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Query: UNIPROT:P06889 (Mol)
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The Denys-Drash syndrome is characterised by a typical nephropathy, genital abnormalities and also predisposes to the development of Wilms' tumor. These patients eventually go into end stage renal failure. A candidate Wilms' tumor gene, WT1, from the 11p13 chromosome region has recently been cloned. We have analysed the DNA sequence in constitutional cells from eight patients and have shown heterozygous mutations in six of them. Four of the mutations were in exon 9, all resulting in missense mutations. Three were at nucleotide position 1180 resulting in an arg > trp amino acid change. The other was at position 1186 converting an asp > asn in the predicted resultant protein. One patient had a missense mutation in exon 8, converting an arg > his. A single base pair insertion at nucleotide position 821 in exon 6 resulted in the generation of a premature stop codon in the last patient. We were unable to find a mutation in one patient despite complete sequencing of the genomic sequence of the gene. The last patient carried a constitutional deletion of the 11p13 region and no additional mutation was found. There was no obvious correlation between the type of mutation and phenotypic expression. These results further demonstrate that the WT1 gene is important in both the development of the kidney and the genito-urinary system.
Hum Mol Genet 1992 Aug
PMID:Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome. 133 6

Using a cosmid clone derived from human Xq28 as a probe which shows cross-species homology, we isolated cDNA clones and the nucleotide sequence analysis of the cDNA revealed that the cDNA is identical to QM cDNA. The QM cDNA has recently been reported as a cDNA with down-regulation in tumorigenic Wilms' tumor microcell hybrid. Comparison of the nucleotide sequences of the cDNA with those of the genomic DNA allowed us to determine the genomic organization of the QM gene. The QM gene consists of at least 7 exons and is located at Xq28. Southern blot analysis of a somatic cell hybrid panel indicates that the QM genes are scattered at least to chromosome 2, 3, 6, 14, 16, and possibly to other chromosomes. Northern blot analysis demonstrated the QM gene is expressed in all the examined adult human tissues as well as cell lines including HeLa cells, fibroblasts, and somatic cell hybrids with increased expression in liver, spleen, testis, and adrenal gland. The results suggest that the QM gene belongs to a new multi-gene family with yet undetermined function.
Hum Mol Genet 1992 Oct
PMID:Genomic organization of a cDNA (QM) demonstrating an altered mRNA level in nontumorigenic Wilms' microcell hybrid cells and its localization to Xq28. 133 45

Comparative histological data suggest that papillary renal cell tumors in adults and Wilms' tumors in children develop from maturation-arrested cells of similar origin. Wilms' tumor is characterized by genetic changes at the chromosome 11p region. In the present study, we have analyzed 10 papillary and 10 non-papillary renal cell tumors and determined the allelic status of 6 loci on the short arm of chromosome 11. Only one papillary renal cell carcinoma among the 20 tumors showed a loss of constitutional heterozygosity for the chromosome 11p region. These data suggest that separate molecular events occur in the development of Wilms' tumor and papillary renal cell tumors, subsequent to the proliferation of maturation-arrested cells of the kidney.
Cell Mol Biol 1992 Feb
PMID:Molecular analysis of the chromosome 11p region in renal cell carcinomas. 134 50

We constructed cosmid libraries from human-hamster somatic cell hybrids that possess all or part of the short arm of chromosome 11 as their only human complement and isolated 129 human 11p clones. These cosmids map to 22 of 25 intervals distinguished by a hybrid panel for chromosome 11p. Forty-eight single-copy sequences were subcloned from 25 cosmids. Six of 17 (35%) single-copy sequences tested identify 11 new polymorphisms. Restriction endonuclease analysis identified CpG islands in 16 of 68 cosmids (23.5%). Analysis of the distribution of restriction endonuclease sites recognizing CpG dinucleotides showed that clusters of these sites, including those associated with the 5' region of an 11p13 Wilms' tumor gene, WT1, can span greater distances than generally recognized. The cosmids reported here should contribute to the construction of long-range physical maps and the isolation of additional genes on the short arm of chromosome 11.
Somat Cell Mol Genet 1992 Sep
PMID:Mapping and characterization of 129 cosmids on human chromosome 11p. 147 12

Many human genetic diseases, including some cancers, are characterized by consistent chromosome abnormalities, such as deletions and translocations. Analyses of these mutations often prove crucial to the eventual cloning and characterization of the gene(s) responsible for the disease. Two methods for analyzing these chromosome abnormalities have been developed in recent years: somatic cell hybridization and pulsed field gel electrophoresis (PFGE). Somatic cell hybridization is a technique for segregating an aberrant chromosome from its normal homologue in a cell derived from an unrelated species, which is usually a rodent. Panels of such hybrids dividing a given chromosomal region into increasingly smaller units can be constructed and used specifically to map DNA probes into those units. PFGE can then be used to define precise physical distances between such an array of chromosome abnormalities. Demonstrations of these analytic techniques are presented, using as an example chromosomal abnormalities involving human chromosome band 11p13, the locus for the Wilms' tumor, aniridia, genitourinary abnormality, and mental retardation (WAGR) syndrome.
Environ Mol Mutagen 1991
PMID:Molecular analysis of chromosomal rearrangements using pulsed field gel electrophoresis and somatic cell hybrids. 166 Aug 7

