Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation of one of two genes: PKD1 (16p13.3) or PKD2 (4q13-23). PKD1 accounts for approximately 85% of pedigrees and is associated with significantly more severe cystic disease. The ADPKD genes encode proteins, polycystin-1 and polycystin-2, which are very different in size and structure, but which have a region of homology and may interact as part of the same complex. Polycystin-1 is a large, integral membrane protein ( approximately 460 kDa) predicted to be involved in cell-cell and/or cell-matrix interactions. Polycystin-2 ( approximately 110 kDa) is related to polycystin-1 and voltage-activated and transient receptor potential channel subunits, suggesting that the polycystins may also be associated with ion transport. A polycystin complex could regulate cellular events (that are abnormal in ADPKD) in response to specific extracellular cues, mediated by controlling cellular Ca(2+)levels and/or other signalling pathways. Recently, two further polycystin-like molecules have been identified, indicating roles for this novel protein family beyond the kidney. A wide range of different mutations to the PKD1 or PKD2 gene have been detected, most predicted to truncate and inactivate the proteins. A somatic second hit may be required for focal cyst development, although there is widespread immunohistochemical evidence of polycystin expression in cystic epithelia. Disruption of the mouse Pkd1 gene leads to death in the perinatal period with massive cystic expansion in homozygotes and age-related cyst development in heterozygotes. Normal renal development in Pkd1(del34/del34)mice up to embryonic day approximately 15.5 suggests a role for polycystin-1 in developing and maintaining the tubular architecture, consistent with the localization of the protein, rather than nephron induction. Renal cystic disease in homo- and heterozygotes of a Pkd2 mouse model with a disrupted exon 1 inserted in tandem with the normal exon (and prone to somatic recombination, which inactivates the gene) supports a role for somatic events in cystogenesis.
Hum Mol Genet 1999
PMID:Autosomal dominant polycystic kidney disease: clues to pathogenesis. 1046 38

Considerable progress toward understanding pathogenesis of autosomal dominant polycystic disease (ADPKD) has been made during the past 15 years. ADPKD is a heterogeneous human disease resulting from mutations in either of two genes, PKD1 and PKD2. The similarity in the clinical presentation and evidence of direct interaction between the COOH termini of polycystin-1 and polycystin-2, the respective gene products, suggest that both proteins act in the same molecular pathway. The fact that most mutations from ADPKD patients result in truncated polycystins as well as evidence of a loss of heterozygosity mechanism in individual PKD cysts indicate that the loss of the function of either PKD1 or PKD2 is the most likely pathogenic mechanism for ADPKD. A novel mouse model, WS25, has been generated with a targeted mutation at Pkd2 locus in which a mutant exon 1 created by inserting a neo(r) cassette exists in tandem with the wild-type exon 1. This causes an unstable allele that undergoes secondary recombination to produce a true null allele at Pkd2 locus. Therefore, the model Pkd2(WS25/-), which carries the WS25 unstable allele and a true null allele, produces somatic second hits during mouse development or adult life and establishes an extremely faithful model of human ADPKD.
Mol Genet Metab 2000 Jan
PMID:Molecular genetics and mechanism of autosomal dominant polycystic kidney disease. 1065 52

Polycystic kidney disease (ADPKD) is a condition with an autosomal dominant mode of inheritance and adult onset. Two forms of the disease, ADPKD1 and ADPKD2, caused by mutations in PKD1 and PKD2, respectively, are very similar, except that ADPKD1 patients run a more severe course. At the cellular level, ADPKD1 was first shown to be recessive, since somatic second hits are perhaps necessary for cyst formation. The near identical phenotype had suggested that ADPKD1 and ADPKD2 might have a similar pathogenesis and that the two gene products, poly- cystins 1 and 2, are part of a common developmental pathway. Work in transgenic mice showed that somatic loss of Pkd2 expression is necessary for renal cyst formation, and recently we showed that somatic mutations inactivating the inherited healthy allele were present in 9 of 23 cysts from a human ADPKD2 kidney, supporting a two-hit loss-of-function model for ADPKD2 cystogenesis. Here, we provide the first direct genetic evidence that polycystins 1 and 2 do interact, perhaps as part of a larger complex. In cystic DNA from a kidney of an ADPKD1 patient, we showed somatic mutations not only in the PKD1 gene of certain cysts, but also in the PKD2 gene of others, generating a trans -heterozygous state with mutations in both genes. One mutation in PKD1 is of germinal nature and the mutation in the PKD2 gene is of somatic nature. The implications of such a situation are enormous, not only for ADPKD, but also for many other conditions with phenotypic heterogeneity and age-dependent penetrance.
Hum Mol Genet 2000 Feb 12
PMID:Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal dominant polycystic kidney disease. 1065 55

