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WILMS TUMOR 1
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Back to UNSW Embryology-Kidney Notes List of OMIM search results *194070 WILMS TUMOR 1; WT1 Alternative titles; symbols NEPHROBLASTOMA table OF CONTENTS  TEXT ALLELIC VARIANTS View List of allelic variants REFERENCES SEE ALSO CONTRIBUTORS CREATION DATE EDIT HISTORY CLINICAL SYNOPSIS Database Links "104 MEDLINE Citations" "16 Protein Links" ALIGN=middle> "25 Nucleotide Links" ALIGN=middle> "2 Genome Links" ALIGN=middle> "UniGene" "Cardiff Human Gene Mutation Database" "Gene Map" "GDB" "Jackson Labs Mouse Database" "Coriell Cell Line Repository" Gene Map Locus: 11p13 Note: pressing the symbol will find the citations in MEDLINE whose text most closely matches the text of the preceding OMIM paragraph, using the Entrez MEDLINE neighboring function.   TEXT Rather numerous instances of multiple sibs with Wilms tumor have been described (Fitzgerald and Hardin, 1955). Strom (1957) described a family with 5 cases in 3 generations. A healthy male had 2 affected children (out of 5) by 1 wife and 1 affected child by another wife. A sister and an aunt of his had died in infancy or early childhood of abdominal tumor. Jolles (1973) described Wilms tumor in a 30-month-old girl and hypernephroma in her 67-year-old paternal grandmother. Brown et al. (1972) reported the occurrence of Wilms tumor in 4 members of 3 successive generations of a family: the proband, a girl, her mother, aunt and grandfather. The presence of Wilms tumor was histopathologically confirmed in 3 of the 4 cases. The right kidney was affected first in all. The aunt eventually developed Wilms tumor of the left kidney leading to her death at age 7. Matsunaga (1981) concluded that inheritance in familial cases, 'which constitute less than 1% of all' cases, is autosomal dominant with variable penetrance and expressivity. About 20% of familial cases are bilateral; about 3% of sporadic cases are bilateral. Bilateral cases may always be familial. Matsunaga (1981) further concluded that his 'host resistance model' fit the data. Knudson and Strong (1972) reviewed and summarized data on 58 familial cases of Wilms tumor. They concluded that bilateral tumors are more likely to be familial, that familial tumors result from 2 mutations, 1 germinal and 1 somatic, and that sporadic tumors result from 2 somatic mutations. Work of Fearon et al. (1984), Koufos et al. (1984), Orkin et al. (1984), and Reeve et al. (1984) demonstrated that homozygosity of 11p change is present in Wilms tumor, thus providing support for the Knudson hypothesis. The syndrome of aniridia, hemihypertrophy and other congenital anomalies with Wilms tumor, subsequently known as the WAGR syndrome, was first described by Miller et al. (1964). Meadows et al. (1974) described a family in which the mother had congenital hemihypertrophy and 3 of her children had Wilms tumor. A fourth child had a urinary tract anomaly. In 1 of the children the Wilms tumor was bilateral and in a second it was multicentric. Bond (1975) found associated congenital anomalies in 5 of 11 cases of bilateral Wilms tumor and in only 3 of 76 cases of unilateral Wilms tumor. See 235000 for discussion of familial hemihypertrophy. Riccardi et al. (1978) observed a triad of aniridia, ambiguous genitalia and mental retardation (AGR triad) in 3 patients with an interstitial deletion of the short arm of chromosome 11. One patient also had Wilms tumor. Among 6 cases, Francke et al. (1978) showed that Wilms tumor was not present in all cases, although aniridia was. For example, between monozygotic twins with an identical deletion of 11p, aniridia and mental retardation were present in both and Wilms tumor in only 1. Only 1 of the other 4 patients had Wilms tumor. The deleted segment common to all was the distal half of 11p13. Anderson et al. (1978) described aniridia, cataract and gonadoblastoma in a mentally retarded girl with an interstitial deletion of the short arm of chromosome 11. Gonadoblastoma occurs as part of the WAGR complex (Junien et al., 1980; Turleau et al., 1981). Because of the importance of awareness of this feature, the 'G' should stand for gonadoblastoma. (The 'G' of WAGR has variously meant to authors 'ambiguous genitalia' (Riccardi et al., 1978), 'genitourinary abnormalities,' or 'gonadoblastoma' (Anderson et al., 1978).) The WAGR complex qualifies as a 'contiguous gene syndrome' (Schmickel, 1986); see 194072. Apparent close linkage of the region determining the WAGR syndrome to the catalase locus (CAT; 115500) means that assay of catalase activity can usefully indicate those cases of new-mutation aniridia that should have surveillance for the development of renal or gonadal tumors (Junien et al., 1980). In a report that focused on the aniridia component of the WAGR syndrome, Gilgenkrantz et al. (1982) analyzed the reported cases of aniridia with interstitial del(11)p. They reported a unique observation of hypertrophic cardiomyopathy in association with aniridia and catalase deficiency in a patient with del(11)(p15.1p12). Using high resolution chromosome banding, Marshall et al. (1982) studied 14 patients with aniridia. Seven were familial and had normal chromosomes; of 7 sporadic cases, 1 showed normal chromosomes and 6 had interstitial deletion of 11p of various lengths. Band 11p13 was included in the deletion in all 6 cases. In the cells of a Wilms tumor, unassociated with the WAGR syndrome and with normal constitutional chromosomes, Kaneko et al. (1981) found an interstitial deletion involving the region 11p14-p13. Mapping studies by de Martinville and Francke (1983, 1984) appeared to rule out a close physical association between HRAS1 and the region responsible for predisposition to Wilms tumor. Of course, deletion may bring them together. They placed HRAS1, HBB and insulin in the 11p15-p14.2 segment. By somatic cell hybridization, Junien et al. (1984) found that HRAS1 maps to 11p15.5-p15.1. In 4 cases of deletion of 11p13 with WAGR, they found that the restriction enzyme digestion patterns typical of HRAS1 were present. Thus, HRAS1 is not deleted in WAGR, a finding consistent with the difference in mapping. Reeve et al. (1984) demonstrated loss of HRAS (190020) in a sporadic case of Wilms tumor. Pointing out the conflicting evidence on the location of HRAS, they concluded that until the chromosomal location of HRAS has been determined with certainty, one cannot exclude a possible functional involvement of this oncogene in Wilms tumor development. From gene dosage studies, Narahara et al. (1984) concluded that both the CAT and the WAGR loci are in the chromosome segment 11p1306-p1305, with CAT distal to WAGR. Nakagome et al. (1984) concluded that deletion of the middle part of the 11p13 band is crucial to the WAGR syndrome; others had suggested that the distal half is of critical importance. Turleau et al. (1984) reviewed a total of 42 cases. Turleau et al. (1984) suggested that the determinant of aniridia may be separate from that for nephroblastoma, on the basis of a boy with deletion of most of 11p13, low catalase, nephroblastoma, chordee and cryptorchidism but normal irides and no mental retardation. The authors pointed out that in all published cases with aniridia the distal half of 11p13 is deleted whereas in their presently reported case there was 'a tiny residual distal segment.' The observation might suggest the order cen--CAT--WILMS--aniridia--tel; however, Narahara et al. (1984) placed the catalase locus distal to the WAGR locus. Riccardi et al. (1982) reported a patient with Wilms tumor and iris dysplasia, not aniridia. In the UK, Shannon et al. (1982) found the incidence of aniridia in cases of Wilms tumor to be 1 in 43. A survey detected 8 living and 3 dead children with Wilms tumor and aniridia. All 8 living children had deletion of 11p13. A high incidence of bilateral Wilms tumor (36%), male sex, early presentation, and advanced maternal age were features of the combined cases. By molecular genetic studies of cells from a patient with aniridia-Wilms tumor, Michalopoulos et al. (1985) concluded that a deletion visible cytologically in 11p13 deleted the catalase loci but not the LDHA locus, which is proximal, nor insulin, gamma-globin loci, HRAS1 and calcitonin, which are located distally. Among 49 children with Wilms tumor without aniridia, only 1 had bilateral renal tumors. By use of RFLPs that map to 11p, Raizis et al. (1985) detected mitotic recombination as the mechanism of homozygosity in a Wilms tumor. Their findings showed that insulin and beta-globin had come to homozygosity in the tumor but PTH remained heterozygous. Thus, PTH must be proximal to 11p13, the cytologically determined site of the Wilms tumor 'gene.' Scoggin et al. (1985) showed that E7-associated cell-surface antigen encoded by chromosome 11 and defined by a monoclonal antibody is deleted in cases of WAGR. This antigen is probably the same as that previously called 'a1' (151250). The studies in cases of WAGR with small deletions of 11p permitted regionalization of the assignment of antigen a1 to 11p13. Comings (1973) proposed that dominantly inherited tumors may arise through inactivation or loss of a pair of regulatory genes that normally suppress the expression of a structural transforming gene. In 4 cases of Wilms tumor, Reeve et al. (1985) found that transcripts of insulin-like growth factor II (IGF2; 147470) were highly elevated as compared with adjacent normal kidney. Furthermore, by in situ hybridization, they mapped the IGF2 gene to 11p14.1, close to the WAGR locus. They proposed that IGF2 is the (or a) transforming gene in Wilms tumor. (Their positioning of the IGF2 locus is inconsistent with that of others who place it in a somewhat more distal band.) Scott et al. (1985) pointed out that Wilms tumor is histologically indistinguishable from the early stages of kidney development. In 12 sporadic cases of Wilms tumor, Scott et al. (1985), like Reeve et al. (1985) found that expression of the IGF2 gene was markedly increased relative to adult tissues, but was comparable to the level of expression in several fetal tissues including kidney, liver, adrenal, and striated muscle. Although this may merely reflect the stage of tumor differentiation, the possibility that IGF2 is involved in the transformation process was raised. Francke (1990) pointed out that the Wilms tumor site is close to that of IGF2, which is a candidate gene for Wilms tumor at that site. Van Heyningen et al. (1985) studied 5 persons with constitutional deletions of 11p. All had aniridia; 2 had had a Wilms tumor removed. Using a cDNA probe for catalase, they showed that the CAT locus was deleted in 4 of 5 and that it must be proximal to the Wilms and aniridia loci. HBB and CALC were deleted in none; therefore, these loci are