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)

We have looked for disease-causing mutations in the PKD1 gene in 20 unrelated ADPKD probands from northern Italy, all members of families in which our previous studies had indicated linkage to PKD1. Using PCR with primer pairs located in the 3' unique region of the gene and heteroduplex DNA analysis, we have detected novel aberrant bands in five affected individuals from the same family, which were absent in 13 other unaffected family members. Cloning and automated DNA sequencing revealed a C to T transition at nucleotide position 3817 of the published cDNA sequence, which created a premature stop codon. The mutation destroyed a MspA1I restriction site, and the abnormal restriction pattern was observed on genomic DNA from all the affected family members. RT-PCR and restriction analysis performed on peripheral white blood cell mRNA showed that in the affected members, both the mutant and the normal transcript are represented. This mutation was not found in the probands of the other families studied. To our knowledge, this is the first nonsense mutation described in the PKD1 gene.
Hum Mol Genet 1995 Aug
PMID:A novel nonsense mutation in the PKD1 gene (C3817T) is associated with autosomal dominant polycystic kidney disease (ADPKD) in a large three-generation Italian family. 758 71

Reactive oxygen species are generated physiologically in cells with a significant increase in certain pathological conditions, such as inflammation, cancer, aging, degenerative disease. If endogenous antioxidant systems, in our study represented by glutathione peroxidase, are exceeded by this oxidant flux, tissue injury may occur. Activity of glutathione peroxidase (GPx) was determined using Beutler's modified spectrophotometric assay in erythrocytes from autosomal dominant polycystic kidney disease patients. Activity of glutathione peroxidase was significantly (at p < 0.0001) lower there (17.75 +/- 3.69 U/g haemoglobin) compared to the control group (23.26 +/- .61 U/g Hb). Lower antioxidant enzyme defence system of ADPKD patients, here represented by GPx, can potentiate injury caused by free radicals and possibly play a role in the progression of autosomal dominant polycystic kidney disease.
Biochem Mol Biol Int 1995 Apr
PMID:Activity of the antioxidant enzyme, glutathione peroxidase, on autosomal dominant polycystic kidney disease patients. 762 19

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease which frequently results in renal failure. The major ADPKD gene, polycystic kidney disease 1 (PKD1), has recently been identified. In an attempt to understand better the aetiology of this disorder we have searched for mutations in the PKD1 gene. Analysis of three regions in the 3' part of the gene has revealed two mutations that occur by a novel mechanism. Both mutations are deletions (of 18 or 20 bp) within the same 75 bp intron and although these deletions do not disrupt the splice donor or acceptor sites at the boundary of the intron, they nevertheless result in aberrant splicing. Two different transcripts are produced in each case; one includes the deleted intron while the other has a 66 bp deletion due to activation of a cryptic 5' splice site. No normal product is generated from the deleted gene. Aberrant splicing probably occurs because the deleted intron is too small for spliceosome assembly using the authentic splice sites; this mechanism has previously only been described from in vitro studies of vertebrate genes. A 9 bp direct repeat has been identified within the intron, which probably facilitated deletion by promoting misalignment of sequence. The possible phenotypic implications of producing more than one aberrant PKD1 transcript in these cases are discussed.
Hum Mol Genet 1995 Apr
PMID:Splicing mutations of the polycystic kidney disease 1 (PKD1) gene induced by intronic deletion. 763 5

Autosomal dominant polycystic kidney disease (ADPKD) is the most common single gene disorder resulting in renal failure. It is generally an adult onset disease, but rarely, cases of severe childhood polycystic disease arise in ADPKD families. The clear clinical anticipation in these pedigrees has led to the suggestion that the mutation may be an unstable trinucleotide repeat. We have now identified a nonsense mutation, Tyr3818Stop, in one such family (P117) within the major ADPKD gene, polycystic kidney disease 1 (PKD1). The mutation is shown to be a de novo change in the father, and of grandpaternal origin. PKD1 manifests as typical adult onset disease in the father, but is seen as severe disease, detected as enlarged polycystic kidneys in utero, in one of a pair of dizygotic twins; the other twin has the mutation but no evidence of cysts, consistent with an adult onset disease course. The finding of the same stable mutation associated with very different disease severity in this family indicates that phenotypic variation in PKD1 is not due to a dynamic mutation. It seems most likely that a small number of modifying factors may radically affect the course of disease in PKD1; identification of such factors will have important prognostic implications in this disorder.
Hum Mol Genet 1996 Apr
PMID:A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1). 884 49

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common single gene diseases in humans. We have identified a synonymous T to C transition polymorphism in exon 46 of the PKD1 gene (12838T-->C, Pro4209Pro). The polymorphism was present with similar frequencies in ADPKD patients and unaffected individuals. The heterozygosity, determined in 89 Italian individuals, was 0.347. The frequency of the rarer allele was 0.222. This polymorphism is easy to determine as it abolishes a naturally occurring Ddel restriction site. The availability of an additional intragenic marker in the PKD1 gene will improve the accuracy of linkage studies in ADPKD families.
Mol Cell Probes 1996 Dec
PMID:A common polymorphism in exon 46 of the human autosomal dominant polycystic kidney disease 1 gene (PKD1). 902 84

