Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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 the most common inherited kidney disease, leading to renal insufficiency and renal transplantation. Mutation screening in the major gene for ADPKD, the polycystic kidney disease type 1 (PKD1) gene, has often been incomplete because of multiple homologous copies of this gene elsewhere on chromosome 16. Furthermore, there are only a few studies investigating genotype-phenotype correlations in patients with ADPKD. In this study, we screened the entire coding region of the PKD1 and PKD2 genes in 17 Finnish families with ADPKD via long-range polymerase chain reaction, single-strand conformation polymorphism analysis, and direct sequencing. We were able to identify mutations co-segregating with ADPKD in all 16 families linked to PKD1 by haplotype analysis. Of these mutations, six were insertions/deletions, five nonsense mutations, and five missense mutations. In the only PKD2-linked family, we found a missense mutation, R322Q. With the exception of one mutation (L845S in PKD1), all mutations were novel. Mutations and their location did not have a strong correlation with the phenotype with the exception of subarachnoidal hemorrhage or brain aneurysm, where mutations were located more often at the 5' end of the PKD1 gene than at the 3' end of the PKD1 gene.
J Mol Med (Berl) 2005 Aug
PMID:Genetics and phenotypic characteristics of autosomal dominant polycystic kidney disease in Finns. 1577 4

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations of PKD1 and PKD2. Murine gene targeting studies have shown that these genes play an essential role in development, with homozygous inactivation resulting in embryonic lethality. Recently, Pkd1-/- lethality has been linked to placental insufficiency. In this study, the placenta was used as a model to identify factors involved in these developmental abnormalities. Microarray analysis of Pkd1-/- placentae showed upregulation of a set of apolipoprotein-related genes. These changes were validated and were found to be associated with increased quantities of apolipoproteins in the amniotic fluid. Increased apolipoprotein gene expression was also observed in Pkd2-/-placentae and in cystic kidneys of Pkd1cond/-; Meox2cre/+ mice. Using chromatin immunoprecipitation assays, we determined that the activity of HNF-4alpha, a major regulator of apolipoprotein gene expression, was also increased in these organs. These findings suggest a potential role for dysregulation of nuclear hormone receptors in the pathogenesis of ADPKD.
Hum Mol Genet 2006 Jan 01
PMID:Loss of polycystin-1 or polycystin-2 results in dysregulated apolipoprotein expression in murine tissues via alterations in nuclear hormone receptors. 1630 Dec 12

Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest inherited human disorders yet remains relatively unknown to the wider medical, scientific and public audience. ADPKD is characterised by the development of bilateral enlarged kidneys containing multiple fluid-filled cysts and is a leading cause of end-stage renal failure (ESRF). ADPKD is caused by mutations in two genes: PKD1 and PKD2. The protein products of the PKD genes, polycystin-1 and polycystin-2, form a calcium-regulated, calcium-permeable ion channel. The polycystin complex is implicated in regulation of the cell cycle via multiple signal transduction pathways as well as the mechanosensory function of the renal primary cilium, an enigmatic cellular organelle whose role in normal physiology is still poorly understood. Defects in cilial function are now documented in several other human diseases including autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome and many animal models of polycystic kidney disease. Therapeutic trials in these animal models of polycystic kidney disease have identified several promising drugs that ameliorate disease severity. However, elucidation of the function of the polycystins and the primary cilium will have a major impact on our understanding of renal cystic diseases and will create exciting new opportunities for the design of disease-specific therapies.
Expert Rev Mol Med 2006 Jan 17
PMID:Molecular pathogenesis of autosomal dominant polycystic kidney disease. 1651 28

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1, encoding polycystin-1 (PC1), or PKD2 (polycystin-2, PC2). Autosomal recessive PKD (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). No molecular link between ADPKD and ARPKD has been determined. Here, we demonstrated, by yeast two-hybrid and biochemical assays, that KIF3B, a motor subunit of kinesin-2, associates with PC2 and FPC. Co-immunoprecipitation experiments using Madin-Darby canine kidney (MDCK) and inner medullary collecting duct (IMCD) cells and human kidney revealed that PC2 and KIF3B, FPC and KIF3B and, furthermore, PC2 and FPC are endogenously in the same complex(es), though no direct association between the PC2 and FPC intracellular termini was detected. In vitro binding and Far Western blot experiments demonstrated that PC2 and FPC are in the same complex only if KIF3B is present, presumably by forming a PC2-KIF3B-FPC complex. This was supported by our observation that altering KIF3B level in IMCD cells by over-expression or siRNA significantly affected complexing between PC2 and FPC. Immunofluorescence experiments showed that PC2, FPC and KIF3B partially co-localized in primary cilia of over-confluent and perinuclear regions of sub-confluent cells. Furthermore, KIF3B mediated functional modulation of purified PC2 channels by FPC in a planer lipid bilayer electrophysiology system. The FPC C-terminus substantially stimulated PC2 channel activity in the presence of KIF3B, whereas FPC or KIF3B alone had no effect. Taken together, we discovered that kinesin-2 is a linker between PC2 and FPC and mediates the regulation of PC2 channel function by FPC. Our study may be important for elucidating common molecular pathways for PKD of different genotypes.
Hum Mol Genet 2006 Nov 15
PMID:Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin. 1700 58