likely to be outside the region 11p15.4-p12. A region of 11p associated with Wilms tumor has also been tied to rhabdomyosarcoma and hepatoblastoma (Koufos et al., 1985); see WT2 (194071). All 3 of these rare embryonal cancers occur in the Beckwith-Wiedemann syndrome (130650). Kozman et al. (1989) found loss of alleles from 11p in a Wilms tumor in a 37-year-old male. The finding indicated a common pathogenesis of childhood and adult types and suggested that molecular genetic studies may be useful in the differentiation of Wilms tumor from renal cell carcinoma or sarcoma when the histologic findings are unclear. Weissman et al. (1987) explored the role of the 11p13 deletion in Wilms tumor by introducing a normal human chromosome 11 into a Wilms tumor cell line by means of the microcell transfer technique. The ability of the cells containing the normal chromosome 11 to form tumors in nude mice was completely suppressed. Schroeder et al. (1987) found that in 5 patients with Wilms tumor and 2 others previously reported, there was a loss of chromosome 11 alleles and that these alleles in all 7 cases were of maternal origin. All of these tumors were sporadic. The authors concluded that the initial mutation, either germinal or somatic, must have occurred on the paternal chromosome. There was no occupational history pointing to an increased risk of mutation in the fathers and, on the average, paternal age was not increased. They stated that the probability of all 7 patients losing the maternal allele in their Wilms tumor tissues, if the loss is indeed random, is less than 1%. By means of RFLPs, Huff et al. (1990) demonstrated that 7 of 8 de novo deletions of band 11p13 were of paternal origin. The 1 case of maternal origin was unremarkable in terms of the size or extent of the deletion, and the child developed Wilms tumor. Transmission of 11p13 deletions by both maternal and paternal carriers of balanced translocations has been reported, although maternal inheritance predominates. These data, in addition to the general predominance of paternally derived, de novo mutations at other loci, suggested that increased frequency of paternal deletions is due to an increased germinal mutation rate in males. Dao et al. (1987) examined the karyotype and chromosome 11 genotype of normal and tumor tissues from 13 childhood renal tumor patients. Tumors of 8 of the 12 Wilms tumor patients showed molecular evidence of loss of 11p DNA sequences by somatic recombination (4 cases), chromosome loss (2 cases), and recombination (2 cases) or chromosome loss and duplication. One malignant rhabdoid tumor in a patient heterozygous for multiple 11p markers did not show any tumor-specific 11p alteration. One of the patients had Perlman syndrome (renal hamartomas, nephroblastomatosis, and fetal gigantism; 267000). Lewis and Yeger (1987) mapped the Wilms tumor region with 4 clones that were derived from the area of deletion in 11p, together with somatic cell hybrids containing chromosome 11 from leukemic T cells with translocation t(11;14), from fibroblasts from a familial aniridia patient with translocation t(4;11), and from lymphoblasts from a patient with Wilms tumor and deletion of 11p but no aniridia. The following order was deduced: centromere--CAT--T-cell break--aniridia break--FSHB--telomere. Porteous et al. (1987) used chromosome-mediated gene transfer to provide an enriched source of DNA markers for 11p. They defined 10 distinct regions of 11p, 5 of which subdivided band 11p13. They also mapped 2 independent 11p13 translocation breakpoints to within the smallest region of overlap defined by WAGR deletions. The first came from a patient with familial aniridia, and the second was found in a neonate with the clinical features of Potter facies and the pathologic features of genitourinary dysplasia, with urethral and ureteral atresia and bilateral undescended testes. Porteous et al. (1987) raised the question of whether Wilms tumor and genitourinary dysplasia are alternative manifestations of mutation at the same locus. Kumar et al. (1987) demonstrated deletion of 11p14-p12 in a Wilms tumor removed from a 9-month-old boy with aniridia. Whereas morphologic transformation of normal human cells by BK virus (BKV) and by BKV DNA and its subgenomic fragments occurs in very low frequency, de Ronde et al. (1988) found that 4 individuals with various deletions in the short arm of one chromosome 11 were unusually susceptible to morphologic transformation. They suggested that the susceptibility might be explained by a 'transformation suppressor' locus situated within the deleted region. The deleted region included that of WAGR; the 'transformation suppressor' locus may be identical to the Wilms tumor locus. Using the fluorescence-activated cell sorter to select a series of somatic cell hybrids with deleted translocated chromosome 11 segregated from its normal homolog, Seawright et al. (1988) analyzed these cell hybrids with gene-specific probes and for cell-surface marker expression to order the markers and find an SRO for WAGR. They found that FSHB maps distal to WAGR and CAT maps proximal to it. Two translocation breakpoints in 11p13 (1 associated with familial aniridia and 1 with a sporadic case of congenital renal dysfunction resulting from urethral and ureteral atresia) mapped within this SRO. Puissant et al. (1988) reported a patient with WAGR and a de novo reciprocal translocation 46,XY,t(5;11)(q11;p13). On Southern blot analysis, the gene encoding catalase had been deleted, but the gene encoding the beta subunit of follicle-stimulating hormone (FSHB) was intact. Using a range of probes for chromosome 11, Mannens et al. (1988) demonstrated that loss of heterozygosity in Wilms tumors may not necessarily involve the proposed Wilms tumor locus at 11p13 and may be limited to 11p15.5. Jeanpierre et al. (1990) found loss of maternal alleles from the 11p15 area of the maternal chromosome in Wilms tumor tissue and a constitutional deletion of 11p13 of the maternal chromosome. There have been other instances in which the 11p region involved in loss of heterozygosity (11p15) is different from the region involved in hereditary predisposition (11p13). See 194071. A separate gene coding for genitourinary dysplasia (symbolized GUD) was suggested by Bonetta et al. (1989), who found that the deletion breakpoint of a translocation t(11;2)(p13;p11) in a patient with Potter facies and genitourinary dysplasia mapped to the same 225-kb pulsed field gel electrophoresis fragment as did the fragment deleted in Wilms tumor. Van Heyningen et al. (1990) suggested that the Wilms tumor gene itself may be responsible for abnormalities of genitourinary development in WAGR as a pleiotropic effect. The suggestion was based on the observations that the tumor predisposition and the genitourinary malformations map to precisely the same area and that the WT candidate gene shows expression in both the developing kidney and gonads. See 137357 for a critique of the separate-gene hypothesis. To localize a candidate for the Wilms tumor gene, Rose et al. (1990) developed a physical map of the 11p13 region by a combination of pulsed field gel electrophoresis and irradiation-reduced somatic cell hybrids of the Goss-Harris type. Restriction fragments contained in 11p13 were visualized directly using interspersed repeated DNA sequences as hybridization probes. The Wilms tumor locus was narrowed down to a region of less than 345 kb, and a transcript was identified with many of the characteristics expected for the Wilms tumor gene: a GC-rich region mapped to the 5-prime end of a transcription unit encoding a zinc finger protein. Call et al. (1990) reported further on these characteristics. The transcription unit spanned approximately 50 kb and encoded an mRNA approximately 3 kb long. The mRNA was expressed predominantly in the kidney and a subset of hematopoietic cells. The polypeptide had features suggesting a role in transcriptional regulation: the presence of 4 zinc finger domains and a region rich in proline and glutamine. The amino acid sequence of the predicted polypeptide showed significant homology to EGR1 (128990) and EGR2 (129010). Gessler et al. (1990) likewise isolated a cDNA clone derived from an RNA highly expressed in fetal kidney which is predicted to encode a Kruppel-like zinc finger protein that is probably a transcription factor. Francke (1990) commented on the significance of this putative gene for Wilms tumor. She compared the finding with that in retinoblastoma where a single gene locus has been found to be responsible. She reviewed the evidence for at least 3 genes capable of producing Wilms tumor: one in 11p13, one in 11p15.5 (194071) and at least one other not situated in either of these regions (194090). In the case of Wilms tumor, it is possible that changes at several sites are collaborative, or perhaps more likely that changes at several alternative sites result in the same tumor. A third model is that of hierarchical gene interaction. If the function of the gene at 11p13 is to turn off the gene at 11p15.5, then loss of 11p13 expression would have the same effect as mutation or allele loss at 11p15.5. The zinc finger protein that is likely to be a transcription factor and was isolated by Call et al. (1990) and Gessler et al. (1990) as the likely 'cause' of Wilms tumor was used by Pritchard-Jones et al. (1990) to study its role in normal development. This was done by in situ mRNA hybridization on sections of human embryos. The candidate Wilms tumor gene was expressed specifically in the condensed mesenchyme, renal vesicle, and glomerular epithelium of the developing kidney, in the related mesonephric glomeruli, and in cells approximating these structures in tumors. The other main sites of expression were the genital ridge, fetal gonad, and mesothelium. This was interpreted as indicating that the anomalies of the urinary tract and genitalia, which are frequent in both sporadic and syndrome-associated Wilms tumors, are a pleiotropic effect of the WT1 gene. Huff et al. (1991) made observations that appeared to differentiate between WT33 and LK15, 2 similar candidate Wilms tumor cDNA clones that were identified on the basis of their expression in fetal kidney and their location within the smallest region of overlap of somatic 11p13 deletions in Wilms tumors. However, Gessler (1991) concluded that LK15 and WT33 are identical, with differences due to alternative splicing at 2 exons. Huff et al. (1991) reported a patient with bilateral Wilms tumor who was heterozygous for a small germinal mutation within the WT1 gene (as identified by the WT33 clone). DNA from both tumors was homozygous for this intragenic deletion, which was predicted to encode a protein truncated by 180 amino acids. Haber et al. (1990) described a sporadic, unilateral Wilms tumor in