Clinicopathologic review of twelve children with nephropathy, Wilms tumor, and genital abnormalities (Drash syndrome)

Jadresić, Lyda; Leake, J.; Gordon, Isky; Dillon, Michael; Grant, Dundas; Pritchard, Jon; Risdon, R. A.; Barratt, T. M.

doi:10.1016/s0022-3476(05)83327-x

Cited by 120 publications

(53 citation statements)

References 28 publications

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“…The glomerular nephropathy, caused by diffuse mesangial sclerosis (DMS), is the most consistent feature of DDS and leads to end-stage renal disease (48,58). The glomerular capillary tuft is surrounded by a layer of glomerular extracellular matrix (ECM), which in turn is surrounded by a visceral epithelial layer consisting of podocyte cells.…”

Section: Wt Associated Syndromes Involving Mutations In Wt1mentioning

confidence: 99%

Insights into the physiological role of WT1 from studies of genetically modified mice

Discenza¹

2004

Physiological Genomics

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. Insights into the physiological role of WT1 from studies of genetically modified mice. Physiol Genomics 16: 287-300, 2004; 10.1152/physiolgenomics.00164.2003.-The identification of WT1 gene mutations in children with WAGR and Denys-Drash syndromes pointed toward a role for WT1 in genitourinary system development. Biochemical analysis of the different WT1 protein isoforms showed that WT1 is a transcription factor and also has the ability to bind RNA. Analysis of WT1 complexes identified several target genes and protein partners capable of interacting with WT1. Some of these studies placed WT1, its downstream targets, and protein partners in a transcriptional regulatory network that controls urogenital system development. We review herein studies on WT1 knockout and transgenic models that have been instrumental in defining a physiological role for WT1 in normal and abnormal urogenital development. kidney development; mouse models WILMS TUMOR (WT), a pediatric kidney cancer, has been the subject of intense clinical and basic research for several years. The implication of the Wilms tumor 1 (WT1) tumor suppressor gene in the etiology of WT illustrated the impact that genetic alterations can have on both development and tumorigenesis. Biochemical studies of the WT1 gene and gene product, as well as the study of patients and genetically modified mice with mutations in WT1 have all contributed in defining a role for WT1 during development. The WT1 Gene, mRNA Transcripts, and Protein IsoformsThe WT1 gene is located at human chromosome position 11p13 ( Fig. 1) and on mouse chromosome 2. Both the mouse and human genes span ϳ50 kb of genomic DNA comprising 10 exons that encode mRNAs of ϳ3 kb (16,37,38). A map of the WT1 gene structure is shown in Fig. 2.WT1 exon 5 and exon 9 are alternatively spliced (37, 47). Inclusion of exon 5 inserts 17 amino acids between the NH 2 -and COOH-terminal domains of WT1 (Fig. 2). The WT1 gene encodes a protein with typical characteristics of a transcription factor (Fig. 2). The NH 2 -terminal domain of WT1 is prolineand glutamine-rich. The COOH-terminal domain of WT1 contains four zinc fingers, each one encoded by an exon, encompassing exons 7 to 10. The zinc fingers are of the Cys 2 -His 2 variety, similar to the DNA-binding domain of the Drosophila Krüppel protein. Two nuclear localization signals have been identified in the zinc finger domain of WT1, one being in zinc finger 1 and the other in zinc fingers 2 and 3 (13). The use of an alternative splice donor site at the end of exon 9 results in the incorporation of three amino acids, lysine, threonine, and serine (KTS), between zinc fingers three and four (Fig. 2). The WT1 proteins have molecular masses of 52-54 kDa depending on the inclusion or exclusion of the two splice inserts (93). The 52-kDa protein corresponds to the WT1 isoform that lacks both alternatively spliced sequences, named WT1(Ϫ/Ϫ), and the 54-kDa protein corresponds to the WT1 isoform that contains both alternatively spliced sequences, named WT1(ϩ/ϩ). The WT1 isoform c...

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Section: Wt Associated Syndromes Involving Mutations In Wt1mentioning

confidence: 99%

Insights into the physiological role of WT1 from studies of genetically modified mice

Discenza¹

2004

Physiological Genomics

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“…In humans, germline single-allele WT1 defects cause urogenital abnormalities and strongly predispose to Wilms' tumor. Male genital ambiguity and a nephropathy that progresses to renal failure are frequent features of the Denys-Drash syndrome (3)(4)(5), due to single-allele WT1 point mutations (6 -8). Less profound genitourinary malformations, such as cryptorchidism and hypospadias, are associated with aniridia and Wilms' tumor (9 -11), which with mental retardation comprise the WAGR syndrome, and result from one WT1 allele loss in a chromosome 11p13 deletion (12).…”

mentioning

confidence: 99%

Sp1 Is a Critical Regulator of the Wilms' tumor-1 Gene

Cohen

Bossone

Zhu

et al. 1997

Journal of Biological Chemistry

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We performed deletion analysis of WT1-reporter constructs containing up to 24 kilobases of 5-flanking and first intron WT1 sequence in stably transfected cultured cells as an unbiased approach to identify cis elements critical for WT1 transcription. Although not a tissuespecific element, a proximate 9-base pair CTC repeat accounted for ϳ80% of WT1 transcription in this assay. Enhancer activity of the element and mutated versions correlated completely with their ability to form a DNAprotein complex in gel shifts. Antibody supershift, oligonucleotide competition, and Southwestern studies indicated that the CTC-binding factor is the transcriptional activator Sp1. Sp1 binds the CTC repeat with an affinity, K D ‫؍‬ 0.37 nM, at least as high as the consensus GC box. Similar CTC repeats are found in promoters of other growth-related genes. Because Sp1 is important for WT1 expression, we examined Sp1 immunohistochemistry in fetal and adult kidney. In a pattern that precedes that of WT1 message, Sp1 immunostaining was highest in uninduced mesenchyme, early tubules, developing podocytes, and mature glomeruli, but was minimal in mature proximal tubules. This work suggests abundant Sp1 may be a prerequisite for WT1 expression, and that Sp1 may have a wider role in nephrogenesis.

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“…However, to demonstrate the relation between 11p LOH and WT tumorigenesis in WTϩGU, more cases need to be accumulated, and it is recommended that polymorphic studies be carried out in WTϩGU patients. The patients described in Table 2 had an earlier onset of WT [18.5 Ϯ 11.1 mo (mean Ϯ SD)] than in most WT cases (43.3 Ϯ 31.6 mo) reported by Breslow et al (3), suggesting that the presence of a predisposing WT1 mutation affects the onset, as shown in DDS patients (13,42). In addition, all the WT1 mutations shown in Table 2 resulted in a truncated protein.…”

Section: Discussionmentioning

confidence: 75%

A Novel WT1 Gene Mutation Associated with Wilms' Tumor and Congenital Male Genitourinary Malformation

et al. 2001

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Clinicopathologic review of twelve children with nephropathy, Wilms tumor, and genital abnormalities (Drash syndrome)

Cited by 120 publications

References 28 publications

Insights into the physiological role of WT1 from studies of genetically modified mice

Insights into the physiological role of WT1 from studies of genetically modified mice

Sp1 Is a Critical Regulator of the Wilms' tumor-1 Gene

A Novel WT1 Gene Mutation Associated with Wilms' Tumor and Congenital Male Genitourinary Malformation

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