCLUSION: In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course.

| S-EPMC1434729 | biostudies-literature

Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease.

Project description:Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.

| S-EPMC4769188 | biostudies-literature

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