Autosomal dominant polycystic kidney disease (ADPKD) occurs by germline mutation in PKD1 or PKD2. Evidence of homozygous inactivation of either gene in human cyst lining cells as well as in mouse knockout models strongly supports a two-hit mechanism for cyst formation. Discovery of trans-heterozygous mutations in PKD1 and PKD2 in a minority of human renal cysts has led to the proposal that such mutations also can play a role in cyst formation. In the current study, we investigated the role of trans-heterozygous mutations in mouse models of polycystic kidney disease. In Pkd1(+/-), Pkd2 (+/-) and Pkd1(+/-) : Pkd2 (+/-) mice, the renal cystic lesion was mild and variable with no adverse effect on survival at 1 year. In keeping with the two-hit mechanism of cyst formation, approximately 70% of kidney cysts in Pkd2 (+/-) mice exhibited uniform loss of polycystin-2 expression. Cystic disease in trans-heterozygous Pkd1(+/-) : Pkd2 (+/-) mice, however, was notable for severity in excess of that predicted by a simple additive effect based on cyst formation in singly heterozygous mice. The data suggest a modifier role for the 'trans' polycystin gene in cystic kidney disease, and support a contribution from threshold effects to cyst formation and growth.
Hum Mol Genet 2002 Aug 01
PMID:Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease. 1214 Jan 87

Autosomal dominant polycystic kidney disease (ADPKD) is a common lethal genetic disorder, characterized by the progressive development of fluid-filled cysts in the kidney, pancreas and liver, and anomalies of the cardiovascular system. Mutations in PKD1 and PKD2, which encode the transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2) respectively, account for almost all cases of ADPKD. However, the mechanisms by which abnormalities in PKD1 and PKD2 lead to aberrant kidney development remain unknown. Recent progress in the understanding of ADPKD has focused on primary cilia, which act as sensory transducers in renal epithelial cells. New evidence shows that a mechanosensitive signal, cilia bending, activates the PC1-PC2 channel complex. When working properly, this functional complex elicits a transient Ca(2+) influx, which is coupled to the release of Ca(2+) from intracellular stores.
Trends Mol Med 2003 Jun
PMID:A tale of two tails: ciliary mechanotransduction in ADPKD. 1282 10

Autosomal dominant polycystic kidney disease (ADPKD) is typified by the accumulation of fluid-filled cysts and abnormalities in renal epithelial cell function. The disease is principally caused by mutations in the gene encoding polycystin-1, a large basolateral plasma membrane protein expressed in kidney epithelial cells. Our studies reveal that, in normal kidney cells, polycystin-1 forms a complex with the adherens junction protein E-cadherin and its associated catenins, suggesting a role in cell adhesion or polarity. In primary cells from ADPKD patients, the polycystin-1/polycystin-2/E-cadherin/beta-catenin complex was disrupted and both polycystin-1 and E-cadherin were depleted from the plasma membrane as a result of the increased phosphorylation of polycystin-1. The loss of E-cadherin was compensated by the transcriptional upregulation of the normally mesenchymal N-cadherin. Increased cell surface N-cadherin in the disease cells in turn stabilized the continued plasma membrane localization of beta-catenin in the absence of E-cadherin. The results suggest that enhanced phosphorylation of polycystin-1 in ADPKD cells precipitates changes in its localization and its ability to form protein complexes that are critical for the stabilization of adherens junctions and the maintenance of a fully differentiated polarized renal epithelium.
Mol Biol Cell 2004 Mar
PMID:A polycystin-1 multiprotein complex is disrupted in polycystic kidney disease cells. 1471 71

Autosomal dominant polycystic kidney disease (ADPKD) maps to chromosome 16p13.3 (PKD1) and to chromosome 4q21-23 (PKD2), with the likelihood of a third unmapped locus. The size and genomic complexity of the PKD1 gene make it impractical to detect mutations for prenatal diagnosis. Therefore, pedigree-based linkage analysis remains useful for diagnosis of ADPKD. Since, the complete genome sequences of chromosome 16p13.3 and 4q21-23 including PKD1 and PKD2, respectively, were reported very recently, in order to do more precise diagnosis of ADPKD, we tried to find microsatellite markers. We performed database searches of 2000 kb of genome sequence across the 16p13.3 and the 4q21-23. To determine the distribution of alleles and the degree of polymorphism of the microsatellites, genotyping experiments were performed on 48 Korean individuals. We found novel 14 microsatellite markers around ADPKD that are more polymorphic and closer to PKD1 or PKD2 than the known markers. The novel microsatellite markers were applied to diagnose ADPKD families. These novel microsatellite markers are not only useful for presymptomatic and prenatal diagnosis of ADPKD, but also applicable in the study of positional cloning, human evolution and tumor biology.
Mol Cell Probes 2004 Jun
PMID:Characterization of microsatellite markers to diagnose ADPKD. 1513 48