which 1 allele of the WT1 candidate gene contained a 25-bp deletion spanning an exon-intron junction and leading to aberrant mRNA splicing and loss of 1 of the 4 zinc finger consensus domains in the protein. The mutation was absent in the affected person's germline, consistent with the somatic inactivation of a tumor suppressor gene. In addition to the intragenic deletion affecting 1 allele, loss of heterozygosity at loci along the entire chromosome 11 indicated an earlier chromosomal nondisjunction and reduplication. Haber et al. (1992) presented evidence that this mutation of the WT1 gene behaves as a dominant negative, suppressing the function of the wildtype protein by a trans-dominant mechanism. They suspected this because the mutated allele was found to be coexpressed with the wildtype allele in a sporadic Wilms tumor. They therefore tested the ability of this mutant WT1 allele, containing an in-frame deletion within the DNA-binding domain, to transform primary baby rat kidney cells. The mutant WT1 gene was found to cooperate with the adenoviral E1A gene in transforming baby rat kidney cells. The wildtype WT1 gene in all of its alternatively spliced forms neither suppressed E1A-induced focus formation nor cooperated with E1A. Hastie (1992) also reviewed the evidence showing that mutations in the WT1 gene behave as dominant negatives, specifically in relation to causation of the Denys-Drash syndrome (DDS). This is proof that a tumor-suppressor gene plays a crucial role in normal genitourinary development. It seems quite clear that there is not a separate gene for the 'G' part of the WAGR syndrome although there is a separate gene for aniridia and almost certainly for mental retardation. Remarkably, 12 out of 25 patients from a total of 4 studies had the arg394-to-trp mutation (194070.0003) in heterozygous form as the cause of the Denys-Drash syndrome. One reason for the preponderance of this mutation is that it represents a C-to-T transition at a CpG dimer. The same can be said for the arg-to-his change (194070.0004). This, however, appeared to be only part of the story since there are other equally vulnerable sites; Hastie (1992) suggested that the zinc fingers carrying these 2 mutations may play a particularly important role in establishing stable binding. Mutations causing the Denys-Drash syndrome are clustered in the zinc finger encoding exons, particularly the exons encoding ZF2 and ZF3. Little et al. (1993) concluded that WT mutations resulting in the Denys-Drash syndrome may operate in a dominant-negative fashion; they observed an arg362-to-ter mutation predicted to result in a protein product lacking zinc fingers 2, 3 and 4, and therefore presumably incapable of binding DNA. Little et al. (1995) found WT1 fusion constructs containing the different classes of DDS-causing mutations. They demonstrated that the DDS mutations, indeed, disrupt DNA binding. They interpreted this as compatible with a dominant-negative mode of action, perhaps through dimerization between different WT1 isoforms. Little et al. (1995) noted that another mechanism by which the loss of DNA-binding could elicit the DDS phenotype would be a disturbed isoform dosage balance. Nordenskjold et al. (1995) screened 27 cases of 46,XY females with gonadal dysgenesis who had previously been screened for and found not to carry SRY gene mutations (480000) to determine whether isolated gonadal dysgenesis might be due to WT mutations. Using denaturing gradient gel electrophoresis, they found a heterozygous point mutation in exon 8 in 1 of these patients: arg366-to-his, which had previously been described in a case of Denys-Drash syndrome (194070.0004). Reevaluation of the clinical data confirmed the diagnosis of Drash syndrome. Based on these results, Nordenskjold et al. (1995) concluded that isolated gonadal dysgenesis is not caused by mutations in the WT1 gene. Ton et al. (1991) demonstrated that the smallest region of overlap between deletions causing Wilms tumor was a 16-kb segment of DNA encompassing one or more of the 5-prime exons of the zinc finger gene located on 11p13, together with an associated CpG island. This supported the authenticity of the zinc finger gene as the disease locus. Kakati et al. (1991) described a family in which a son had bilateral WT and an extra ring chromosome in the lymphocytes and in kidney tissue. The size of the ring varied considerably from cell to cell. A daughter had unilateral WT and an abnormal clone containing a small ring chromosome in PHA-stimulated and EBV-transformed lymphocytes. The mother, who was unaffected, had a karyotype similar to that of the daughter with WT. Kakati et al. (1991) hypothesized that the son's large ring chromosome was an amplified form of the small ring inherited from the mother. Chromosome 11 was cytogenetically normal in all cells examined in the affected children and the unaffected mother. The WT1 gene comprises 10 exons, encoding a complex pattern of mRNA species. Four distinct transcripts are expressed, reflecting the presence or absence of 2 alternative splices (Haber et al., 1991). The conservation in structure and relative levels of the 4 WT1 mRNA species suggests that each encoded polypeptide makes a significant contribution to normal gene function. The control of cellular proliferation and differentiation exerted by the WT1 gene products may involve interactions between the 4 polypeptides with distinct targets and functions. Using polyclonal antibodies, Dressler and Douglass (1992) detected high levels of Pax-2 (PAX2) expression in the epithelial cells of human Wilms tumors. In the mouse they showed by immunocytochemistry that expression of the Pax-2 gene was localized to the nuclei of condensing mesenchyme cells and their epithelial derivatives in the developing kidney. The data suggested that Pax-2 is a transcription factor that is active during the mesenchyme-to-epithelium transition in early kidney development and in Wilms tumor. Pax-2 is a member of the family of genes identified in the mouse on the basis of a common protein coding domain, the paired-box, first described in the Drosophila segmentation genes 'paired' and 'gooseberry.' The Pax genes are expressed during embryogenesis in a tissue-restricted manner. The gene mutant in Waardenburg syndrome (193500) is the human homolog of the Pax-3 gene and the gene mutant in aniridia (106210) is the human homolog of the Pax-6 gene. To facilitate the search for small deletions and point mutations in the WT1 gene, Gessler et al. (1992) established the genomic organization of the gene and determined the sequence of all 10 exons and the flanking intron DNA. The pattern of alternative splicing in 2 regions was characterized in detail. In 2 cases in which a Wilms tumor contained a somatic WT1 mutation, Park et al. (1993) found that nephrogenic rests in the same kidneys had the identical mutation. Thus, nephrogenic rests and Wilms tumor are topographically distinct lesions that are clonally derived from an early renal stem cell. Inactivation of WT1 appears to be an early genetic event that can lead to the formation of nephrogenic rests, enhancing the probability that additional genetic hits will lead to Wilms tumor. In the case of both P53 (191170) and retinoblastoma (180200), characterization of the tumor suppressor genes was provided by the dramatic growth-suppressing properties when the genes were reintroduced into cells containing inactivated endogenous genes. Similar studies in Wilms tumors had been complicated by the existence of multiple genetic loci implicated in different subsets of tumors and by the unavailability of appropriate target cell lines. To obtain an appropriate cell line for studying WT1 function, Haber et al. (1993) inoculated minced human Wilms tumors subcutaneously into nude mice and then adapted the tumor explants to growth in vitro. They found that 1 cell line could be propagated indefinitely in tissue culture without loss of tumorigenic potential. Transfection of each of 4 wildtype WT1 isoforms suppressed the growth of these cells. The endogenous WT1 transcript in these cells was devoid of exon 2 sequences, a splicing alteration that was also detected in varying amounts in all Wilms tumors tested but not in normal kidney. Production of this abnormal transcript, which encodes a functionally altered protein, may represent a distinct mechanism for inactivating WT1 in Wilms tumors. Varanasi et al. (1994) analyzed the structural integrity of the entire WT1 gene in 98 sporadic Wilms tumors. By PCR-SSCP, they found that mutations in the WT1 gene are rare, occurring in only 6 tumors analyzed. In 1 sample, 2 independent intragenic mutations inactivated both WT1 alleles, providing a singular example of 2 different somatic alterations restricted to the WT1 gene. The data, together with the previously ascertained occurrence of large deletions/insertions in WT1, defined the frequency at which the WT1 gene is altered in sporadic tumors. By gene targeting in embryonic stem cells, Kreidberg et al. (1993) introduced a mutation into the murine WT1 tumor suppressor gene. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos demonstrated a failure of kidney and gonad development. Specifically, at day 11 of gestation, the cells of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the Wolffian duct, and the inductive events that lead to formation of the metanephric kidney did not occur. In addition, the mutation caused abnormal development of the mesothelium, heart, and lungs. The results established a crucial role for WT1 in early urogenital development. Gerald et al. (1995) reported the first example of a specific tumor associated with consistent translocation involving WT1. Desmoplastic small round cell tumor (DSRCT) is associated with a recurrent chromosomal translocation, t(11;22)(p13;q12). DSRCT is characterized by a predilection for young males, abdominal serosal involvement, poor prognosis, and a primitive histologic appearance. Gerald et al. (1995) found that the chromosome translocation breakpoints involved the intron between WT1 exons 7 and 8 and the intron between EWS (133450) exons 7 and 8. Chimeric transcripts corresponding to the fusion gene were detected in 4 of 6 cases of DSRCT. Analyses of these transcripts showed an in-frame fusion of RNA encoding the amino-terminal domain of EWS to both alternatively spliced forms of the last 3 zinc fingers of the DNA-binding domain of WT1. The chimeric products were predicted to modulate transcription at WT1 target sites and contribute to development of this unique tumor. WT1 encodes a zinc finger protein expressed as distinct isoforms. Both constitutional and somatic mutations disrupting the DNA-binding domain of WT1 result in a potentially dominant-negative phenotype. In generating inducible cell lines expressing wildtype isoforms of WT1 