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The Wilms tumor suppressor gene WT1 is essential for early urogenital development: homozygous mutations in WT1 result in embryonic lethality due to a failure in the development of kidneys and gonads. In the adult kidney, WT1 expression is limited to the glomerular podocytes. Several human nephrotic diseases arise from mutations of the WT1 gene, including mutations that affect its zinc-fingers and alternative splicing of +/-KTS isoforms. These include WAGR (for Wilms tumor, aniridia, genitourinary anomalies, and mental retardation), and Frasier and Denys-Drash syndromes. Recent advances including the development of transgenic mouse models and conditionally immortalized podocyte cell lines are beginning to shed light on WTI's crucial role in podocyte function.

Byline: M. Salem (1), Y. Kinoshita (1), T. Tajiri (1), R. Souzaki (1), K. Tatsuta (1), M. Higashi (1), T. Izaki (1), K. Kohashi (2), M. Tsuneyoshi (2), T. Taguchi (1) Keywords: Wilms tumor; HER2; Epithelial; Blastemal; Mesenchymal Abstract: Human epidermal growth factor receptors (HER) play a critical role in the branching morphogenesis of renal tubules. In the current study, we analyzed the expression of HER2 in Wilms tumor and assessed the role of this gene in the tumorgenesis of Wilms tumor. During the period from 1960 to 2005, 40 patients with Wilms tumor were treated in our department. Twenty-four of those patients (except those with clear cell sarcoma of the kidney and malignant rhabdoid tumor of the kidney) were collected and assessed. The histological component of each Wilms tumor was divided into three categories (epithelial, blastemal, and mesenchymal) and the extent of HER2 protein expression was analyzed immunohistochemically. The normal kidney tissue accompanied with 12 cases of Wilms tumor was also examined. In the normal kidney, HER2 showed a strong immunoreactivity in the cell membranes of the collecting tubules and in the endothelial cells. Of 24 cases, 15 cases showed an epithelial component, while 24 cases had a blastemal component and 21 cases had a mesenchymal component, respectively. Among the 15 specimens with epithelial cell differentiation, eight (53.3%) showed HER2 immunoreactive epithelial cells. HER2 immunoreactive blastemal cells were present in 11 (45.8%) of 24 specimens with blastemal cells. On the other hand, only 3 (14.3%) of 21 specimens containing mesenchymal cells showed HER2 immunoreactivity. These results suggest that the extent of HER2 expression is associated with epithelial differentiation in Wilms tumor. These histological findings may therefore help to explain the development of Wilms tumor from the standpoint of histological differentiation. Author Affiliation: (1) Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan (2) Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan Article History: Registration Date: 01/08/2006 Online Date: 25/08/2006

Abstract The WT1 gene encodes a zinc finger transcription factor involved in kidney and gonadal development and, when mutated, in the occurrence of kidney tumor and glomerular diseases. Patients with [...]

Byline: Lei Shao (1), D. Ashley Hill (2), Elizabeth J. Perlman (3) Keywords: Bcl-2; CD34; clear cell sarcoma of the kidney; mesoblastic nephroma,WT-1; Wilms tumor Abstract: The confident diagnosis of renal spindle cell tumors in children is often difficult. An immunohistochemical study of WT-1, Bcl-2, and CD34 was performed to determine their expression profiles and to assess the potential utility of these immunohistochemical markers in the differential diagnosis of 36 cases of renal spindle cell tumors of childhood. The cases included 11 stromal predominant Wilms tumors, 12 cellular mesoblastic nephromas, 9 clear cell sarcomas of the kidney (CCSK), and 4 monophasic synovial sarcomas. WT-1 was uniformly positive in primitive undifferentiated stromal Wilms tumors (6 of 6) and negative in the differentiating and differentiated stromal elements of Wilms tumors (0 of 5). WT-1 was also negative in cellular mesoblastic nephromas (0 of 12), CCSKs (0 of 12), and synovial sarcomas (0 of 4). Bcl-2 was expressed in all stromal Wilms tumors (11 of 11), all synovial sarcomas (4 of 4), some CCSKs (4 of 9), and none of the cellular mesoblastic nephromas (0 of 12). Although CD34 was absent in the tumor cells of all the tumors studied (0 of 36), CD34 immunohistochemistry nicely demonstrated the evenly distributed septal capillaries characteristic of CCSK in all 9 cases of this tumor. We conclude that a combination of WT-1 and Bcl-2 immunohistochemistry may aid in the distinction of stromal Wilms tumor, monophasic synovial sarcoma, cellular mesoblastic nephroma, and CCSK. Author Affiliation: (1) Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, 2401 Gillham Road, Suite 2567, Kansas City, MO, 64108, USA (2) Department of Pathology and Immunology, Washington University Medical Center, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA (3) Department of Pathology and Laboratory Medicine, Children's Memorial Medical Center, 2300 Children's Plaza, Box 17, Chicago, IL, 60614, USA Article History: Registration Date: 01/01/2004 Received Date: 12/04/2004 Accepted Date: 13/07/2004 Online Date: 08/11/2004