The human Wilms' tumor predisposition gene, WT1, is a Cys-His zinc finger polypeptide which appears to be a transcription factor controlling gene expression during embryonic kidney development. In order to analyze the role of the WT1 gene in nephroblast differentiation, we have isolated the murine homolog of human WT1. An extremely high level of amino acid sequence conservation (greater than 95%) extends throughout all regions of the predicted mouse and human WT1 polypeptides. Two alternative splices within the WT1 transcript have been conserved between mice and humans, suggesting that these have functional significance. Expression of the mouse WT1 mRNA in fetal kidney increases during late gestation, peaks just prior to or shortly after birth, and declines dramatically by 15 days postpartum. Developmental regulation of WT1 expression appears to be selective for the kidney. The restriction of WT1 expression to a limited number of tissues is in contrast to previously described tumor suppressor genes. In addition, the narrow window of time during which WT1 is expressed at high levels in the kidney is consistent with the origin of Wilms' tumor from primitive nephroblasts and the postulated role of this gene as a negative regulator of growth.
Mol Cell Biol 1991 Mar
PMID:Isolation, characterization, and expression of the murine Wilms' tumor gene (WT1) during kidney development. 167 9

A high frequency of point mutations at codon 12 of the Ki-ras gene has previously been reported for rat kidney mesenchymal tumors induced by methylating N-nitroso compounds. In this study, we analyzed renal tumors with divergent histogenesis, i.e., mesenchymal tumors (sarcomas), cortical epithelial tumors (carcinomas), and embryonal tumors (nephroblastomas). Renal mesenchymal tumors and carcinomas were induced in juvenile or young adult Wistar rats by a single dose of N-nitrosodimethylamine (NDMA) while nephroblastomas were induced in Nb hooded rats by a single transplacental dose of N-nitrosoethylurea (NEU). Nephroblastomas developing spontaneously in WAB/Not rats were also examined. Amplification of Ki-ras sequences from formalin-fixed, paraffin-embedded tissue by the polymerase chain reaction was followed by direct DNA sequencing. GGT----GAT point mutations at codon 12 of the Ki-ras gene were found in 9 of 12 (75%) renal mesenchymal tumors and in 9 of 12 (75%) cortical epithelial tumors induced by NDMA. Even higher incidences were observed in nephroblastomas (8/8; 100%) induced by NEU and in spontaneous nephroblastomas (10/11; 91%). These results indicate that Ki-ras mutations are frequent events during the development of kidney tumors irrespective of their histogenesis and suggest that they may play an important role in renal carcinogenesis in rats. These data further indicate that mutational activation of Ki-ras proto-oncogenes in carcinogen-induced rat kidney tumors occurs in a tissue-specific, rather than cell-specific, manner.
Mol Carcinog 1991
PMID:Ki-ras mutations in spontaneous and chemically induced renal tumors of the rat. 179 84

The complete nucleotide sequence derived from a genomic clone and two cDNA clones of the creA gene of Aspergillus nidulans is presented. The gene contains no introns. The derived polypeptide of 415 amino acids contains two zinc fingers of the C2H2 class, frequent S(T)PXX motifs, and an alanine-rich region indicative of a DNA-binding repressor protein. The amino acid sequence of the zinc finger region has 84% similarity to the zinc finger region of Mig1, a protein involved in carbon catabolite repression in yeast cells, and it is related both to the mammalian Egr1 and Egr2 proteins and to the Wilms' tumor protein. A deletion removing the creA gene was obtained, by using in vitro techniques, in both a heterokaryon and a diploid strain but was unobtainable in a pure haploid condition. Evidence is presented suggesting that the phenotype of such a deletion, when not complemented by another creA allele, is leaky lethality allowing limited germination of the spore but not colony formation. This phenotype is far more extreme than that of any of the in vivo-generated mutations, and thus either the gene product may have an activator activity as well as a repressor function or some residual repressor function may be required for full viability.
Mol Cell Biol 1991 Nov
PMID:Analysis of the creA gene, a regulator of carbon catabolite repression in Aspergillus nidulans. 192 72

We present evidence that differences in the levels of N-myc mRNA among different cell types are the result of posttranscriptional control. First, we noted that while steady-state mouse N-myc mRNA could be detected only in fetal mouse brain, it was transcribed at an equivalent rate in adult brain, liver, spleen, and placenta and in fetal brain. Similarly, the human N-myc gene was transcribed at an equivalent rate in HeLa cells, which do not accumulate this RNA in the cytoplasm, and cell lines G401 (a Wilms tumor-derived cell line) and SKNMc (established from a primitive neuroepithelioma), which do express N-myc RNA. As expected, the N-myc promoter functioned at equivalent rates, as demonstrated by the level of a reporter gene, when introduced into these cell types by using a recombinant adenovirus vector. The suggestion that posttranscriptional mechanisms control the level of this RNA was supported by the observation that sequences in the N-myc third exon specifically decreased the level of E1A mRNA when these sequences were placed downstream of the E1A promoter in a recombinant adenovirus. Finally, we further localized these sequences to a 600-bp fragment of the third exon by introducing various subclones of this sequence downstream of the E1A promoter in both viral and plasmid vectors.
Mol Cell Biol 1990 Dec
PMID:Regulation of N-myc gene expression: use of an adenovirus vector to demonstrate posttranscriptional control. 214 26

Children with associated Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome) frequently have a cytogenetically visible germ line deletion of chromosomal band 11p13. In accordance with the Knudson hypothesis of two-hit carcinogenesis, the absence of this chromosomal band suggests that loss of both alleles of a gene at 11p13 causes Wilms' tumor. Consistent with this model, chromosomes from sporadically occurring Wilms' tumor cells frequently show loss of allelic heterozygosity at polymorphic 11p15 loci, and therefore it has been assumed that allelic loss extends proximally to include 11p13. We report here that in samples from five sporadic Wilms' tumors, allelic loss occurred distal to the WAGR locus on 11p13. In cells from one tumor, mitotic recombination occurred distal to the gamma-globin gene on 11p15.5. Thus, allelic loss in sporadic Wilms' tumor cells may involve a second locus on 11p.
Mol Cell Biol 1989 Apr
PMID:Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumor cells. 254 77


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