Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Constitutional point mutations in the zinc finger (ZF) region of the Wilms' tumour suppressor gene 1 (WT1) lead to Denys-Drash syndrome (DDS). Patients with this syndrome display renal failure, Wilms' tumour (WT) and pseudohermaphroditism. DDS WT1 mutations fall into three major categories: (a) missense mutations altering amino acids which directly interact with the DNA target; (b) substitution of amino acids involved in zinc complexing; and (c) nonsense mutations leading to the removal of at least two zinc fingers. We have expressed the WT1 zinc fingers as glutathione-S-transferase fusion proteins, with the lysine-threonine-serine (KTS) alternate splice between ZF3 and ZF4 either present or absent. WT1 fusion constructs with all three classes of DDS mutation were also created. Wild-type and mutant fusion proteins were assayed for their DNA-binding affinity using four previously identified WT1 DNA targets: an EGR1 consensus site; murine insulin-like growth factor 2 promoter 2 (IGF2P2); a (TCC)n motif from the PDGFA-chain promoter; and +P5, a genomic fragment isolated by its affinity for WT1 + KTS. WT1-KTS bound all four targets, but WT1 + KTS only bound +P5. All three classes of DDS mutation investigated, with or without KTS, abolished binding to all four targets. This provides evidence that DDS mutations act either as dominant-negative antimorphs, or elicit their effect through disturbed isoform dosage balance.
Hum Mol Genet 1995 Mar
PMID:DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations. 779 87

To determine the Na+/K+ ATPase independent 22Na+ influx into erythrocytes (E) from normal subjects (N), from essential hypertensive patients (EH), and from renal failure patients with secondary hypertension (SH), these studies involved two assay conditions. The erythrocyte suspensions were incubated for 30 minutes at 37 degrees C under two assay conditions: (i) with assay buffers containing 5mEq/L KC1 and varying amounts of NaCl (5 to 100 mEq/L) and (ii) with assay buffers with a range of KC1 (5 to 100 mEq/L) and a constant amount of 5 mEq/L NaCl. The ouabain insensitive percent uptake of 22Na+ in 2 x 10(9) E/mL from N, EH, and SH were 2.77 +/- 0.34, 4.37 +/- 0.83, and 3.72 +/- 0.60, respectively, when the assay media contained equimolar amounts of NaCl and KC1 (5 mEq/L each). The 22Na+ uptake was decreased gradually by progressive increasing concentrations of NaCl or of KC1 in the assay media. When erythrocytes were incubated in assay buffers containing either 50mEq/L NaCl with 5 mEq/L KC1 and 50 mEq/L KC1 with 5 mEq/L NaCl, the relative percentages of 22Na+ uptake in erythrocytes became significantly increased [65% increases in EH, 17% increases in SH over that in N subjects, 41% increases in EH over that of SH subjects; and, 49% increases in EH, 23% increases in SH other than in N subjects, 21% increases in EH over that of SH subjects, respectively]. None of the other assay media showed such differences in the 22Na+ uptake values.(ABSTRACT TRUNCATED AT 250 WORDS)
Biochem Mol Biol Int 1994 Oct
PMID:Sodium-22 uptake in erythrocytes can differentiate between the essential and the secondary hypertensive patient. 783 33

Dent's disease, an X-linked renal tubular disorder, is a form of Fanconi syndrome which is characterized by proteinuria, hypercalciuria, nephrocalcinosis, kidney stones and renal failure. Previous studies localised the gene responsible to Xp11.22, within a microdeletion involving the hypervariable locus DXS255. Further analysis using new probes which flank this locus indicate that the deletion is less than 515 kb. A 185 kb YAC containing DXS255 was used to screen a cDNA library from adult kidney in order to isolate coding sequences falling within the deleted region which may be implicated in the disease aetiology. We identified two clones which are evolutionarily conserved, and detect a 9.5 kb transcript which is expressed predominantly in the kidney. Sequence analysis of 780 bp of ORF from the clones suggests that the identified gene, termed hCIC-K2, encodes a new member of the CIC family of voltage-gated chloride channels. Genomic fragments detected by the cDNA clones are completely absent in patients who have an associated microdeletion. On the basis of the expression pattern, proposed function and deletion mapping, hCIC-K2 is a strong candidate for Dent's disease.
Hum Mol Genet 1994 Nov
PMID:Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis). 787 26