as well as WT1 mutants, Englert et al. (1995) observed dramatic differences in the subnuclear localization of the induced proteins. The WT1 isoform that binds with high affinity to a defined DNA target, WT1(-KTS), was diffusely localized throughout the nucleus. In contrast, expression of an alternative splicing variant with reduced DNA binding affinity, WT1(+KTS), or WT1 mutants with a disrupted zinc finger domain resulted in a speckled pattern of expression within the nucleus. Though similar in appearance, the localization of WT1 variants to subnuclear clusters was clearly distinct from that of the essential splicing factor SC35, suggesting that WT1 is not directly involved in pre-mRNA splicing. Localization to subnuclear clusters required the M terminus of WT1 and coexpression of a truncated WT1 mutant and wildtype WT1(-KTS) resulted in a physical association, the redistribution of WT1(-KTS) from a diffuse to a speckled pattern, and the inhibition of its transactivational activity. These observations suggested to the authors that different WT1 isoforms and WT1 mutants have distinct subnuclear compartments. Dominant-negative WT1 proteins physically associate with wildtype WT1 in vivo and may result in its sequestration within subnuclear structures. Products of the steroidogenic factor-1 (SF1; 184757) and WT1 genes are essential for mammalian gonadogenesis prior to sexual differentiation. In males, SF1 participates in sexual development by regulating expression of the polypeptide hormone Mullerian inhibiting substance (MIS; 600957). Nachtigal et al. (1998) showed that WT1-KTS isoforms associate and synergize with SF1 to promote MIS expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome, fail to synergize with SF1. Additionally, the X-linked, candidate dosage-sensitive sex-reversal (DSS; 300018) gene, DAX1 (300200), antagonizes synergy between SF1 and WT1, most likely through a direct interaction with SF1. Nachtigal et al. (1998) proposed that WT1 and DAX1 functionally oppose each other in testis development by modulating SF1-mediated transactivation. Little and Wells (1997) pointed out that only 5% of sporadic Wilms tumors have intragenic WT1 mutations, but more than 90% of patients with the Denys-Drash syndrome carry constitutional intragenic WT1 mutations. WT mutations have also been reported in juvenile granulosa-cell tumor, non-asbestos-related mesothelioma Park et al. (1993), desmoplastic small round cell tumor, and acute myeloid leukemia. Schumacher et al. (1997) identified 19 hemizygous WT1 gene mutations/deletions in tissue samples from 64 patients. The histology of the tumors with mutations was stromal-predominant in 15, triphasic in 3, blastemal-predominant in 1, and unknown in 2 cases. Among 21 patients with stromal-predominant tumors, 15 had WT1 mutations and 10 of these were present in the germline. Of the patients with germline alterations, 6 had associated genitourinary (GU) tract malformations and a unilateral tumor, 2 had a bilateral tumor and normal GU tracts, and 2 had a unilateral tumor and normal GU tracts. Three mutations were tumor-specific and were found in patients with unilateral tumors without genital tract abnormalities. These data demonstrated the correlation of WT1 mutations with stromal-predominant histology, suggesting that a germline mutation in WT1 predisposes to the development of tumors with this histology. Twelve mutations were nonsense mutations resulting in truncation at different positions in the WT1 protein, and only 2 were missense mutations. Of the stromal-predominant tumors, 67% showed loss of heterozygosity, and in 1 tumor a different somatic mutation in addition to the germline mutation was identified. Thus, in a large proportion of a histopathologically distinct subset of Wilms tumors, the classic 2-hit inactivation model, with loss of a functional WT1 protein, is the underlying cause of tumor development. Little et al. (1992) demonstrated that each parental allele of WT1 is equivalently expressed in normal fetal kidneys and Wilms tumors. On the other hand, Jinno et al. (1994) identified imprinting of WT1, with maternal expression in about half of preterm placental villus and fetal brain tissue. Further extensive studies showed that maternal monoallelic expression was observed in 39% of the samples, while the expression in other samples was biallelic. Mitsuya et al. (1997) studied the allele-specific expression of WT1 as well as of IGF2 and H19 in fibroblasts and lymphocytes. The expression profiles of IGF2 and H19 were constant and consistent with those in other tissues. The unexpected finding was paternal or biallelic expression of WT1 in fibroblasts and lymphocytes. This, together with the previous findings of maternal or biallelic expression in placenta and brain, suggested that the allele-specific regulatory system of WT1 is unique and may be controlled by a putative tissue- and individual-specific modifier. Miyagawa et al. (1998) focused on the ectopic formation of skeletal muscle in Wilms tumors. They presented evidence supporting a negative regulatory role for WT1 in myogenesis. Their findings suggested that the metanephric-mesenchymal stem cells of the kidney may have the capacity to differentiate into skeletal muscle cells as well as epithelial cells. Normally, the expression of WT1 appears to prevent this ectopic differentiation program from being activated. In vitro studies suggested that WT1 may play a direct role in suppressing the formation of skeletal muscle. Jeanpierre et al. (1998) identified WT1 mutations in patients with isolated diffuse mesangial sclerosis (256370), i.e., patients without pseudohermaphroditism and/or Wilms tumor which represent the other features of the Denys-Drash syndrome (DDS; 194080). In 4 of 10 patients, they found heterozygous mutations in the WT1 gene. Two mutations were different from those described in DDS patients. An analysis of genotype/phenotype correlation, on the basis of a WT1 mutation database of 84 germline mutations, demonstrated an association between mutations in exons 8 and 9 and DMS; among patients with DMS, a higher frequency of exon 8 mutations among 46,XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions. Beckwith (1998) provided useful data on the age at diagnosis of the first Wilms tumor in cases of syndrome-associated WT. Among 121 cases of Wiedemann-Beckwith syndrome, 96% were diagnosed by age 8 years; the oldest WBS patient had WT detected at 10 years, 2 months. Among 203 patients with hemihyperplasia, 94% were detected by age 8; the oldest HH patient had WT detected at 12 years, 4 months. Among 61 WAGR patients, Wilms tumor was detected in 98% by age 6 years; the oldest WAGR patient had WT detected at 7 years, 3 months. Among 52 patients with Denys-Drash syndrome, WT was detected in 96% by age 5 years; the oldest DDS patient had WT detected at 6 years of age. ALLELIC VARIANTS     .0001 WAGR SYNDROME [WT1, 17-BP DEL, EX4] Pelletier et al. (1991) reported constitutional mutations within the WT1 genes of 2 persons with a combination of Wilms tumor and genital abnormalities. They interpreted the findings as evidence of a role for a recessive oncogene in mammalian development. One patient (P.G.) had bilateral Wilms tumor, hypospadias, and undescended left testis. A small deletion in exon 4 was observed in a PCR product from chromosome 11, which was retained in P.G.'s first Wilms tumor. Specimens of a second tumor revealed both a normal PCR product of about 130 bp and the deleted product of 110 bp. In the tumor tissue, only the 110-bp fragment was found. Pelletier et al. (1991) concluded that in both tumors reduction to homozygosity for the WT1 allele containing a small deletion in exon 4 contributed to tumor formation. Sequence analysis of the abnormal allele showed a 17-bp deletion predicted to cause premature polypeptide chain termination in the exon. The deletion occurred between 2 copies of the pentanucleotide sequence TGACA. P.G.'s germline mutation appeared to be the consequence of either polymerase skipping during DNA replication or an unequal crossover event.     .0002 WAGR SYNDROME [WT1, 1-BP DEL, EX6, FS] In patient T.S., born with hypospadias and bilateral cryptorchidism and later developing Wilms tumor, Pelletier et al. (1991) found, by single strand conformation polymorphism (SSCP) analysis, a difference in the mobility pattern of exon 6 due to a single nucleotide deletion, a guanosine, in exon 6, which was predicted to cause early termination of translation. The father had been treated successfully for Wilms tumor in 1959. This was probably the first documentation of a transmitted WT1 mutation in familial Wilms tumor.     .0003 DENYS-DRASH SYNDROME [WT1, ARG394TRP] Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms tumor. In 10 cases of the syndrome, Pelletier et al. (1991) found point mutations in the zinc finger domains of one WT1 gene. Nine of these mutations were found within exon 9 (zinc finger III); the remaining mutation was in exon 8 (zinc finger II). These mutations directly affected DNA sequence recognition. In 2 families analyzed, the mutations were shown to arise de novo. Wilms tumors from 3 individuals and 1 juvenile granulosa cell tumor demonstrated reduction to homozygosity for the mutated WT1 allele. In 7 of the 10 cases, the change was a substitution of tryptophan for arginine at codon 394. Several of the patients with a 46,XY karyotype had ambiguous or female external genitalia with dysgenic or streak gonads. All the patients had nephropathy, which was commonly described as focal or diffuse mesangial sclerosis. Two patients had gonadoblastoma, and one of these also had juvenile granulosa cell tumor. (Although this syndrome had commonly been referred to as Drash syndrome (194080), Pelletier et al. (1991) referred to it as the Denys-Drash syndrome since the constellation of anomalies was first described in the French literature by Denys et al. (1967).) In a 46,XY individual with ambiguous genitalia, rudimentary uterus, fimbriated fallopian tubes, and streak gonads, who was described in greater detail by McCoy et al. (1983), Bruening et al. (1992) demonstrated a point mutation within exon 9, which converted arginine-394 to tryptophan. The patient's mother did not carry the mutation. Baird et al. (1992) found this mutation, a C-to-T transition at nucleotide 1180, in 3 of 8 patients with the Denys-Drash syndrome. Coppes et al. (1992) found the arg394-to-trp (exon 9) mutation in 2 of 3 patients with the Denys-Drash syndrome. Unlike patients in previous reports, one of the patients inherited the mutant allele from his phenotypically unaffected father. The father had no abnormalities and, in particular, he had bilaterally descended testes of normal volume and a normal penis without hypospadias. He had donated his kidney for transplantation to his son with Denys-Drash syndrome. Little et al. (1993) reported the same mutation.     .0004 DENYS-DRASH SYNDROME [WT1, ARG366HIS] One of 10 patients studied by Pelletier et al. (1991) had a germline mutation resulting in substitution of histidine for arginine at codon 366. The same mutation was observed by Baird et al. (1992).     .0005 DENYS-DRASH SYNDROME [WT1, ASP396GLY] One of the 10 patients studied by Pelletier et al. (1991) had a germline mutation in the WT1 gene leading to substitution of glycine for aspartic acid at codon 396.     .0006 DENYS-DRASH SYNDROME [WT1, ASP396ASN] One of the 10 patients studied by Pelletier et al. (1991) had a germline mutation of the WT1 gene resulting in substitution of asparagine for aspartic acid at codon 396. Baird et al. (1992) found the same mutation, a G-to-A transition at nucleotide 1186, in 1 of 8 patients with Denys-Drash syndrome. The asp396-to-asn mutation was also reported by Little et al. (1993); a G-to-A transition affecting ZF3 was present in heterozygous state constitutionally and was homozygous in the bilateral Wilms tumor.     .0007 DENYS-DRASH SYNDROME [WT1, ARG394PRO] In a phenotypic female with a 46,XY chromosome constitution and nephropathy with Wilms tumor, Bruening et al. (1992) identified a guanine to cytosine transversion in exon 9, converting arginine-394 to proline. Genomic DNA from this patient (J.K.) was available only from a Wilms tumor specimen embedded in paraffin. Bruening et al. (1992) suspected that, like other patients with Denys-Drash syndrome (Pelletier et al., 1991), J.K. was germline hemizygous for this mutation.     .0008 DENYS-DRASH SYNDROME [WT1, CYS330TYR] In a patient (K.J.) with Denys-Drash syndrome, Bruening et al. (1992) identified a point mutation within exon 7 (zinc finger I) converting cysteine-330 to tyrosine. The patient had a 46,XX karyotype and mild clitoromegaly. Nephropathy was present and both kidneys showed extensive intralobar persistent renal blastema but no overt Wilms tumor.     .0009 DENYS-DRASH SYNDROME [WT1, IVS9DS, G-A, +5] In C.S., a patient with renal failure due to glomerular sclerosis associated with female external genitalia and a 46,XY karyotype, Bruening et al. (1992) discovered a mutation by SSCP which was found to represent a guanine-to-adenine transition at position +5 of the splice donor site within intron 9. It appeared that the mutation affected the alternative splice site selection at exon 9. The various WT1 splice forms have a similar relative abundance in different mouse and human tissues as well as in different Wilms tumors. These splice forms are referred to as A, which lacks both alternatively spliced exons; B, which contains the first alternatively spliced exon; C, which contains the second alternatively spliced exon; and D, which contains both alternatively chosen exons. Several isoforms may have different functions.     .0010 WILMS TUMOR [WT1, ARG-TER, ZF3] In an infant who presented with simultaneous bilateral Wilms tumor at the age of 11 months, Little et al. (1992) found a point mutation at a CpG dinucleotide in zinc finger 3, changing a C to a T at nucleotide 350 and resulting in an arginine becoming a stop codon. The mutation was detected constitutionally in both tumors of the patient. It was present in heterozygous state in 1 tumor and in somatic cells, whereas due to hemizygosity, the other tumor carried only the mutant allele. Neither parent carried the mutation.     .0011 WILMS TUMOR [WT1, ARG-CYS, ZF2] In a 3-year-old child with unilateral sporadic Wilms tumor and no family history of renal neoplasia or associated anomalies or cytogenetic abnormalities, Little et al. (1992) found a C-to-T transversion at nucleotide 339 of zinc finger 2, resulting in an arginine to cysteine amino acid change. The mutation was present in only 1 allele of the tumor and was not present constitutionally or in either of the parents. Furthermore, it was not found in any of 34 normal, unrelated Caucasians.     .0012 DENYS-DRASH SYNDROME [WT1, HIS377TYR] In constitutional DNA from a patient with Denys-Drash syndrome, Coppes et al. (1992) found a C-to-T transition of nucleotide 1129 converting amino acid residue his377 to tyr. The change occurred in exon 8.     .0013 DENYS-DRASH SYNDROME [WT1, CYS360GLY] In a patient with unilateral Wilms tumor and 'Drash' nephropathy, Little et al. (1993) described a T-to-G transversion converting codon 360 from cysteine to glycine. The mutation was heterozygous in both the constitution and the tumor.     .0014 DENYS-DRASH SYNDROME [WT1, ARG362TER] In a 46,XY patient with micropenis and cryptorchidism, bilateral Wilms tumor, and 'Drash' nephropathy, Little et al. (1993) described a C-to-T transition converting codon 362 from arginine to a stop codon. It was present in heterozygous state in the constitution and homozygous state in the tumors. Since the mutation affected ZF2, resulting in a truncated protein interfering with DNA binding, Little et al. (1993) suggested that missense mutations operate by a dominant-negative mechanism.     .0015 DENYS-DRASH SYNDROME [WT1, HIS373GLN] In a 46,XY patient with hypospadias and 'Drash' nephropathy, Little et al. (1993) described a C-to-G transversion converting codon 373 in ZF2 from histidine to glutamine.     .0016 MESOTHELIOMA [WT1, SER273GLY] Park et al. (1993) showed that the WT1 gene, in addition to being expressed in tissues of the genitourinary system, is also expressed at high levels in many supportive structures of mesodermal origin in the mouse. Furthermore, they described a case of adult human mesothelioma that contained a homozygous A-to-G transition resulting in a serine to glycine substitution at codon 273. Normal tissue from the patient showed no evidence of this mutation, indicating that it was absent from the germline and arose as a somatic mutation within the tumor. Mesothelioma is a tumor derived from the peritoneal lining. The particular tumor studied was of the rare multicystic type which is not metastatic and has been classified as a hamartoma or a developmental abnormality of borderline malignancy (Salazar et al., 1972). Unlike most mesotheliomas, multicystic tumors are not associated with a history of asbestos exposure. Park et al. (1993) screened 32 specimens of asbestos-related mesothelioma and found no WT1 mutations. The ser273-to-gly mutation was the first reported outside the zinc finger domain that leads to an amino acid substitution rather than a termination codon. Codon 273 is highly conserved across species. Whereas wildtype WT1 represses transcription from the early growth response-1 (EGR1; 128990) promoter, following cotransfection into NIH 3T3 cells, Park et al. (1993) found that insertion of the ser273-to-gly mutation resulted in a WT1 protein that activated transcription from the EGR1 promoter.     .0017 WILMS TUMOR, FAMILIAL [WT1, ARG362TER] Kaplinsky et al. (1996) identified a nonsense mutation in the WTN gene in the Wilms tumor of 3 sisters who had the same father but 2 different mothers: a C-to-T transition at nucleotide 1084 (relative to the A of the ATG initiation codon) of the WT1 gene resulted in an arg362-to-ter substitution within zinc finger II. The mutation was predicted to result in the production of a truncated WT1 polypeptide unable to bind DNA. Two other sibs, both male, were unaffected. Two of the sisters had unilateral Wilms tumor, 1 had bilateral disease. The father, although a carrier, had never developed WT. Kaplinsky et al. (1996) commented that this may be due to incomplete penetrance, which is not gender related. Alternatively, the father could be mosaic for the WT1 mutation, such that mutant cells had not substantially contributed to development of the urogenital system. A third possibility is that genomic imprinting of the mutated WT1 allele is responsible for masking its expression in the male carrier. In the proband, analysis of DNA from a Wilms tumor revealed loss of heterozygosity with retention of 1 set of conformers present in the proband and the father. This pattern is classical for tumor suppressor gene analysis and suggested the unmasking of a recessive mutation by loss of the wildtype allele.     .0018 FRASIER SYNDROME [WT1, IVS9DS, C-T, +4] Frasier syndrome (136680) is a rare disorder defined by male pseudohermaphroditism and progressive glomerulopathy (Frasier et al., 1964; Haning et al., 1985; Kinberg et al., 1987). Patients present with normal female external genitalia, streak gonads, and XY karyotype, and frequently develop gonadoblastoma (Blanchet et al., 1977). Glomerular symptoms consist of childhood proteinuria and nephrotic syndrome, characterized by nonspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood. Wilms tumor is not a feature of the syndrome. In contrast with Frasier syndrome, most individuals with Denys-Drash syndrome (194080) have ambiguous genitalia or a female phenotype, an XY karyotype, and dysgenetic gonads. Renal symptoms are characterized by diffuse mesangial sclerosis, usually before the age of 1 year, and the patients frequently develop Wilms tumor. Alternative splicing of WT1 generates 4 isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows the addition of 3 amino acids (lys-thr-ser, or KTS) between the third and fourth zinc fingers of the WT1 protein (Haber et al., 1991). Barbaux et al. (1997) demonstrated that Frasier syndrome was caused by a mutation in the donor splice site in intron 9 of WT1, with the predicted loss of the so-called +KTS isoform. Examination of WT1 transcripts showed a diminution of the +KTS/-KTS isoform ratio in patients with Frasier syndrome. Three unrelated patients presented with persistent proteinuria between the ages of 2 and 6 years and subsequently developed nephrotic syndrome that progressed to end-stage renal failure between 9 and 35 years of age. Renal biopsies performed before the onset of renal insufficiency showed minimal nonspecific glomerular changes in 1 patient and focal and segmental glomerular sclerosis in the other 2 patients. All 3 patients underwent successful kidney transplantation without recurrence of the nephrotic syndrome. Evaluation of primary amenorrhea in these 3 females with normal female phenotype led to diagnosis of 46,XY gonadal dysgenesis. One of the 3 patients developed gonadoblastoma, which was diagnosed when she was 19; no recurrence was observed after surgical treatment. The other 2 patients underwent bilateral surgical gonadectomy. Two of 3 patients were found to carry the C-to-T transition at position +4 of intron 9 in 1 allele. This nucleotide substitution was not detected in the DNA from either parent, indicating a de novo mutation. A third patient was found to have a mutation in intron 9 at position +6, substituting a thymidine for an adenine (194070.0019). A screen of the SRY gene (480000) had failed to detect mutations in any of the 3 patients. Klamt et al. (1998) reported 3 cases of Frasier syndrome and the IVS9DS+4C-T mutation. Barbosa et al. (1999) stated that 18 patients with Frasier syndrome had been described, all with heterozygous point mutations affecting the donor splice site of intron 9 of WT1; none had presented with Wilms tumor. They described 2 patients with Frasier syndrome and the IVS9DS+4C-T mutation; one of these patients also had Wilms tumor. The mutation was detected in both peripheral blood and in tumor-derived DNA of the patient with Frasier syndrome and Wilms tumor. The congenital anomalies in these 2 patients were the same as in other cases of Frasier syndrome: female external genitalia, in spite of a 46,XY karyotype, and streak gonads. The nephroblastoma in the patient with Wilms tumor had been diagnosed at the age of 3 years. The possibility that the patient actually represented a case of Denys-Drash syndrome was rejected because of normal histology of the kidney removed at age 3; the late onset of proteinuria; the slow progression of nephropathy, once developed; and the presence of a complete female phenotype with dysgenetic gonads, typical of Frasier syndrome. Thus this is the only one of 20 patients carrying mutations within splice site 2 of exon 9 of the WT1 gene who developed Wilms tumor in association with the features of Frasier syndrome.     .0019 FRASIER SYNDROME [WT1, IVS9DS, A-T, +6] See 194070.0018 and Barbaux et al. (1997).     .0020 FRASIER SYNDROME [WT1, IVS9DS, G-A, +5] Klamt et al. (1998) described 6 cases of an IVS9DS+5G-A mutation in the WT1 gene. Merging of mutational data from 18 cases demonstrated a striking bias: 15 of the 18 cases showed either the +4C-T (194070.0018) or the +5G-A mutations. This mutational hotspot probably results from the potential to deaminate 5-methylcytosine at the +4/+5 CpG dinucleotide. Klamt et al. (1998) showed that disruption of alternative splicing at the exon 9 donor splice site prevents synthesis of the usually more abundant WT1 +KTS isoform from the mutant allele. In contrast to Denys-Drash syndrome, no mutant protein is produced. The splice mutation leads to an imbalance of WT1 isoforms in vivo, as detected by RT-PCR on streak gonadal tissue. Thus, WT1 isoforms must have different functions, and the pathology of Frasier syndrome suggests that gonadal development may be particularly sensitive to imbalance or relative underrepresentation of the WT1 +KTS isoform. (The +KTS isoform has 3 additional amino acids, lys-thr-ser, between the third and fourth zinc fingers of the WT1 protein (Haber et al., 1991).)     .0021 MESANGIAL SCLEROSIS, ISOLATED DIFFUSE [WT1, HIS377TYR] In a 46,XX female with normal external genitalia and normal puberty associated with isolated diffuse mesangial sclerosis (256370), Jeanpierre et al. (1998) demonstrated an 1129C-T transition in exon 8 of the WT1 gene that produced an his377-to-tyr (H377Y) amino acid substitution. The first symptoms occurred at the age of 6 months; end-stage renal failure was present by age 3 years and 10 months.     .0022 MESANGIAL SCLEROSIS, ISOLATED DIFFUSE [WT1, PHE383LEU] In a male patient with normal external genitalia and normal puberty associated with isolated diffuse mesangial sclerosis (256370), Jeanpierre et al. (1998) found an 1147T-C transition in exon 9, leading to an phe383-to-leu (F383L) amino acid substitution in the WT1 protein.     .0023 MESANGIAL SCLEROSIS, ISOLATED DIFFUSE [WT1, ASP396ASN ] In a 46,XX female with normal external genitalia and DMS (256370), Jeanpierre et al. (1998) found an 1186G-A transition in exon 9 of the WT1 gene, leading to a asp396-to-asn (D396N) amino acid substitution in the WT1 protein.   SEE ALSO Babaian et al. (1980) ; Cordero et al. (1980) ; DiGeorge and Harley (1966) ; Francke et al. (1979) ; Fraumeni and Glass (1968) ; Huerre et al. (1983) ; Juberg et al. (1975) ; Kaufman et al. (1973) ; Knudson and Strong (1975) ; Kolata (1980) ; Kontras and Newton (1974) ; Ladda et al. (1974) ; Neidhardt (1972) ; Pelletier et al. (1991) ; Slater and de Kraker (1982) ; Turleau et al. (1984) ; Yunis and Ramsay (1980) REFERENCES 1. Anderson, S. R.; Geertinger, P.; Larsen, H.-W.; Mikkelsen, M.; Parving, A.; Vestermark, S.; Warburg, M. : Aniridia, cataract and gonadoblastoma in a mentally retarded girl with deletion of chromosome 11: a clinicopathological case report. Ophthalmologica 176: 171-177, 1978.   2. Babaian, R. J.; Skinner, D. G.; Waisman, J. : Wilms' tumor in the adult patient: diagnosis, management, and review of the world medical literature. Cancer 45: 1713-1719, 1980. PubMed ID : 6245783   3. Baird, P. N.; Santos, A.; Groves, N.; Jadresic, L.; Cowell, J. K. : Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome. Hum. Molec. Genet. 1: 301-305, 1992. PubMed ID : 1338906   4. Barbaux, S.; Niaudet, P.; Gubler, M.-C.; Grunfeld, J.-P.; Jaubert, F.; Kuttenn, F.; Fekete, C. N.; Souleyreau-Therville, N.; Thibaud, E.; Fellous, M.; McElreavey, K. : Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nature Genet. 17: 467-470, 1997. PubMed ID : 9398852   5. Barbosa, A. S.; Hadjiathanasiou, C. G.; Theodoridis, C.; Papathanasiou, A.; Tar, A.; Merksz, M.; Gyorvari, B.; Sultan, C.; Dumas, R.; Jaubert, F.; Niaudet, P.; Moreira-Filho, C. A.; Cotinot, C.; Fellous, M. : The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor. Hum. Mutat. 13: 146-153, 1999.   6. Beckwith, J. B. : Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am. J. Med. Genet. 79: 268-273, 1998. PubMed ID : 9781906   7. Blanchet, P.; Daloze, P.; Lesage, R.; Papas, S.; van Campenhout, J. : XY gonadal dysgenesis with gonadoblastoma discovered after kidney transplantation. Am. J. Obstet. Gynec. 129: 221-222, 1977. PubMed ID : 331956   8. Bond, J. V. : Bilateral Wilms' tumor: age at diagnosis, associated congenital anomalies, and possible pattern of inheritance. Lancet II: 482-484, 1975. PubMed ID : 51289   9. Bonetta, L.; Huang, A.; Gregoris, M.; Yeger, H.; Williams, B. R. G. : Characterization of a homozygous deletion mapping to the Wilms tumor region on 11p13. (Abstract) Cytogenet. Cell Genet. 51: 965, 1989.   10. Brown, W. T.; Puranik, S. R.; Altman, D. H.; Hardin, H. C., Jr. : Wilms' tumor in three successive generations. Surgery 72: 756-761, 1972. PubMed ID : 4342979   11. Bruening, W.; Bardeesy, N.; Silverman, B. L.; Cohn, R. A.; Machin, G. A.; Aronson, A. J.; Housman, D.; Pelletier, J. : Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development. Nature Genet. 1: 144-148, 1992. PubMed ID : 1302008   12. Call, K. M.; Glaser, T.; Ito, C. Y.; Buckler, A. J.; Pelletier, J.; Haber, D. A.; Rose, E. A.; Kral, A.; Yeger, H.; Lewis, W. H.; Jones, C.; Housman, D. E. : Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60: 509-520, 1990. PubMed ID : 2154335   13. Comings, D. E. : A general theory of carcinogenesis. Proc. Nat. Acad. Sci. 70: 3324-3328, 1973. PubMed ID : 4202843   14. Coppes, M. J.; Liefers, G. J.; Higuchi, M.; Zinn, A. B.; Balfe, J. W.; Williams, B. R. G. : Inherited WT1 mutation in Denys-Drash syndrome. Cancer Res. 52: 6125-6128, 1992. PubMed ID : 1327525   15. Cordero, J. F.; Li, F. P.; Holmes, L. B.; Gerald, P. S. : Wilms tumor in five cousins. Pediatrics 66: 716-719, 1980. PubMed ID : 6253867   16. Dao, D. D.; Schroeder, W. T.; Chao, L.-Y.; Kikuchi, H.; Strong, L. C.; Riccardi, V. M.; Pathak, S.; Nichols, W. W.; Lewis, W. H.; Saunders, G. F. : Genetic mechanisms of tumor-specific loss of 11p DNA sequences in Wilms tumor. Am. J. Hum. Genet. 41: 202-217, 1987. PubMed ID : 3039839   17. de Martinville, B.; Francke, U. : HRAS1, insulin and beta-globin map outside of 11p11.2-p14.1. (Abstract) Cytogenet. Cell Genet. 37: 530, 1984.   18. de Martinville, B.; Francke, U. : The c-Ha-ras1, insulin and beta-globin loci map outside the deletion associated with aniridia-Wilms' tumour. Nature 305: 641-643, 1983. PubMed ID : 6312329   19. Denys, P.; Malvaux, P.; van den Berghe, H.; Tanghe, W.; Proesmans, W. : Association d'un syndrome anatomo-pathologique de pseudohermaphrodisme masculin, d'une tumeur de Wilms, d'une nephropathie parenchymateuse et d'un mosaicisme XX/XY. Arch. Franc. Pediat. 24: 729-739, 1967. PubMed ID : 4292870   20. de Ronde, A.; Mannens, M.; Slater, R. M.; Hoovers, J.; Heyting, C.; Bleeker-Wagemakers, E. M.; Leschot, N. J.; Van Strien, A.; Sol, C. J. A.; Ter Schegget, J.; Van der Noordaa, J. : Morphological transformation by early region human polyomavirus BK DNA of human fibroblasts with deletions in the short arm of one chromosome 11. J. Gen. Virol. 69: 467-471, 1988. PubMed ID : 2828520   21. DiGeorge, A. M.; Harley, R. D. L. : The association of aniridia, Wilms tumor and genital abnormalities. Arch. Ophthal. 75: 796-798, 1966. PubMed ID : 4287042   22. Dressler, G. R.; Douglass, E. C. : Pax-2 is a DNA-binding protein expressed in embryonic kidney and Wilms tumor. Proc. Nat. Acad. Sci. 89: 1179-1183, 1992. PubMed ID : 1311084   23. Englert, C.; Vidal, M.; Maheswaran, S.; Ge, Y.; Ezzell, R. M.; Isselbacher, K. J.; Haber, D. A. : Truncated WT1 mutants alter the subnuclear localization of the wild-type protein. Proc. Nat. Acad. Sci. 92: 11960-11964, 1995. PubMed ID : 8618823   24. Fearon, E. R.; Vogelstein, B.; Feinberg, A. P. : Somatic deletion and duplication of genes on chromosome 11 in Wilms' tumours. Nature 309: 176-178, 1984. PubMed ID : 6325939   25. Fitzgerald, W. L.; Hardin, H. C., Jr. : Bilateral Wilms' tumor in a Wilms tumor family: case report. J. Urol. 73: 468-474, 1955.   26. Francke, U. : A gene for Wilms tumour?. Nature 343: 692-694, 1990. PubMed ID : 2154698   27. Francke, U.; Holmes, L. B.; Atkins, L.; Riccardi, V. M. : Aniridia-Wilms' tumor association: evidence for specific deletion of 11p13. Cytogenet. Cell Genet. 24: 185-192, 1979. PubMed ID : 225131   28. Francke, U.; Riccardi, V. M.; Hittner, H. M.; Borges, W. : Interstitial del(11p) as a cause of the aniridia-Wilms tumor association: band localization and a heritable basis. (Abstract) Am. J. Hum. Genet. 30: 81A, 1978.   29. Frasier, S. D.; Bashore, R. A.; Mosier, H. D. : Gonadoblastoma associated with pure gonadal dysgenesis in monozygotic twins. J. Pediat. 64: 740-745, 1964.   30. Fraumeni, J. F., Jr.; Glass, A. G. : Wilms' tumor and congenital aniridia. J.A.M.A. 206: 825-828, 1968. PubMed ID : 4300348   31. Gerald, W. L.; Rosai, J.; Ladanyi, M. : Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor. Proc. Nat. Acad. Sci. 92: 1028-1032, 1995. PubMed ID : 7862627   32. Gessler, M. : Personal Communication. Marburg, Germany, 10/17/1991.   33. Gessler, M.; Konig, A.; Bruns, G. A. P. : The genomic organization and expression of the WT1 gene. Genomics 12: 807-813, 1992. PubMed ID : 1572653   34. Gessler, M.; Poustka, A.; Cavenee, W.; Neve, R. L.; Orkin, S. H.; Bruns, G. A. P. : Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343: 774-778, 1990. PubMed ID : 2154702   35. Gilgenkrantz, S.; Vigneron, C.; Gregoire, M. J.; Pernot, C.; Raspiller, A. : Association of del(11)(p15.1p12), aniridia, catalase deficiency, and cardiomyopathy. Am. J. Med. Genet. 