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the formation of fluid-filled cysts in the kidney and progressive renal failure. Other manifestations of ADPKD include the formation of cysts in other organs (liver, pancreas, and spleen), hypertension, cardiac defects, and cerebral aneurysms. The loss of function of the polycystin -1 and -2 results in the formation of epithelium-lined cysts, a process that depends on initial epithelial proliferation. cDNA microarrays powerfully monitor gene expression and have led to the discoveries of pathways regulating complex biological processes. We undertook to profile the gene expression patterns of epithelial cells derived from the cysts of ADPKD patients using the cDNA microarray technique. Candidate genes that were differently expressed in cyst tissues were identified. 19 genes were up-regulated, and 6 down-regulated. Semi-quantitative RT-PCR results were consistent with the microarray findings. To distinguish between normal and epithelial cells, we used the hierarchical method. The results obtained may provide a molecular basis for understanding the biological meaning of cytogenesis.
J Biochem Mol Biol 2004 Sep 30
PMID:The gene expression profile of cyst epithelial cells in autosomal dominant polycystic kidney disease patients. 1547 26

Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of renal failure and is characterized by the formation of many fluid-filled cysts in the kidneys. It is a systemic disorder that is caused by mutations in PKD1 or PKD2. Homozygous inactivation of these genes at the cellular level, by a 'two-hit' mechanism, has been implicated in cyst formation but does not seem to be the sole mechanism for cystogenesis. We have generated a novel mouse model with a hypomorphic Pkd1 allele, Pkd1(nl), harbouring an intronic neomycin-selectable marker. This selection cassette causes aberrant splicing of intron 1, yielding only 13-20% normally spliced Pkd1 transcripts in the majority of homozygous Pkd1(nl) mice. Homozygous Pkd1(nl) mice are viable, showing bilaterally enlarged polycystic kidneys. This is in contrast to homozygous knock-out mice, which are embryonic lethal, and heterozygous knock-out mice that show only a very mild cystic phenotype. In addition, homozygous Pkd1(nl) mice showed dilatations of pancreatic and liver bile ducts, and the mice had cardiovascular abnormalities, pathogenic features similar to the human ADPKD phenotype. Removal of the neomycin selection-cassette restored the phenotype of wild-type mice. These results show that a reduced dosage of Pkd1 is sufficient to initiate cystogenesis and vascular defects and indicate that low Pkd1 gene expression levels can overcome the embryonic lethality seen in Pkd1 knock-out mice. We propose that in patients reduced PKD1 expression of the normal allele below a critical level, due to genetic, environmental or stochastic factors, may lead to cyst formation in the kidneys and other clinical features of ADPKD.
Hum Mol Genet 2004 Dec 15
PMID:Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. 1549 22

Autosomal dominant polycystic kidney disease (ADPKD) is primarily characterized by renal cysts and progression to renal failure. It is a genetically heterogeneous disease, with mutations in the PKD1 gene accounting for the majority of cases. Direct mutation detection for PKD1-linked ADPKD or type 1 is complicated by the large size and complex genomic structure of PKD1. This paper describes a microsatellite marker-based assay for PGD in couples at risk of transmitting ADPKD type 1. During PGD, genetic analysis is carried out on single blastomeres biopsied from preimplantation embryos obtained after IVF, and only embryos unaffected by the disease under investigation are selected for transfer. Single-cell genetic analysis relied on a fluorescent duplex-PCR of linked polymorphic markers followed by fragment length determination on an automated sequencer. The co-amplification of the intragenic KG8 and the extragenic D16S291 marker at the single-cell level was evaluated in pre-clinical tests on lymphoblasts and research blastomeres. The developed assay proved to be efficient (96.1% amplification) and accurate (1.4% allele drop-out and 4.3% contamination), and can be applied in all informative ADPKD type 1 couples. From five clinical cycles carried out for three couples, two pregnancies ensued, resulting in the birth of two healthy children.
Mol Hum Reprod 2005 Jan
PMID:PGD for autosomal dominant polycystic kidney disease type 1. 1559 52


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