Polycystic kidney disease (PKD) is characterized by multiple renal cysts, which ultimately result in renal failure. We have reported the identification of a new gene, Ke 6, within the major histocompatibility complex, which is downregulated in two different mouse models of heritable PKD (N. Aziz, M. Maxwell, B. St.-Jacques, and B.M. Brenner. Mol. Cell. Biol. 13: 1847-1853, 1993). The Ke 6 gene gives rise to two transcripts, Ke 6a and Ke 6b. Ke 6a protein has significant homology to several mammalian and bacterial steroid dehydrogenases. The homology of Ke 6a protein to specific functional domains of the human and rat 11 beta-hydroxysteroid dehydrogenase enzyme (11 beta-HSD), which inactivates glucocorticoids, is substantial. We report here that the Ke 6 gene and the 11 beta-HSD gene are regulated in the same aberrant pattern in the cpk mouse. The strong evidence for a critical role of steroids in cystogenesis leads us to propose that a possible elevation of intrahepatic and intrarenal steroid levels occurs in the cpk mouse as a result of repression of steroid metabolic enzymes, which ultimately leads to development of cysts.
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PMID:Coordinate regulation of 11 beta-HSD and Ke 6 genes in cpk mouse: implications for steroid metabolic defect in PKD. 797 82

Dent's disease is a familial proximal renal tubular disorder which is associated with low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, kidney stones and renal failure. The mode of inheritance and the primary defect for this disorder are unknown. An analysis of 5 unrelated British families revealed a greater disease severity in males and an absence of male to male transmission. This suggested an X-linked inheritance and we investigated this further by linkage studies in 33 members (12 affected, 21 unaffected) from two 3-generation families. Twenty X-linked polymorphic markers were used and linkage was established with the Xp11 loci ARAFI, DXS426, DXS255 and DXS988 with peak LOD scores and recombination fractions (theta) of 5.42 (theta = 0.000), 3.61 (theta = 0.000), 5.48 (theta = 0.000) and 4.25 (theta = 0.045) respectively. In addition, DXS255 revealed a microdeletion in the affected members of one family, thereby further localising Dent's disease to Xp11.22. Combined multilocus linkage analysis and deletion mapping studies defined the locus order Xpter-MAOB-(ARAFI, DXS426)-SYP-TFE3-(DXS255, DENT'S)-DXS988-Xcen, thereby mapping the microdeletion associated with Dent's disease to a 4 centiMorgan interval flanked by TFE3 and DXS988. Thus, Dent's disease is an X-linked disorder which is associated with a microdeletion of Xp11.22, and a further characterisation of this gene will help to elucidate the factors controlling proximal renal tubular function and the development of kidney stones.
Hum Mol Genet 1993 Dec
PMID:Dent's disease, a renal Fanconi syndrome with nephrocalcinosis and kidney stones, is associated with a microdeletion involving DXS255 and maps to Xp11.22. 811 83

Polycystic kidney disease (PKD) is characterized by progressive enlargement of the kidneys due to numerous expanding cysts ultimately leading to renal failure. We have identified a gene, Ke 6, located within the H-2K/tw5 region on mouse chromosome 17, which is downregulated in two distinct murine models of heritable PKD. Ke 6 is a member of the short-chain alcohol dehydrogenase family and possess remarkable amino acid sequence conservation with several bacterial proteins with oxidoreductase function. The Ke 6 gene gives rise to two transcripts--a 1-kb Ke 6a mRNA which is abundant in kidney and liver tissue and a 1.4-kb Ke 6b mRNA which is found at a moderate level in spleen tissue. We report here the complete nucleotide sequence of Ke 6a cDNA and the expression of the Ke 6 gene in murine models of PKD. The Ke 6 gene may be intimately involved in the manifestation of these cystic kidney diseases.
Mol Cell Biol 1993 Mar
PMID:Downregulation of Ke 6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease. 844 17