13: 39-49, 1982. PubMed ID : 6127950   36. Haber, D. A.; Buckler, A. J.; Glaser, T.; Call, K. M.; Pelletier, J.; Sohn, R. L.; Douglass, E. C.; Housman, D. E. : An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor. Cell 61: 1257-1269, 1990. PubMed ID : 2163761   37. Haber, D. A.; Park, S.; Maheswaran, S.; Englert, C.; Re, G. G.; Hazen-Martin, D. J.; Sens, D. A.; Garvin, A. J. : WT1-mediated growth suppression of Wilms tumor cells expressing a WT1 splicing variant. Science 262: 2057-2059, 1993. PubMed ID : 8266105   38. Haber, D. A.; Sohn, R. L.; Buckler, A. J.; Pelletier, J.; Call, K. M.; Housman, D. E. : Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc. Nat. Acad. Sci. 88: 9618-9622, 1991. PubMed ID : 1658787   39. Haber, D. A.; Timmers, H. T. M.; Pelletier, J.; Sharp, P. A.; Housman, D. E. : A dominant mutation in the Wilms tumor gene WT1 cooperates with the viral oncogene E1A in transformation of primary kidney cells. Proc. Nat. Acad. Sci. 89: 6010-6014, 1992. PubMed ID : 1321431   40. Haning, R. V., Jr.; Chesney, R. W.; Moorthy, A. V.; Gilbert, E. F. : A syndrome of chronic renal failure and XY gonadal dysgenesis in young phenotypic females without genital ambiguity. Am. J. Kidney Dis. 6: 40-48, 1985. PubMed ID : 3895900   41. Hastie, N. D. : Dominant negative mutations in the Wilms tumour (WT1) gene cause Denys-Drash syndrome--proof that a tumour-suppressor gene plays a crucial role in normal genitourinary development. Hum. Molec. Genet. 1: 293-295, 1992. PubMed ID : 1338905   42. Huerre, C.; Despoisse, S.; Gilgenkrantz, S.; Lenoir, G. M.; Junien, C. : c-Ha-ras1 is not deleted in aniridia-Wilms' tumour association. Nature 305: 638-641, 1983. PubMed ID : 6312328   43. Huff, V.; Meadows, A.; Riccardi, V. M.; Strong, L. C.; Saunders, G. F. : Parental origin of de novo constitutional deletions of chromosomal band 11p13. Am. J. Hum. Genet. 47: 155-160, 1990. PubMed ID : 1971994   44. Huff, V.; Miwa, H.; Haber, D. A.; Call, K. M.; Housman, D.; Strong, L. C.; Saunders, G. F. : Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT. Am. J. Hum. Genet. 48: 997-1003, 1991. PubMed ID : 1673293   45. Jeanpierre, C.; Antignac, C.; Beroud, C.; Lavedan, C.; Henry, I.; Saunders, G.; Williams, B.; Glaser, T.; Junien, C. : Constitutional and somatic deletions of two different regions of maternal chromosome 11 in Wilms tumor. Genomics 7: 434-438, 1990. PubMed ID : 1973142   46. Jeanpierre, C.; Denamur, E.; Henry, I.; Cabanis, M.-O.; Luce, S.; Cecille, A.; Elion, J.; Peuchmaur, M.; Loirat, C.; Niaudet, P.; Gubler, M.-C.; Junien, C. : Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database. Am. J. Hum. Genet. 62: 824-833, 1998. PubMed ID : 9529364   47. Jinno, Y.; Yun, K.; Nishiwaki, K.; Kubota, T.; Ogawa, O.; Reeve, A. E.; Niikawa, N. : Mosaic and polymorphic imprinting of the WT1 gene in humans. Nature Genet. 6: 305-309, 1994. PubMed ID : 8012395   48. Jolles, B. : Wilms' tumor in father and son. Lancet I: 207, 1973. PubMed ID : 4118827   49. Juberg, R. C.; St. Martin, E. C.; Hundley, J. R. : Familial occurrence of Wilms's tumor: nephroblastoma in one of monozygous twins and in another sibling. Am. J. Hum. Genet. 27: 155-169, 1975. PubMed ID : 164771   50. Junien, C.; Huerre, C.; Despoisse, S.; Gilgenkrantz, S.; Lenoir, G. M. : c-Ha-ras1 is not deleted in del (11p13) Wilms' tumor (WAGR) and maps to 11p15.1-11p15.5. (Abstract) Cytogenet. Cell Genet. 37: 503, 1984.   51. Junien, C.; Turleau, C.; de Grouchy, J.; Said, R.; Rethore, M.-O.; Tenconi, R.; Dufier, J. L. : Regional assignment of catalase (CAT) gene to band 11p13: association with the aniridia-Wilms' tumor-gonadoblastoma (WAGR) complex. Ann. Genet. 23: 165-168, 1980. PubMed ID : 6252821   52. Kakati, S.; Xiao, H.; Siddiqui, S. Y.; Sreekantaiah, C.; Weier, H.-U. G.; Green, D. M.; Fisher, J. E.; Allen, J. E. : Constitutional extra chromosomal element in a family with Wilms' tumor. Hum. Genet. 87: 183-188, 1991. PubMed ID : 1648545   53. Kaneko, Y.; Celida Egues, M.; Rowley, J. D. : Interstitial deletion of short arm of chromosome 11 limited to Wilms' tumor cells in a patient without aniridia. Cancer Res. 41: 4577-4578, 1981. PubMed ID : 6272980   54. Kaplinsky, C.; Ghahremani, M.; Frishberg, Y.; Rechavi, G.; Pelletier, J. : Familial Wilms' tumor associated with a WT1 zinc finger mutation. Genomics 38: 451-453, 1996. PubMed ID : 8975729   55. Kaufman, R. L.; Vietti, T. J.; Wabner, C. I. : Wilms' tumor in father and son. Lancet I: 43, 1973. PubMed ID : 4118565   56. Kinberg, J. A.; Angle, C. R.; Wilson, R. B. : Nephropathy-gonadal dysgenesis, type 2: renal failure in three siblings with XY dysgenesis in one. Am. J. Kidney Dis. 9: 507-510, 1987. PubMed ID : 3591796   57. Klamt, B.; Koziell, A.; Poulat, F.; Wieacker, P.; Scambler, P.; Berta, P.; Gessler, M. : Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. Hum. Molec. Genet. 7: 709-714, 1998. PubMed ID : 9499425   58. Knudson, A. G., Jr.; Strong, L. C. : Familial Wilms's tumor. (Letter) Am. J. Hum. Genet. 27: 809-810, 1975. PubMed ID : 173187   59. Knudson, A. G., Jr.; Strong, L. C. : Mutation and cancer: a model for Wilms' tumor of the kidney. J. Nat. Cancer Inst. 48: 313-324, 1972.   60. Kolata, G. B. : Genes and cancer: the story of Wilms tumor. Science 207: 970-971, 1980. PubMed ID : 6243422   61. Kontras, S. B.; Newton, W. A., Jr. : Familial Wilms' tumor. Birth Defects Orig. Art. Ser. X(4): 187-188, 1974.   62. Koufos, A.; Hansen, M. F.; Copeland, N. G.; Jenkins, N. A.; Lampkin, B. C.; Cavenee, W. K. : Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism. Nature 316: 330-334, 1985. PubMed ID : 2991766   63. Koufos, A.; Hansen, M. F.; Lampkin, B. C.; Workman, M. L.; Copeland, N. G.; Jenkins, N. A.; Cavenee, W. K. : Loss of alleles at loci on human chromosome 11 during genesis of Wilms' tumour. Nature 309: 170-172, 1984. PubMed ID : 6325936   64. Kozman, H. M.; Clarke, J. M.; Little, M. H.; Smith, P. J. : Molecular genetic evidence for common pathogenesis of childhood and adult Wilms' tumor. Cancer Genet. Cytogenet. 38: 121-125, 1989. PubMed ID : 2540899   65. Kreidberg, J. A.; Sariola, H.; Loring, J. M.; Maeda, M.; Pelletier, J.; Housman, D.; Jaenisch, R. : WT-1 is required for early kidney development. Cell 74: 679-691, 1993. PubMed ID : 8395349   66. Kumar, S.; Harrison, C. J.; Heighway, J.; Marsden, H. B.; West, D. C.; Jones, P. M. : A cell line from Wilms' tumour with deletion in short arm of chromosome 11. Int. J. Cancer 40: 499-504, 1987. PubMed ID : 2444543   67. Ladda, R. L.; Atkins, L.; Littlefield, J. : Computer-assisted analysis of chromosomal abnormalities: detection of a deletion in aniridia Wilms' tumor syndrome. Science 185: 784-787, 1974. PubMed ID : 4367262   68. Lewis, W. H.; Yeger, H. : Characterization of the aniridia-Wilms tumor association region of chromosome 11. (Abstract) Cytogenet. Cell Genet. 46: 650, 1987.   69. Little, M.; Holmes, G.; Bickmore, W.; van Heyningen, V.; Hastie, N.; Wainwright, B. : DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations. Hum. Molec. Genet. 4: 351-358, 1995. PubMed ID : 7795587   70. Little, M.; Wells, C. : A clinical overview of WT1 gene mutations. Hum. Mutat. 9: 209-225, 1997. PubMed ID : 9090524   71. Little, M. H.; Dunn, R.; Byrne, J. A.; Seawright, A.; Smith, P. J.; Pritchard-Jones, K.; van Heyningen, V.; Hastie, H. D. : Equivalent expression of paternally and maternally inherited WT1 alleles in normal fetal tissue and Wilms' tumours. Oncogene 7: 635-641, 1992. PubMed ID : 1314367   72. Little, M. H.; Prosser, J.; Condie, A.; Smith, P. J.; Van Heyningen, V.; Hastie, N. D. : Zinc finger point mutations within the WT1 gene in Wilms tumor patients. Proc. Nat. Acad. Sci. 89: 4791-4795, 1992. PubMed ID : 1317572   73. Little, M. H.; Williamson, K. A.; Mannens, M.; Kelsey, A.; Gosden, C.; Hastie, N. D.; van Heyningen, V. : Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. Hum. Molec. Genet. 2: 259-264, 1993. PubMed ID : 8388765   74. Mannens, M.; Slater, R. M.; Heyting, C.; Bliek, J.; de Kraker, J.; Coad, N.; de Pagter-Holthuizen, P.; Pearson, P. L. : Molecular nature of genetic changes resulting in loss of heterozygosity of chromosome 11 in Wilms' tumours. Hum. Genet. 81: 41-48, 1988. PubMed ID : 2848758   75. Marshall, L. S.; Qureshi, A. R.; DiGeorge, A. M.; Kistenmacher, M. L.; Punnett, H. H. : Aniridia and the 11p13 deletion. (Abstract) Am. J. Hum. Genet. 34: 74A, 1982.   76. Matsunaga, E. : Genetics of Wilms' tumor. Hum. Genet. 57: 231-246, 1981. PubMed ID : 6265341   77. McCoy, F. E., Jr.; Franklin, W. A.; Aronson, A. J.; Spargo, B. H. : Glomerulonephritis associated with male pseudohermaphroditism and nephroblastoma. Am. J. Surg. Path. 7: 387-395, 1983. PubMed ID : 6307071   78. Meadows, A. T.; Lichtenfeld, J. L.; Koop, C. E. : Wilms' tumor in three children of a woman with congenital hemihypertrophy. New Eng. J. Med. 291: 23-24, 1974. PubMed ID : 4364969   79. Michalopoulos, E. E.; Bevilacqua, P. J.; Stokoe, N.; Powers, V. E.; Willard, H. F.; Lewis, W. H. : Molecular analysis of gene deletion in aniridia--Wilms tumor association. Hum. Genet. 70: 157-162, 1985. PubMed ID : 2989154   80. Miller, R. W.; Fraumeni, J. F., Jr.; Manning, M. D. : Association of Wilms' tumor with aniridia, hemihypertrophy and other congenital malformations. New Eng. J. Med. 270: 922-927, 1964.   81. Mitsuya, K.; Sui, H.; Meguro, M.; Kugoh, H.; Jinno, Y.; Niikawa, N.; Oshimura, M. : Paternal expression of WT1 in human fibroblasts and lymphocytes. Hum. Molec. Genet. 6: 2243-2246, 1997. PubMed ID : 9361029   82. Miyagawa, K.; Kent, J.; Moore, A.; Charlieu, J.-P.; Little, M. H.; Williamson, K. A.; Kelsey, A.; Brown, K. W.; Hassam, S.; Briner, J.; Hayashi, Y.; Hirai, H.; Yazaki, Y.; van Heyningen, V.; Hastie, N. D. : Loss of WT1 function leads to ectopic myogenesis in Wilms' tumour. (Letter) Nature Genet. 18: 15-17, 1998. PubMed ID : 9425891   83. Nachtigal, M. W.; Hirokawa, Y.; Enyeart-VanHouten, D. L.; Flanagan, J. N.; Hammer, G. D.; Ingraham, H. A. : Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell 93: 445-454, 1998. PubMed ID : 9590178   84. Nakagome, Y.; Ise, T.; Sakurai, M.; Nakajo, T.; Okamoto, E.; Takano, T.; Nakahori, Y.; Tsuchida, Y.; Nagahara, N.; Takada, Y.; Ohsawa, Y.; Sawaguchi, S.; Toyosaka, A.; Kobayashi, N.; Matsunaga, E.; Saito, S. : High-resolution studies in patients with aniridia-Wilms tumor association, Wilms tumor or related congenital abnormalities. Hum. Genet. 67: 245-248, 1984. PubMed ID : 6088386   85. Narahara, K.; Kikkawa, K.; Kimira, S.; Kimoto, H.; Ogata, M.; Kasai, R.; Hamawaki, M.; Matsuoka, K. : Regional mapping of catalase and Wilms tumor--aniridia, genitourinary abnormalities, and mental retardation triad loci to the chromosome segment 11p1305-p1306. Hum. Genet. 