The Wilms' tumor suppressor gene, Wt1, encodes a transcription factor critical for development of the urogenital system. To identify lineages within the developing urogenital system that have a cell-autonomous requirement for Wt1, chimeric mice were generated from, Wt1-null ES cells. Males with large contributions of Wt1-/- cells showed hypoplastic and dysgenic testes, with seminiferous tubules lacking spermatogonia. Wt1-null cells contributed poorly to both somatic and germ cell lineages within the developing gonad, suggesting an unexpected role for Wt1 in germ cell development in addition to a role in the development of the somatic lineages of the gonad. Wt1 expression was detected in embryonic germ cells beginning at embryonic day 11.5 after migrating primordial germ cells (PGCs) have entered the gonad. Germ cells isolated flora Wt1-null embryos showed impaired growth in culture, further demonstrating a role for Wt1 in germ cell proliferation or survival. Therefore, Wt1 plays important, and in some cases previously unrecognized, roles in multiple lineages during urogenital development. Keywords: Wt1; Germ cells; Gonadal development

Byline: Ryuji Fukuzawa (1), Rosemary W. Heathcott (1), Makoto Sano (2), Ian M. Morison (1), Kankatsu Yun (3), Anthony E. Reeve (1) Keywords: Bcl-2; beta-catenin; nephroblastoma; WT1 Abstract: Wilms tumors with WT1 mutations [WT1(-)] have a stromal-predominant histology with varying extents of rhabdomyogenesis. These tumors also frequently have mutations in the beta-catenin gene (CTNNB1). We have investigated the molecular events that may explain the origins of rhabdomyogenesis in WT1(-) tumors. Of 35 Wilms tumors, we identified 12 with WT1 mutations, of which 9 carried CTNNB1 mutations. We compared WT1 wild-type tumors [WT1(+)] with WT1(-) tumors for histological features, localization of beta-catenin, Bcl-2 expression, and apoptosis using an in-situ end-labeling technique. WT1(+) tumors showed triphasic and blastemal- and epithelial predominant-histology. Expression of WT1, beta-catenin, and Bcl-2 recapitulated those of normal kidney epithelial development. Localization of beta-catenin was observed in the cytoplasm and cytoplasmic membrane of early glomerular epithelial structures. Bcl-2 is also expressed in condensing blastema and early glomerular epithelial structures which had little apoptosis. WT1(-) tumors, regardless of whether CTNNB1 mutations were detected or not, showed a stromal-rich phenotype with abundant expression of beta-catenin in the nucleus of the rhabdomyoblasts. Bcl-2 was expressed in rhabdomyoblasts, but not in blastemal cells undergoing apoptosis, suggesting that WT1 regulates Bcl-2 positively in the epithelial pathway, but negatively in the myogenic pathway. These data indicate that mutations in WT1 might alter the Wnt signaling pathway and Bcl-2 related-apoptosis. In WT1(-) tumors, the nuclear accumulation of beta-catenin and Bcl-2 expression are associated with rhabdomyogenesis, and dysregulation of Bcl-2 may be a mechanism by which the histogenesis (loss of blastemal component, muscle differentiation) may be explained. Author Affiliation: (1) Department of Biochemistry, Cancer Genetics Laboratory, University of Otago, P.O. Box 56, Dunedin, New Zealand (2) Department of Pathology, Nihon University School of Medicine, 30-1 Ohyaguchi-kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan (3) Department of Pathology, University of Otago, P.O. Box 193, Dunedin, New Zealand Article History: Registration Date: 01/01/2003 Received Date: 06/03/2003 Accepted Date: 29/07/2003 Online Date: 04/03/2004