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cystic tubule enlargement and expansion of the interstitium associated with fibrosis. Our previous studies have analyzed the increased proliferation of cystic epithelial cells and this study examines the basis of increased proliferation of interstitial fibroblasts associated with ADPKD disease progression. ADPKD fibroblasts show phenotypic alterations in vitro, have acquired the capacity to grow in soft agar, and show an increased mitogenic response to a variety of growth factors particularly acidic FGF (aFGF). ELISA, Western immunoblot analysis, and immunocytochemistry showed increased aFGF content in ADPKD tissues and fibroblasts in culture, and aFGF was secreted into the extracellular matrix and conditioned medium, respectively. No alterations in aFGF receptor number were found, but Scatchard analysis of 125I-aFGF binding suggested an increased affinity of binding to the low affinity receptor, and covalent cross-linking analysis suggested the presence of novel putative receptors (120 kDa) in ADPKD fibroblasts. Signaling abnormalities were found, since aFGF incubation resulted in the tyrosine phosphorylation of additional substrates, more rapidly and for a more sustained duration in ADPKD fibroblasts than in normal fibroblasts. These findings suggest an important role for acidic FGF in the hyperproliferation of interstitial fibroblasts associated with disease progression in human ADPKD.
Biochem Mol Med 1997 Aug
PMID:Acidic FGF regulation of hyperproliferation of fibroblasts in human autosomal dominant polycystic kidney disease. 925 83

Autosomal dominant polycystic kidney disease (ADPKD), Type I is a common genetic disorder and an important cause of renal failure. The disease is characterized by progressive cyst formation in a variety of organs including the kidney, liver and pancreas. We have previously shown that in the case of PKD1, renal cyst development is likely to require somatic inactivation of the normal allele coupled to a germline PKD1 mutation. In this report, we have used unique reagents to show that intragenic, somatic mutations are common in hepatic cysts. All pathogenic mutations were shown to have altered the previously normal copy of the gene. These data extend the "two-hit" model of cystogenesis to include a second focal manifestation of the disease.
Mol Cell 1998 Aug
PMID:Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease. 973 62

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder with progressive distension of multiple tubular segments, and is manifested by fluid accumulation, growth of epithelial cells, and remodeling of the extracellular matrix, ultimately resulting in renal insufficiency in one half of affected individuals. The process causing the progressive loss of renal tissue is unclear. Recent studies demonstrate that apoptosis is one of the major histopathologic features of ADPKD and may be causally related to the progressive deterioration of the renal function in this population. Further studies are required to elucidate the mechanisms by which some cysts upregulate the process of programmed cell death in the kidney.
Diagn Mol Pathol 1998 Apr
PMID:Pathogenesis of autosomal dominant polycystic kidney disease: role of apoptosis. 978 3

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in one of three genes: PKD1 on chromosome 16 accounts for approximately 85% of cases whereas PKD2 on chromosome 4 accounts for approximately 15%. Mutations in the PKD3 gene are rare. All patients present with similar clinical phenotypes, and the cardinal symptom is the formation of fluid-filled cysts in the kidneys. Previous work has provided data supporting the notion that cysts in ADPKD1 are focal in nature and form after loss of function of polycystin 1. This became evident by demonstrating that the normal PKD1 allele was inactivated somatically by loss of heterozygosity or by mutagenesis in a subset of renal or liver cysts examined. We show in this report, for the first time, multiple novel somatic mutations within the PKD2 gene of epithelial cells, in both kidneys of an ADPKD2 patient. From a total of 21 cysts examined, seven (33%) had the same C insertion within the inherited wild-type allele. In two other cysts, a nonsense mutation and a splice site AG deletion had occurred in a PKD2 allele that could not be identified as the inherited wild-type or mutant. We suggest that the autosomal dominant form of ADPKD2 occurs by a cellular recessive mechanism, supporting a two-hit model for cyst formation.
Hum Mol Genet 1999 Mar
PMID:Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease. 994 10

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germ line mutations in at least three ADPKD genes. Two recently isolated ADPKD genes, PKD1 and PKD2, encode integral membrane proteins of unknown function. We found that PKD2 upregulated AP-1-dependent transcription in human embryonic kidney 293T cells. The PKD2-mediated AP-1 activity was dependent upon activation of the mitogen-activated protein kinases p38 and JNK1 and protein kinase C (PKC) epsilon, a calcium-independent PKC isozyme. Staurosporine, but not the calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N', N'-tetraacetate], inhibited PKD2-mediated signaling, consistent with the involvement of a calcium-independent PKC isozyme. Coexpression of PKD2 with the interacting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 activation. The synergistic signaling between PKD1 and PKD2 involved the activation of two distinct PKC isozymes, PKC alpha and PKC epsilon, respectively. Our findings are consistent with others that support a functional connection between PKD1 and PKD2 involving multiple signaling pathways that converge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. Activation of these signaling cascades may promote the full maturation of developing tubular epithelial cells, while inactivation of these signaling cascades may impair terminal differentiation and facilitate the development of renal tubular cysts.
Mol Cell Biol 1999 May
PMID:Cellular activation triggered by the autosomal dominant polycystic kidney disease gene product PKD2. 1020 66


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