66: 181-185, 1984. PubMed ID : 6325323   86. Neidhardt, M. : Wilms-tumor und Aniridie--ein genetisch fixiertes Syndrome?. Klin. Paediat. 184: 312-316, 1972.   87. Nordenskjold, A.; Fricke, G.; Anvret, M. : Absence of mutations in the WT1 gene in patients with XY gonadal dysgenesis. Hum. Genet. 96: 102-104, 1995. PubMed ID : 7607640   88. Orkin, S. H.; Goldman, D. S.; Sallan, S. E. : Development of homozygosity for chromosome 11p markers in Wilms' tumour. Nature 309: 172-174, 1984. PubMed ID : 6325937   89. Park, S.; Bernard, A.; Bove, K. E.; Sens, D. A.; Hazen-Martin, D. J.; Garvin, A. J.; Haber, D. A. : Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms' tumour. Nature Genet. 5: 363-367, 1993. PubMed ID : 8298644   90. Park, S.; Schalling, M.; Bernard, A.; Maheswaran, S.; Shipley, G. C.; Roberts, D.; Fletcher, J.; Shipman, R.; Rheinwald, J.; Demetri, G.; Griffin, J.; Minden, M.; Housman, D. E.; Haber, D. A. : The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma. Nature Genet. 4: 415-420, 1993. PubMed ID : 8401592   91. Pelletier, J.; Bruening, W.; Kashtan, C. E.; Mauer, S. M.; Manivel, J. C.; Striegel, J. E.; Houghton, D. C.; Junien, C.; Habib, R.; Fouser, L.; Fine, R. N.; Silverman, B. L.; Haber, D. A.; Housman, D. : Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67: 437-447, 1991. PubMed ID : 1655284   92. Pelletier, J.; Bruening, W.; Li, F. P.; Haber, D. A.; Glaser, T.; Housman, D. E. : WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature 353: 431-434, 1991. PubMed ID : 1654525   93. Porteous, D. J.; Bickmore, W.; Christie, S.; Boyd, P. A.; Cranston, G.; Fletcher, J. M.; Gosden, J. R.; Rout, D.; Seawright, A.; Simola, K. O. J.; van Heyningen, V.; Hastie, N. D. : HRAS1-selected chromosome transfer generates markers that colocalize aniridia- and genitourinary dysplasia-associated translocation breakpoints and the Wilms tumor gene within band 11p13. Proc. Nat. Acad. Sci. 84: 5355-5359, 1987. PubMed ID : 3037545   94. Pritchard-Jones, K.; Fleming, S.; Davidson, D.; Bickmore, W.; Porteous, D.; Gosden, C.; Bard, J.; Buckler, A.; Pelletier, J.; Housman, D.; van Heyningen, V.; Hastie, N. : The candidate Wilms' tumour gene is involved in genitourinary development. Nature 346: 194-197, 1990. PubMed ID : 2164159   95. Puissant, H.; Azoulay, M.; Serre, J.-L.; Piet, L.; Junien, C. : Molecular analysis of a reciprocal translocation t(5;11)(q11;p13) in a WAGR patient. Hum. Genet. 79: 280-282, 1988. PubMed ID : 2841227   96. Raizis, A. M.; Becroft, D. M.; Shaw, R. L.; Reeve, A. E. : A mitotic recombination in Wilms tumor occurs between the parathyroid hormone locus and 11p13. Hum. Genet. 70: 344-346, 1985. PubMed ID : 2991119   97. Reeve, A. E.; Eccles, M. R.; Wilkins, R. J.; Bell, G. I.; Millow, L. J. : Expression of insulin-like growth factor-II transcripts in Wilms' tumour. Nature 317: 258-260, 1985. PubMed ID : 2995817   98. Reeve, A. E.; Housiaux, P. J.; Gardner, R. J. M.; Chewings, W. E.; Grindley, R. M.; Millow, L. J. : Loss of a Harvey ras allele in sporadic Wilms' tumour. Nature 309: 174-176, 1984. PubMed ID : 6325938   99. Riccardi, V. M.; Hittner, H. M.; Strong, L. C.; Fernbach, D. J.; Lebo, R.; Ferrell, R. E. : Wilms tumor with aniridia/iris dysplasia and apparently normal chromosomes. J. Pediat. 100: 574-577, 1982. PubMed ID : 6278119   100. Riccardi, V. M.; Sujansky, E.; Smith, A. C.; Francke, U. : Chromosomal imbalance in the aniridia--Wilms' tumor association: 11p interstitial deletion. Pediatrics 61: 604-610, 1978. PubMed ID : 208044   101. Rose, E. A.; Glaser, T.; Jones, C.; Smith, C. L.; Lewis, W. H.; Call, K. M.; Minden, M.; Champagne, E.; Bonetta, L.; Yeger, H.; Housman, D. E. : Complete physical map of the WAGR region of 11p13 localizes a candidate Wilms' tumor gene. Cell 60: 405-508, 1990. PubMed ID : 2406020   102. Salazar, H.; Kanbour, A.; Burgess, F. : Ultrastructure and observations on the histogenesis of mesotheliomas 'adenomatoid tumors' of the female genital tract. Cancer 29: 141-152, 1972. PubMed ID : 4332312   103. Schmickel, R. D. : Chromosomal deletions and enzyme deficiencies. J. Pediat. 108: 244-246, 1986. PubMed ID : 3944710   104. Schroeder, W. T.; Chao, L.-Y.; Dao, D. D.; Strong, L. C.; Pathak, S.; Riccardi, V.; Lewis, W. H.; Saunders, G. F. : Nonrandom loss of maternal chromosome 11 alleles in Wilms tumors. Am. J. Hum. Genet. 40: 413-420, 1987. PubMed ID : 2883892   105. Schumacher, V.; Schneider, S.; Figge, A.; Wildhardt, G.; Harms, D.; Schmidt, D.; Weirich, A.; Ludwig, R.; Royer-Pokora, B. : Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology. Proc. Nat. Acad. Sci. 94: 3972-3977, 1997. PubMed ID : 9108089   106. Scoggin, C. H.; Fisher, J. H.; Shoemaker, S. A.; Morse, H.; Leigh, T.; Riccardi, V. M. : The E7-associated cell-surface antigen: a marker for the 11p13 chromosomal deletion associated with aniridia-Wilms tumor. Am. J. Hum. Genet. 37: 883-889, 1985. PubMed ID : 2996335   107. Scott, J.; Cowell, J.; Robertson, M. E.; Priestley, L. M.; Wadey, R.; Hopkins, B.; Pritchard, J.; Bell, G. I.; Rall, L. B.; Graham, C. F.; Knott, T. J. : Insulin-like growth factor-II gene expression in Wilms' tumour and embryonic tissues. Nature 317: 260-262, 1985. PubMed ID : 2995818   108. Seawright, A.; Fletcher, J. M.; Fantes, J. A.; Morrison, H.; Porteous, D. J.; Li, S. S.-L.; Hastie, N. D.; Van Heyningen, V. : Analysis of WAGR deletions and related translocations with gene-specific DNA probes, using FACS-selected cell hybrids. Somat. Cell Molec. Genet. 14: 21-30, 1988. PubMed ID : 2829363   109. Shannon, R. S.; Mann, J. R.; Harper, E.; Harnden, D. G.; Morten, J. E. N.; Herbert, A. : Wilms's tumour and aniridia: clinical and cytogenetic features. Arch. Dis. Child. 57: 685-690, 1982. PubMed ID : 6289758   110. Slater, R. M.; de Kraker, J. : Chromosome number 11 and Wilms' tumor. Cancer Genet. Cytogenet. 5: 237-245, 1982. PubMed ID : 6279277   111. Strom, T. : A Wilms' tumor family. Acta Paediat. 46: 601-604, 1957.   112. Ton, C. C. T.; Huff, V.; Call, K. M.; Cohn, S.; Strong, L. C.; Housman, D. E.; Saunders, G. F. : Smallest region of overlap in Wilms tumor deletions uniquely implicates an 11p13 zinc finger gene as the disease locus. Genomics 10: 293-297, 1991. PubMed ID : 1646159   113. Turleau, C.; de Grouchy, J.; Dufier, J. L.; Phuc, L. H.; Schmelck, P. H.; Rappaport, R.; Nihoul-Fekete, C.; Diebold, N. : Aniridia, male pseudohermaphroditism, gonadoblastoma, mental retardation, and del 11p13. Hum. Genet. 57: 300-306, 1981. PubMed ID : 6114032   114. Turleau, C.; de Grouchy, J.; Nihoul-Fekete, C.; Dufier, J. L.; Chavin-Colin, F.; Junien, C. : Del11p13/nephroblastoma without aniridia. Hum. Genet. 67: 455-456, 1984. PubMed ID : 6092262   115. Turleau, C.; de Grouchy, J.; Tournade, M.-F.; Gagnadoux, M.-F.; Junien, C. : Del 11p/aniridia complex: report of three patients and review of 37 observations from the literature. Clin. Genet. 26: 356-362, 1984. PubMed ID : 6094051   116. van Heyningen, V.; Bickmore, W. A.; Seawright, A.; Fletcher, J. M.; Maule, J.; Fekete, G.; Gessler, M.; Bruns, G. A. P.; Huerre-Jeanpierre, C.; Junien, C.; Williams, B. R. G.; Hastie, N. D. : Role for the Wilms tumor gene in genital development?. Proc. Nat. Acad. Sci. 87: 5383-5386, 1990. PubMed ID : 1973540   117. van Heyningen, V.; Boyd, P. A.; Seawright, A.; Fletcher, J. M.; Fantes, J. A.; Buckton, K. E.; Spowart, G.; Porteous, D. J.; Hill, R. E.; Newton, M. S.; Hastie, N. D. : Molecular analysis of chromosome 11 deletions in aniridia-Wilms tumor syndrome. Proc. Nat. Acad. Sci. 82: 8592-8596, 1985. PubMed ID : 3001710   118. Varanasi, R.; Bardeesy, N.; Ghahremani, M.; Petruzzi, M.-J.; Nowak, N.; Adam, M. A.; Grundy, P.; Shows, T. B.; Pelletier, J. : Fine structure analysis of the WT1 gene in sporadic Wilms tumor. Proc. Nat. Acad. Sci. 91: 3554-3558, 1994. PubMed ID : 8170946   119. Weissman, B. E.; Saxon, P. J.; Pasquale, S. R.; Jones, G. R.; Geiser, A. G.; Stanbridge, E. J. : Introduction of normal human chromosome into a Wilms' tumor cell line controls its tumorigenic expression. Science 236: 175-180, 1987. PubMed ID : 3031816   120. Yunis, J. J.; Ramsay, K. C. : Familial occurrence of the aniridia-Wilms tumor syndrome with deletion 11p13-14.1. J. Pediat. 96: 1027-1030, 1980. PubMed ID : 6246230   CLINICAL SYNOPSIS View Clinical Synopsis Entry   CONTRIBUTORS Victor A. McKusick - updated : 3/1/1999 Victor A. McKusick - updated : 10/28/1998 Stylianos E. Antonarakis - updated : 6/1/1998 Victor A. McKusick - updated : 5/13/1998 Victor A. McKusick - updated : 4/20/1998 Victor A. McKusick - updated : 12/29/1997 Victor A. McKusick - updated : 12/19/1997 Victor A. McKusick - updated : 12/2/1997 Victor A. McKusick - updated : 5/8/1997 Victor A. McKusick - updated : 2/4/1997 CREATION DATE Victor A. McKusick : 6/2/1986 EDIT HISTORY carol : 3/3/1999 terry : 3/1/1999 alopez : 1/12/1999 dkim : 12/4/1998 carol : 11/4/1998 terry : 10/28/1998 terry : 6/3/1998 carol : 6/2/1998 terry : 6/1/1998 terry : 5/29/1998 alopez : 5/21/1998 alopez : 5/19/1998 terry : 5/13/1998 carol : 5/6/1998 terry : 4/20/1998 dholmes : 1/23/1998 dholmes : 1/12/1998 terry : 12/29/1997 terry : 12/19/1997 jenny : 12/2/1997 terry : 11/26/1997 mark : 9/1/1997 alopez : 6/20/1997 mark : 5/8/1997 alopez : 5/6/1997 mark : 2/5/1997 jenny : 2/4/1997 terry : 1/21/1997 mark : 2/5/1996 terry : 1/27/1996 mark : 1/18/1996 mark : 10/4/1995 carol : 3/3/1995 jason : 7/18/1994 davew : 6/1/1994 warfield : 3/31/1994 mimadm : 2/21/1994 ALLELIC VARIANTS 0001 : WAGR SYNDROME Mutation : WT1, 17-BP DEL, EX4 0002 : WAGR SYNDROME Mutation : WT1, 1-BP DEL, EX6, FS 0003 : DENYS-DRASH SYNDROME Mutation : WT1, ARG394TRP 0004 : DENYS-DRASH SYNDROME Mutation : WT1, ARG366HIS 0005 : DENYS-DRASH SYNDROME Mutation : WT1, ASP396GLY 0006 : DENYS-DRASH SYNDROME Mutation : WT1, ASP396ASN 0007 : DENYS-DRASH SYNDROME Mutation : WT1, ARG394PRO 0008 : DENYS-DRASH SYNDROME Mutation : WT1, CYS330TYR 0009 : DENYS-DRASH SYNDROME Mutation : WT1, IVS9DS, G-A, +5 0010 : WILMS TUMOR Mutation : WT1, ARG-TER, ZF3 0011 : WILMS TUMOR Mutation : WT1, ARG-CYS, ZF2 0012 : DENYS-DRASH SYNDROME Mutation : WT1, HIS377TYR 0013 : DENYS-DRASH SYNDROME Mutation : WT1, CYS360GLY 0014 : DENYS-DRASH SYNDROME Mutation : WT1, ARG362TER 0015 : DENYS-DRASH SYNDROME Mutation : WT1, HIS373GLN 0016 : MESOTHELIOMA Mutation : WT1, SER273GLY 0017 : WILMS TUMOR, FAMILIAL Mutation : WT1, ARG362TER 0018 : FRASIER SYNDROME Mutation : WT1, IVS9DS, C-T, +4 0019 : FRASIER SYNDROME Mutation : WT1, IVS9DS, A-T, +6 0020 : FRASIER SYNDROME Mutation : WT1, IVS9DS, G-A, +5 0021 : MESANGIAL SCLEROSIS, ISOLATED DIFFUSE Mutation : WT1, HIS377TYR 0022 : MESANGIAL SCLEROSIS, ISOLATED DIFFUSE Mutation : WT1, PHE383LEU 0023 : MESANGIAL SCLEROSIS, ISOLATED DIFFUSE Mutation : WT1, ASP396ASN Back to UNSW Embryology-Kidney Notes

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