Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat

Burn, Timothy C.; Connors, Timothy D.; Dackowski, William; Petry, Linda R.; Raay, Terence J. Van; Millholland, John M.; Venet, Marc; Miller, Glenn A.; Hakim, Ramond M.; Landes, Gregory M.; Kilnger, Katherine W.; Qian, Feng; Onuchic, Luiz Fernando; Watnick, Terry; Germino, Gregory G.; Doggett, Norman A.

doi:10.1093/hmg/4.4.575

Cited by 216 publications

(59 citation statements)

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“…Most notable among these is the larger size of the coding region (approximately 12.9 kb compared with approximately 3 kb) and the GC richness of the DNA, resulting in a higher level of CpG dinucleotides that are known warm spots for mutations (38). In addition, special factors, such as a polypyrimidine tract in IVS21 and six pseudogenes that match much of the 5Ј two thirds of PKD1, may increase the somatic mutation level at PKD1 (29,39,40). A significant level of de novo germline mutations at PKD1 emphasize that new mutations occur at a significant level at this locus (38).…”

Section: Discussionmentioning

confidence: 99%

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

Harris

Bae

Rossetti

et al. 2006

Journal of the American Society of Nephrology

235

177

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Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P ‫؍‬ 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.

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Section: Discussionmentioning

confidence: 99%

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

Harris

Bae

Rossetti

et al. 2006

Journal of the American Society of Nephrology

235

177

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show abstract

“…They are characterized by fluid-filled cysts that result from unregulated expansion of renal epithelial cells. The most frequent form of PKD, autosomal dominant PKD (ADPKD), is caused by mutations in PKD1 and PKD2 (Burn et al, 1995;Hughes et al, 1995;Mochizuki et al, 1996;The International Polycystic Kidney Disease Consortium, 1995). These genes encode polycystin 1 (PKD1; polycystic kidney disease 1), an 11-transmembrane-domain protein, and polycystin 2 (PKD2; polycystic kidney disease 2), a member of the transient receptor potential (TRP) superfamily.…”

Section: Introductionmentioning

confidence: 99%

The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity

et al. 2010

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SUMMARYThe RNA-binding protein Bicaudal C is an important regulator of embryonic development in C. elegans, Drosophila and Xenopus. In mouse, bicaudal C (Bicc1) mutants are characterized by the formation of fluid-filled cysts in the kidney and by expansion of epithelial ducts in liver and pancreas. This phenotype is reminiscent of human forms of polycystic kidney disease (PKD). Here, we now provide data that Bicc1 functions by modulating the expression of polycystin 2 (Pkd2), a member of the transient receptor potential (TRP) superfamily. Molecular analyses demonstrate that Bicc1 acts as a post-transcriptional regulator upstream of Pkd2. It regulates the stability of Pkd2 mRNA and its translation efficiency. Bicc1 antagonized the repressive activity of the miR-17 microRNA family on the 3ЈUTR of Pkd2 mRNA. This was substantiated in Xenopus, in which the pronephric defects of bicc1 knockdowns were rescued by reducing miR-17 activity. At the cellular level, Bicc1 protein is localized to cytoplasmic foci that are positive for the Pbody markers GW182 and HEDLs. Based on these data, we propose that the kidney phenotype in Bicc1 -/-mutant mice is caused by dysregulation of a microRNA-based translational control mechanism.

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“…Autosomal dominant PKD (ADPKD; MIM 173900 and MIM 173910) occurs in 1:400-1:1000 individuals and is caused by mutations in the PKD1 or PKD2 genes. [1][2][3][4] Autosomal recessive PKD (ARPKD; MIM 263200) occurs in 1:20,000 live births and is caused by defects in the PKHD1 gene. 5,6 Although these gene mutations are essential for development of each PKD phenotype, their effects are regulated by nongenetic factors.…”

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confidence: 99%

Kidney Injury Accelerates Cystogenesis via Pathways Modulated by Heme Oxygenase and Complement

Zhou¹,

Ouyang²,

Schoeb³

et al. 2012

Journal of the American Society of Nephrology

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AKI accelerates cystogenesis. Because cystogenic mutations induce strong transcriptional responses similar to those seen after AKI, these responses may accelerate the progression of cystic renal disease. Here, we modulated the severity of the AKI-like response in Cys1 cpk/cpk mice, a model that mimics autosomal recessive polycystic kidney disease. Specifically, we induced or inhibited activity of the renoprotective enzyme heme oxygenase (HO) and determined the effects on renal cystogenesis. We found that induction of HO attenuated both renal injury and the rate of cystogenesis, whereas inhibition of HO promoted cystogenesis. HO activity mediated the response of NFkB, which is a hallmark transcriptional feature common to both cystogenesis and AKI. Among the HO-modulated effects we measured, expression of complement component 3 (C3) strongly correlated with cystogenesis, a functionally relevant association as suggested by Cys1 cpk/cpk mice with genetically induced C3 deficiency. Because both C3 deficiency and HO induction reduce cyst number and cyst areas, these two factors define an injury-stimulated cystogenic pathway that may provide therapeutic targets to slow the formation of new renal cysts and the growth of existing cysts.

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Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat

Cited by 216 publications

References 0 publications

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity

Kidney Injury Accelerates Cystogenesis via Pathways Modulated by Heme Oxygenase and Complement

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