Mutations in PKD1 cause dominant polycystic kidney disease (PKD), characterized by large fluid-filled kidney cysts in adult life, but the molecular mechanism of cystogenesis remains obscure. Ostrom et al. [Dev. Biol., 219, 250-258 (2000)] showed that reduced dosage of Pax2 caused increased apoptosis, and ameliorated cystogenesis in Cpk mutant mice with recessive PKD. Pax2 is expressed in condensing metanephrogenic mesenchyme and arborizing ureteric bud, and plays an important role in kidney development. Transient Pax2 expression during fetal kidney mesenchyme-to-epithelial transition, as well as in nascent tubules, is followed by marked down-regulation of Pax2 expression. Here, we show that in humans with PKD, as well as in Pkd1(del34/del34) mutant mice, Pax2 was expressed in cyst epithelial cells, and facilitated cyst growth in Pkd1(del34/del34) mutant mice. In Pkd1(del34/del34) mutant kidneys, the expression of Pax2 persisted in nascent collecting ducts. In contrast, homozygous Pkd1(del34/del34) fetal mice carrying mutant Pax2 exhibited ameliorated cyst growth, although reduced cystogenesis was not associated with increased apoptosis. Pax2 expression was attenuated in nascent collecting ducts and absent from remnant cysts of Pkd1(del34/del34)/Pax2(1Neu/+) mutant mice. To investigate whether the Pkd1 gene product, Polycystin-1, regulates Pax2, MDCK cells were engineered constitutively expressing wild-type Pkd1; Pax2 protein levels and promoter activity were both repressed in MDCK cells over-expressing Pkd1, but not in cells without transgenic Pkd1. These data suggest that polycystin-1-deficient tubular epithelia persistently express Pax2 in ADPKD, and that Pax2 or its pathway may be an appropriate target for the development of novel therapies for ADPKD.
Hum Mol Genet 2006 Dec 15
PMID:Pax2 gene dosage influences cystogenesis in autosomal dominant polycystic kidney disease. 1708 50

Autosomal dominant polycystic kidney disease (ADPKD) is estimated to affect 1/600-1/1000 individuals worldwide. The disease is characterized by age dependent renal cyst formation that results in kidney failure during adulthood. Although ultrasound imaging may be an adequate diagnostic tool in at risk individuals older than 30, this modality may not be sufficiently sensitive in younger individuals or for those from PKD2 families who have milder disease. DNA based assays may be indicated in certain clinical situations where imaging cannot provide a definitive clinical diagnosis. The goal of this study was to evaluate the utility of direct DNA analysis in a test sample of 82 individuals who were judged to have polycystic kidney disease by standard clinical criteria. The samples were analyzed using a commercially available assay that employs sequencing of both genes responsible for the disorder. Definite disease causing mutations were identified in 34 (approximately 42%) study participants. An additional 30 (approximately 37%) subjects had either in frame insertions/deletions, non-canonical splice site alterations or a combination of missense changes that were also judged likely to be pathogenic. We noted striking sequence variability in the PKD1 gene, with a mean of 13.1 variants per participant (range 0-60). Our results and analysis highlight the complexity of assessing the pathogenicity of missense variants particularly when individuals have multiple amino acid substitutions. We conclude that a significant fraction of ADPKD mutations are caused by amino acid substitutions that need to be interpreted carefully when utilized in clinical decision-making.
Mol Genet Metab
PMID:Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. 1757 68

Autosomal dominant polycystic kidney disease, caused by mutations in the PKD1 gene, is characterized by progressive deterioration of kidney function due to the formation of thousands of cysts leading to kidney failure in mid-life or later. How cysts develop and grow is currently unknown, although extensive research revealed a plethora of cellular changes in cyst lining cells. We have constructed a tamoxifen-inducible, kidney epithelium-specific Pkd1-deletion mouse model. Upon administration of tamoxifen to these mice, a genomic fragment containing exons 2-11 of the Pkd1-gene is specifically deleted in the kidneys and cysts are formed. Interestingly, the timing of Pkd1-deletion has strong effects on the phenotype. At 1 month upon gene disruption, adult mice develop only a very mild cystic phenotype showing some small cysts and dilated tubules. Young mice, however, show massive cyst formation. In these mice, at the moment of gene disruption, cell proliferation takes place to elongate the nephron. Our data indicate that Pkd1 gene deficiency does not initiate sufficient autonomous cell proliferation leading to cyst formation and that additional stimuli are required. Furthermore, we show that one germ-line mutation of Pkd1 is already associated with increased proliferation.
Hum Mol Genet 2007 Dec 15
PMID:Kidney-specific inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. 1793 18