Byline: Noel A. Brownlee (1), Debra J. Hazen-Martin (1), A. Julian Garvin (2), Gian G. Re (1) Keywords: Key words: p53, p21, Mdm-2, congenital mesoblastic nephroma, clear cell sarcoma of the kidney, Wilms tumor Abstract: Mutation of p53 has been implicated in progression of classical Wilms tumor (WT) into the anaplastic variant (AWT), drug resistance, and poor prognosis. Because of prognostic similarities, clear cell sarcoma of the kidney (CCSK) has been classified with AWT and other aggressive pediatric renal tumors, apart from congenital mesoblastic nephroma (CMN), which is instead a relatively benign tumor of neonates. Initially, CCSK and CMN were assumed to be ontologically related, but the role of p53 in the pathogenesis of either disease has not been sufficiently evaluated as in AWT. We examined the status of p53 in CMN and CCSK in comparison to AWT by immunohistochemistry and mRNA analysis of p53, the downstream effector p21 .sup.WAF-1/CIP-1 (p21), the multidrug resistance gene MDR-1, a putative target of p53, and the p53-antagonist Mdm-2. Surprisingly, strong p53 nuclear immunoreactivity was found in cultures from two CMN specimens, but not in frozen or fixed tumor tissue from five other CMN specimens, nor in cell lines or tumor tissue from CCSK. Sequence analysis excluded p53 mutations. The size of the p53 mRNA in CMN and CCSK primary tumors excluded gross deletions or rearrangements. Low levels of Mdm-2 mRNA in CCSK and CMN primary tumors and cultures did not support a role for Mdm-2. Absence of MDR-1 mRNA excluded MDR-1 in the drug-resistant phenotype of CCSK. Cisplatin-induced p21 transactivation assays and G.sub.1 cell cycle arrest analyses showed that p21 transactivation and G.sub.1 arrest occurred in both CCSK and CMN cultures, demonstrating integrity of the p53 signal transduction pathway. Absence of p53 functional abnormalities excluded relationships between CCSK and CMN as in AWT, supporting the association of cellular CMN with congenital fibrosarcomas as more recently proposed. Author Affiliation: (1) Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA , US (2) Pathology Department, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA , US Article note: Received November 12, 2001 accepted February 4, 2002.

Byline: M. Rigolet (1), M. Faussillon (1), D. Baudry (1), C. Junien (1), C. Jeanpierre (1) Keywords: Keywords Wilms tumor; Differential gene expression; cDNA expression array Abstract: In order to identify genes or pathways involved in Wilms tumor etiology, we used the Atlas Cancer cDNA expression array to compare the gene expression profiles of five tumors, one Wilms tumor cell line (SK-NEP1), and normal mature and fetal kidneys. Of 588 genes tested, 153 had a different expression pattern in tumors compared with mature kidney. Ninety-six genes were differentially expressed in tumors compared with both normal mature and fetal kidney, and 57 genes had expression profiles similar to that of fetal kidney, which may reflect the developmental stage of the tumor cells. Comparison of the expression patterns of tumors shows that only 13% of the differentially expressed genes are constantly up- or downregulated in the five tumors tested, and this provides molecular evidence of tumor heterogeneity. We then confirmed the differential expression by an independent method, using quantitative reverse transcriptase polymerase chain reaction for two of the differentially expressed genes, MMP-14 and cyclin D2. Analysis of expression levels in a panel of 40 tumors showed that 30% overexpressed MMP-14 and 80% overexpressed cyclin D2. Profiling of gene expression using cDNA arrays in a large tumor panel will ultimately lead to the molecular classification of tumors, the identification of prognosis markers, and the design of targeted therapy. Author Affiliation: (1) U383 INSERM, Hopital Necker-Enfants Malades, Universite Rene Descartes, 149 rue de Sevres, 75015 Paris, France. Rigolet@necker.fr, FR Article note: Received: 7 February 2001 / Revised: 8 June 2001 / Accepted: 9 June 2001

Results point out that the Wilms' tumor suppresor gene, WT1, encodes upto 24 protein isoforms through a combination of alternative splicing, translational start sites, and RNA editing. Two alternative splice products with only three amino acid difference between them exhibit different biologcal functions.