The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its high expression in the thymus and spleen and the presence of DNA binding sites for Fli-1 in a number of lymphoid cell-specific gene suggest that Fli-1 is involved in the regulation of lymphopoiesis. Activation of the Fli-1 gene by either chromosomal translocation or viral insertion leads to Ewing's sarcoma in humans and erythroleukemia in mice, respectively. Thus, Fli-1 is normally involved in pathways involved in the regulation of cell growth and differentiation. We have generated H-2Kk-Fli-1 transgenic mice that overexpress Fli-1 in various mouse tissues, with the highest levels of Fli-1 protein in the thymus and spleen. These Fli-1 transgenic mice developed a high incidence of a progressive immunological renal disease and ultimately died of renal failure caused by tubulointerstitial nephritis and immune-complex glomerulonephritis. The incidences of renal disease correlated with the levels of Fli-1 protein in lymphoid tissues of transgenic lines. The hypergammaglobulinemia, splenomegaly, B-cell hyperplasia, accumulation of abnormal CD3+ B220+ T lymphoid cells and CD5+ B220+ B cells in peripheral lymphoid tissues, and detection of various autoantibodies in the sera of diseased Fli-1 transgenic mice suggested the involvement of an immune dysfunction in the pathogenesis of the renal disease. In addition, splenic B cells from transgenic mice exhibited increased proliferation and prolonged survival in vitro in response to mitogens. Taken together, these data suggest that overexpression or ectopic expression of Fli-1 perturbs normal lymphoid cell function and programmed cell death. Thus, H-2Kk-Fli-1 transgenic mice may serve as a murine model for autoimmune disease in humans, such as systemic lupus erythematosus.
Mol Cell Biol 1995 Dec
PMID:An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes. 852 63

Idiopathic nephrotic syndrome (INS) in childhood is characterized by massive proteinuria and minimal glomerular changes. Most patients with INS respond to steroid therapy. INS is generally regarded as a sporadic disease with favorable outcome. We investigated a distinct subgroup of nephrosis--the familial form of steroid resistant INS (SRN). These patients always progress to end-stage renal failure within a few years and show absence of recurrence of the disease after renal transplantation. The occurrence of the disorder in siblings and the high incidence of inbreeding in these families made an autosomal recessive mode of inheritance very likely. We performed whole genome linkage analysis in nine multiplex families of European or Northern African origin. Our results allowed us to assign a disease locus (SRN1) to a defined chromosomal region on 1q25-1q31, thus confirming the existence of a distinct entity of autosomal recessive nephrosis. Exclusion of linkage to the entire region in one family proves genetic heterogeneity.
Hum Mol Genet 1995 Nov
PMID:Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. 858 95

The aim of this study was to highlight a possible new non-aluminum phosphate-binder to limit hyperphosphatemia in patients with renal failure. Lanthanum chloride hydrate was evaluated as a dietary phosphate binder in rats. Aluminum chloride hexahydrate was evaluated as a reference. Animals were divided in five groups (6 animals per group): 1 control group (C), 2 aluminum groups (Al1 and Al2), receiving different doses of aluminum chloride hexahydrate and 2 lanthanum groups (La1 and La2), receiving different doses of lanthanum chloride hydrate. During the treatment, urine and stools were collected. At the end of the treatment animals were sacrificed and plasma and different organs were collected (liver, spleen, kidneys, brain and femur). To highlight the possible transfer of lanthanum in rat tissues, a long-term (100 days) study was carried with a high dose. At the end of the treatment, lanthanum determinations were carried out on several tissues (liver, spleen, kidneys, brain, femur and lungs). Determinations of phosphorus and calcium levels in plasma indicated that lanthanum chloride hydrate showed as good results as aluminum chloride hexahydrate. Lanthanum chloride hydrate significantly (p < 0.01) reduced the bone phosphorus burden. Decreases of urinary excretion and increases in fecal excretion of phosphorus indicated a severe phosphorus depletion in all treatments (Al and La). Unfortunately, in the long-term study, lanthanum traces could only be determined in the different tissues but not in plasma. However, in comparison with the equivalent aluminum treatment, the transfer of lanthanum was less important than aluminum transfer. Consequently, lanthanum could provide a possible alternative to aluminum.
Res Commun Mol Pathol Pharmacol 1995 Sep
PMID:A possible non-aluminum oral phosphate binder? A comparative study on dietary phosphorus absorption. 868 Aug 6

1. The endothelins (ETs) are potent vasoactive peptides which are involved in diverse biological processes, such as contraction, neuromodulation, and neurotransmission, as well as in certain pathophysiological conditions including cardiac and renal failure. 2. The diversity of action of ETs may be attributed to (i) the existence of a number of receptor subtypes, and (ii) the G-protein-mediated activation of different signal transduction pathways. 3. The combined action of these two variables modulates the response, since different receptor subtypes can stimulate and/or inhibit the cAMP and cGMP cascades.
Cell Mol Neurobiol 1995 Oct
PMID:Endothelin receptor heterogeneity, G-proteins, and signaling via cAMP and cGMP cascades. 871 41


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