Polycystic kidney disease (ADPKD) results from failure of the kidney to properly maintain three-dimensional structure after loss of either polycystin-1 or -2. Mice with kidney selective inactivation of Pkd1 during embryogenesis develop profound renal cystic disease and die from renal failure within 3 weeks of birth. In this model, cysts form exclusively from cells in which Cre recombinase is active, but the apparent pace of cyst expansion varies by segment and cell type. Intercalated cells do not participate in cyst expansion despite the presence of cilia up to at least postnatal day 21. Cystic segments show a persistent increase in proliferation as determined by bromodeoxyuridine (BrdU) incorporation; however, the absolute proliferative index is dependent on the underlying proliferative potential of kidney tubule cells. Components of the extracellular regulated kinase (MAPK/ERK) pathway from Ras through MEK1/2 and ERK1/2 to the effector P90(RSK) are activated in both perinatal Pkd1 and adult Pkd2 ortholgous gene disease models. The pattern of MAPK/ERK activation is focal and does not correlate with the pattern of active proliferation identified by BrdU uptake. The possibility of a causal relationship between ERK1/2 activation and cyst cell proliferation was assessed in vivo in the acute perinatal Pkd1 model of ADPKD using MEK1/2 inhibitor U0126. U0126 treatment had no effect on progression of cyst formation in this model at doses sufficient to reduce phospho-ERK1/2 in cystic kidneys. Cysts in ADPKD exhibit both increased proliferation and activation of MAPK/ERK, but cyst growth is not prevented by inhibition of ERK1/2 activation.
Hum Mol Genet 2008 Jun 01
PMID:Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. 1826 4

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic disease predominantly caused by alteration or dysregulation of the PKD1 gene, which encodes polycystin-1 (PC1). The disease is characterized by the progressive expansion of bilateral fluid-filled renal cysts that ultimately lead to renal failure. Individual cysts, even within patients with germline mutations, are genetically heterogeneous, displaying diverse chromosomal abnormalities. To date, the molecular mechanisms responsible for this genetic heterogeneity remain unknown. Using a lentiviral-mediated siRNA expression model of Pkd1 hypomorphism, we show that loss of PC1 function is sufficient to produce centrosome amplification and multipolar spindle formation. These events lead to genomic instability characterized by gross polyploidism and mitotic catastrophe. Following these dramatic early changes, the cell population rapidly converges toward a stable ploidy in which centrosome amplification is significantly decreased, though cytological abnormalities such as micronucleation, chromatin bridges and aneuploidy remain common. In agreement with our in vitro findings, we provide the first in vivo evidence that significant centrosome amplification occurs in kidneys from conditional Pkd1 knockout mice at early and late time during the disease progression as well as in human ADPKD patients. These findings establish a novel function of PC1 in ADPKD pathogenesis and a genetic mechanism that may underlie the intrafamilial variability of ADPKD progression.
Hum Mol Genet 2008 Sep 15
PMID:Loss of polycystin-1 causes centrosome amplification and genomic instability. 1856 6

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of renal, hepatic and pancreatic cysts and by non-cystic manifestations such as abnormal vasculature and embryo left-right asymmetry development. Polycystin-2 (PC2), in which mutations account for 10-15% of ADPKD, was previously shown to down-regulate cell proliferation, but the underlying mechanism was not elucidated. Here, we demonstrate that PC2, but not pathogenic mutants E837X and R872X, represses cell proliferation through promoting the phosphorylation of eukaryotic translation initiation factor eIF2alpha by pancreatic ER-resident eIF2alpha kinase (PERK). ER stress is known to enhance eIF2alpha phosphorylation through up-regulating PERK kinase activity (assessed by phosphorylated PERK). During ER stress, PC2 knockdown also repressed eIF2alpha phosphorylation but did not alter PERK phosphorylation, indicating that PC2 facilitates the eIF2alpha phosphorylation by PERK. PC2 was found to be in the same complex as PERK and eIF2alpha. Together, we demonstrate that PC2 negatively controls cell growth by promoting PERK-mediated eIF2alpha phosphorylation, presumably through physical interaction, which may underlie a pathogenesis mechanism of ADPKD and indicates that PC2 is an important regulator of the translation machinery.
Hum Mol Genet 2008 Oct 15
PMID:Polycystin-2 down-regulates cell proliferation via promoting PERK-dependent phosphorylation of eIF2alpha. 1866 56


<< Previous 1 2 3 4 5 6 7 Next >>