Research has been conducted on the alternative splicing of the Wt1 which results in the amino acid insertion or omission between zinc fingers. Results demonstrate the functions for the splice variants and indicate the importance of the +KTS variants in regulating Sry in the sex determination pathway.

Byline: Vikas R. Dharnidharka (1), E. Cristy Ruteshouser (3), Seymour Rosen (2), Harry Kozakewich (2), H. William Harris Jr. (1), John T. Herrin (1), Vicki Huff (3) Keywords: KeywordsaDenys-Drash syndrome; Diffuse mesangial sclerosis; Congenital nephrotic syndrome; Wilms tumor 1 gene; Pulmonary dysplasia Abstract: While a genetic basis for the association of developmental lung and kidney defects has been suspected, the involvement of specific genes in this process is under active investigation. We report such a possible genetic linkage present in identical twins with a mutant Wilms tumor (WT1) gene. Twin girls, born at 35 weeks gestation, manifested symptoms of congenital nephrotic syndrome, renal failure, and severe respiratory abnormalities refractory to assisted ventilation. Both died at 1 month of age. Renal biopsies and autopsy kidney tissue from both the girls revealed diffuse mesangial sclerosis (DMS). Autopsy lung tissue revealed pulmonary dysplasia and hypoplasia in both twins. The WT1 gene from renal tissue in both twins was analyzed for mutations using polymerase chain reaction (PCR) amplification and the single-strand conformation polymorphism (SSCP) technique. Both twins possessed an identical missense mutation in exon 8 of the WT1 gene, resulting in replacement of arginine by histidine at amino acid 366 (arg366his) in the WT1 protein. This mutation has previously been described in Denys-Drash syndrome. The WT1 gene plays a role in mesenchymal epithelial (ME) interactions in the developing urogenital system, and possibly has a similar role during lung morphogenesis. We propose that this WT1 gene mutation contributes to both DMS and developmental pulmonary abnormalities by altering ME interactions in both organs. Author Affiliation: (1) Division of Nephrology, Department of Pediatric Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA, US (2) Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA, US (3) Division of Pediatrics, University of Texas MD Anderson Medical Center, Houston, Texas, USA, US (4) Division of Pediatric Nephrology, Shands Children's Hospital and University of Florida Health Science Center, PO Box 100296, 1600 SW Archer Road, Gainesville, FL 32610-0296, USA e-mail: vikasmd@peds.ufl.edu Tel.: +1-352-392-4434, Fax: +1-352-392-7107, US Article note: Received: 13 June 2000 / Revised: 1 November 2000 / Accepted: 2 November 2000

Results show that a 17 amino acid domain of the Wilms' tumor suppressor protein WT1 is an independent transcriptional activation domain requiring the prostate apoptosis response protein 4 (par4) for its function. Mutation in the domain abolishes par4 interaction suggesting that it acts like a coactivator of the domain.

Byline: Jerry W. Hussong (1), Sherrie L. Perkins (1), Vicki Huff (2), J. Matthew McDonald (2), Theodore J. Pysher (1), J. Bruce Beckwith (3), Cheryl M. Coffin (1) Keywords: Key words: Wilm's tumor, neural, familial, cytogenetics Abstract: Wilms' tumor (WT) is the most common renal malignancy of children. While most occur sporadically, a small percentage are familial or occur as part of a developmental syndrome. Classic WTs exhibit a triphasic histologic pattern composed of blastema, epithelium, and stroma. Occasionally, heterologous elements may also be observed. In this study we investigated a series of four WTs that occurred within a single familial aggregate and contained focal areas of neural differentiation. The tumors were evaluated histologically for the presence of neural elements and immunohistochemically for expression of neural-related markers. Genetic linkage analysis was performed on 3 of the 4 WTs. In addition to the classic triphasic histology, the WTs contained tumor rosettes (4/4), ganglion cells (2/4), foci of ganglioneuromatous differentiation (2/4), and anaplasia (1/4). Staining for chromogranin, S-100, synaptophysin, vimentin, and neuron-specific enolase was positive in all 4 tumors within the areas of neural differentiation whereas staining for CD99 (013) and glial fibrillary acidic protein was negative. Linkage analysis studies suggest that the familial predisposition gene segregating in this family is at 19q13.4. To our knowledge, this is the first reported series of WTs with neural differentiation that occurred within a single family aggregate. Genetic linkage analysis of this family is consistent with linkage to the FWT2 WT predisposition gene at 19q13.4. We propose that these tumors may represent a unique manifestation of tumor susceptibility in this family. Author Affiliation: (1) Departments of Pathology, Primary Children's Medical Center, University of Utah Health Sciences Center and ARUP Institute and Laboratories, 100 N. Medical Drive, Salt Lake City, UT 84132, USA, US (2) Department of Pathology, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA, US (3) Department of Pathology, Loma Linda University, AH 327, Loma Linda, CA 92350, USA, US Article note: Received May 14, 1999 accepted November 22, 1999.

The Wilms tumor suppressor WT1 (ital), which encodes a transcriptional activator of amphiregulin (ital), is discussed. WT1 (ital) codes for a zinc finger transcription factor likely to be a factor in kidney tumorigenesis and differentiation. Hybridization to high-density oligonucleotide arrays was used to look for native genes, the expression of which is altered after inducible expression of WT1 (ital).

Byline: Kathryn Pritchard-Jones (1) Keywords: Key wordsaNephrotic syndrome; Diffuse mesangial sclerosis; Frasier syndrome; Denys-Drash syndrome; Nephrogenic rests Abstract: The Wilms tumour gene, WT1, has been shown to play an important role in normal development of the kidney and gonad. Constitutional mutations predispose to both malformation and childhood tumours of these organs. There is a genotype-phenotype correlation, with missense mutations producing more severe abnormalities than complete absence of one allele. Two syndromes with early-onset protein-losing nephropathy can be distinguished according to the type of WT1 mutation. Children with apparently isolated diffuse mesangial sclerosis may also be WT1 mutation carriers. WT1 is not the major gene mutated in Wilms tumour, but has given important insights into the molecular genetics of this childhood embryonal kidney cancer. Recommendations for management of children suspected of having a WT1 mutation are discussed. Author Affiliation: (1) Section of Paediatric Oncology, Institute of Cancer Research/Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK, e-mail: kpj@icr.ac.uk, Tel.: +44-181-642-6011 Ext 3496, Fax: +44-181-770-7168, GB Article note: Received: 2 September 1998 / Revised: 30 October 1998 / Accepted: 4 November 1998

The Wilms tumor-suppressor gene WT1 was originally identified through its involvement in the development of a pediatric kidney tumor. Recent genetic data show that mutations in the WT1 gene cause a variety of other diseases, and new biochemical evidence suggests that the WT1 protein is not only a transcription factor but might also act at the post-transcriptional level.

The tumor suppressor WT1 has been demonstrated to have a wide variety of activities in vitro and is required for metanephric development in vivo. In the experiments presented here, the Xenopus pronephros was used as a simple model system to examine the activity of Xenopus WT1(xWT1) during kidney development. xWT1 was ectopically expressed in Xenopus embryos by mRNA injection and found to inhibit pronephric tubule development. Confocal microscopy confirmed this observation and revealed that the inhibition was the result of a failure to form a pronephric anlage of appropriate size rather than a defect in epithelialization. Examination of Xlim-1 expression, an early molecular marker of pronephric specification, in tailbud embryos indicated that injected xWT1 mRNA inhibited pronephric specification prior to any overt sign of morphogenesis (Xenopus stage 21). These results suggest that xWT1 may act to repress tubule-specific gene expression in the portion of the pronephros fated to form its vascular structure, the glomus. Key Words: pronephros; organogenesis; WT1; glomus; pronephric tubules.

Byline: Paul S. Thorner (1), Jeremy A. Squire (2) Keywords: Key words: neuroblastoma, Ewing sarcoma, PNET, rhabdomyosarcoma, synovial sarcoma, Wilms tumor Abstract: The field of molecular genetics continues to see an ever increasing number of applications to pediatric tumor analysis. Studies in pediatric tumors have identified novel genes and other genetic changes, a large number of which reflect one of the following mechanisms: (1) activation of proto-oncogenes (2) loss of tumor suppressor genes or (3) creation of novel fusion proteins. At least one of these mechanisms is operational in each of the following pediatric tumors: neuroblastoma, Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET), intra-abdominal desmoplastic small-cell tumor, rhabdomyosarcoma, synovial sarcoma, and Wilms tumor. Out of this research has come not only an increased understanding of oncogenesis but also, for each of the tumors listed above, diagnostic and/or prognostic markers that can be used by the pathologist and oncologist to improve overall patient management. Author Affiliation: (1) Department of Pediatric Laboratory Medicine, Division of Pathology, Hospital for Sick Children and the University of Toronto, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8 , CA (2) Division of Cellular and Molecular Biology, Ontario Cancer Institute and the University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9 , CA Article note: Received November 20, 1997 accepted April 20, 1998.

Constitutional MT1 mutations have been found in patients with isolated diffuse mesangial sclerosis (DMA) or Denys-Drash syndrome. A computerized mutation database has been used for analysis of correlations of genotypes and phenotypes. A series of 24 patients was analyzed. Ten had isolated DMS (IDMS), ten had DDS, and 4 had urogenital abnormalities and/or Wilms tumor (WT). WT1 heterozygous mutations were found in 16 patients, of whom four presented with IDMS.

Relaxation of imprinting at the insulin-like growth factor II (IFG-II)/H19 locus is a major mechanism involved in the onset of sporadic Wilms tumor and several other embryonal tumors. The high prevalence of histologically abnormal foci in kidney adjacent to Wilms tumors suggests that tumor-predisposing genetic/epigenetic lesion might also be found at high frequency in Wilms tumor-bearing kidneys. Focusing on Wilms tumors with relaxation of IFG-II imprinting, we determined the frequency of epigenetic change at the IFG-II/H19 locus in adjacent kidney. In all kidneys adjacent to these Wilms tumors, we detected substantial mosaicism for a population of cells with relaxation of IFG-II imprinting and biallelic H19 methylation, regardless of whether the patient had a tumor-predisposing syndrome or not. The high proportion of epigenetically modified cells among 'normal' tissue indicates that the epigenetic error occurred very early in development, before the onset of Wilms tumor. Not only does this suggest that the major Wilms tumor-predisposing event occurs within the first few days of development, but it also suggests that sporadic Wilms tumor may represent one end of a spectrum of overgrowth disorders characterized by mosaic epigenetic change at the IFG-II/H19 locus.

Osteosarcoma cell lines with inducible expression of wild-type WT1 isoforms and WT1 mutants were used to study the expression pattern of Wilms tumor (WT) gene transcripts in mice. Treatment with the tetracycline-regulated promoter induced the localized diffusion of the WT1 isoforms to subnuclear clusters. A comparison with the diffusion pattern of the splicing factor SC35 showed that WT1 is not involved in mRNA splicing. Further evidence revealed that coexpression of the WT1 isoform with the WT1 mutants results to a speckled pattern and inhibition of transactivational activity. These results suggest that WT1 isoforms and WT1 mutants diffuse in distinct regions within the nucleus.

Germline loss-of-function mutations at the Wilms tumor (WT) suppressor locus WT] are associated with a predisposition to Wts and mild genital system anomalies. In contrast, germ-line missense mutations within the WT] gene encoding the DNA-binding domain often yield a more severe phenotype consisting of WT, sexual ambiguity, and renal nephropathy. In this report, we demonstrate that the products of mutant alleles that impair DNA recognition can antagonize WT1-mediated transcriptional repression. We demonstrate that WT1 can self-associate in vitro and in vivo and that the responsible domain maps to the amino-terminal region of the protein. Oligomers of full-length protein form less efficiently or produce less stable complexes than oligomers between truncated polypeptides and full-length protein. Our data suggest a molecular mechanism to explain how WT] mutations may act in deregulating cellular proliferation and differentiation.

Tumor predisposition gene (WT1) plays an important role in transcriptional and posttranscriptional RNA processing. WT1 and the splicing factor colocalize in speckles and coiled bodies. An immunoprecipitation shows that WT1 isoforms interact directly with one or more components of splicing machinery and COS studies suggest that WT1 associates mainly with DNA in transcription factor domains.

Analysis of Wilms tumor shows that biallelic expression of IGF2 is associated with H19 expression. A reversal of DNA methylation of maternally inherited IGF2 and H19 alleles is involved in the relaxation of IGF2 imprinting in these tumors. The epigenetic methylation changes in the tumors associated with this relaxation are localized to the maternal IGF2 and H19 alleles.

Wilms' tumor is a kind of malignant tumor found in the kidneys, almost always in children. It is the most common such tumor in children; about one child of every 10,000 develops Wilms' tumor. The standard treatment involves surgical removal of the tumor, resection of the kidney or kidneys as necessary, chemotherapy and radiation therapy. This combination of treatment is successful in about 80% of the cases. Wilms' tumor seems to originate in genetic abnormalities. The primary chromosomes involved are believed to be band p13 of chromosome 11, a set of nearby genes including two tumor suppressor genes known as WT1 and WT2, and sometimes the p53 tumor suppressor gene on chromosome 17. Damage to other chromosomes can also lead to Wilms' tumor and related disorders.

Data obtained from a single-strand conformational polymorphism (SSCP) assay, which was used to analyze the structural integrity of the Wilms tumor (WTI) gene, was used to define the frequency at which the WTI gene modified in sporadic tumors. Wilms tumor, which occurs often in children less than five years of age, is an embryonal malignancy of the kidney.

13. Bruening W, Gros P, Sato T, Stanimir J. Nakamura Y, et al. 1993. Analysis of the 11p13 Wilms' tumor suppressor gene (WT1) in ovarian tumors. Cancer Invest. 11 (4):393-99 [...]

The WT1 gene in 50 Wilms tumors was studied by single-strand conformational polymorphism analysis to identify possible homozygous point mutations associated with this disease. The results showed that a subset of Wilms tumors can be characterized by two somatic point mutations in exon 8 and exon 10 of the WT1 gene. These results suggest that a subset of Wilms tumor may be explained by a two-hit mutational model which leads to inactivation of WT1.

A study was done to determine whether the platelet-derived growth factor A (PDGF-A) gene is transcriptionally repressed by the Wilms tumor suppressor geneproduct (WT1), which is a zinc-finger DNA-binding protein. This was in view of the observed overexpression of PDGF-A in Wilms tumor, an embryonic kidney malilgnancy. The results showed that WT1 bound to several sites of the promoterregion of PDGF-A. The results indicate that kidney development and other biologycal development processes involve a mechanism for the downregulation of a growth factor gene and of an autocrine process.

The Wilms tumor suppressor gene wt1 encodes a zinc finger DNA binding protein, WT1, that functions as a transcriptional repressor. The fetal mitogen insulin-like growth factor II (IGF-II) is overexpressed in Wilms tumors and may have autocrine effects in tumor progression. The major fetal IGF-II promoter was defined in transient transfection assays as a region spanning from nucleotides -295 to +135, relative to the transcription start site. WT1 bound to multiple sites in this region and functioned as a potent repressor of IGF-II transcription in vivo. Maximal repression was dependent on the presence of WT1 binding sites on each side of the transcriptional initiation site. These findings provide a molecular basis for overexpression of IGF-II in Wilms tumors and suggest that WT1 negatively regulates blastemal cell proliferation by limiting the production of a fetal growth factor in the developing vertebrate kidney., Wilms tumor is a pediatric malignancy thought to arise when multipotent kidney blastemal cells fail to differentiate and instead continue to proliferate after birth [1]. The occurrence of both sporadic [...]

The WT1 gene codes for a putative transcription factor whose mutated form is associated with the development of Wilms tumor. It was previously noted that the mutated allele could be co-expressed with the wild-type allele in patients with sporadic Wilms tumor. To determine if the mutant allele could elicit trans-dominant expression, transformation studies were carried out on primary baby rat kidney cells. The results showed that mutant WT1 acted cooperatively with the adenoviral E1 gene in the transformation process. The wild type allele was not capable of suppressing the effects of WT1, indicating that it acts in a trans-dominant manner.