scholarly journals Analysis of the Wilms' Tumor Suppressor Gene (WT1) in Patients 46,XY Disorders of Sex Development

2011 ◽  
Vol 96 (7) ◽  
pp. E1131-E1136 ◽  
Author(s):  
B. Köhler ◽  
H. Biebermann ◽  
V. Friedsam ◽  
J. Gellermann ◽  
R. F. Maier ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Gonadal Dysgenesis ◽  
Kidney Development ◽  
Wilms Tumor ◽  
Disorders Of Sex Development ◽  
Suppressor Gene ◽  
Sex Development ◽  
Cryptorchid Testis

Abstract Context: The Wilms' tumor suppressor gene (WT1) is one of the major regulators of early gonadal and kidney development. WT1 mutations have been identified in 46,XY disorders of sex development (DSD) with associated kidney disease and in few isolated forms of 46,XY DSD. Objective: The objective of the study was the evaluation of WT1 mutations in different phenotypes of isolated 46,XY DSD and clinical consequences. Design: The design of the study was: 1) sequencing of the WT1 gene in 210 patients with 46,XY DSD from the German DSD network, consisting of 150 males with severe hypospadias (70 without cryptorchidism, 80 with at least one cryptorchid testis), 10 males with vanishing testes syndrome, and 50 raised females with partial to complete 46,XY gonadal dysgenesis; and 2) genotype-phenotype correlation of our and all published patients with 46,XY DSD and WT1 mutations. Results: We have detected WT1 mutations in six of 80 patients with severe hypospadias (7.5%) and at least one cryptorchid testis and in one of 10 patients with vanishing testes syndrome (10%). All patients except one developed Wilms' tumor and/or nephropathy in childhood or adolescence. Conclusion: WT1 analysis should be performed in newborns with complex hypospadias with at least one cryptorchid testis and in isolated 46,XY partial to complete gonadal dysgenesis. Kidney disease might not develop until later life in these cases. WT1 analysis is mandatory in all 46,XY DSD with associated kidney disease. WT1 analysis is not indicated in newborns with isolated hypospadias without cryptorchidism. Patients with WT1 mutations should be followed up closely because the risk of developing a Wilms' tumor, nephropathy, and/or gonadal tumor is very high.

scholarly journals Identification of Novel Wilms' Tumor Suppressor Gene Target Genes Implicated in Kidney Development

2007 ◽  
Vol 282 (22) ◽  
pp. 16278-16287 ◽  
Author(s):  
Ho-Shik Kim ◽  
Myoung Shin Kim ◽  
Anne L. Hancock ◽  
James C. P. Harper ◽  
Jik Young Park ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Target Genes ◽  
Kidney Development ◽  
Wilms Tumor ◽  
Suppressor Gene ◽  
Gene Target

Wt1-expressing progenitors contribute to multiple tissues in the developing lung

2013 ◽  
Vol 305 (4) ◽  
pp. L322-L332 ◽  
Author(s):  
Elena Cano ◽  
Rita Carmona ◽  
Ramón Muñoz-Chápuli
Keyword(s):  
Smooth Muscle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Fluorescent Protein ◽  
Wilms Tumor ◽  
Yellow Fluorescent Protein ◽  
Suppressor Gene ◽  
Differentiation Potential ◽  
Mesenchymal Transition ◽  
Lung Morphogenesis

Lungs develop from paired endodermal outgrowths surrounded by a mesodermal mesenchyme. Part of this mesenchyme arises from epithelial-mesenchymal transition of the mesothelium that lines the pulmonary buds. Previous studies have shown that this mesothelium-derived mesenchyme contributes to the smooth muscle of the pulmonary vessels, but its significance for lung morphogenesis and its developmental fate are still little known. We have studied this issue using the transgenic mouse model mWt1/IRES/GFP-Cre (Wt1cre) crossed with the Rosa26R-EYFP reporter mouse. In the developing lungs, Wt1, the Wilms' tumor suppressor gene, is specifically expressed in the embryonic mesothelium. In the embryos obtained from the crossbreeding, the Wt1-expressing cell lineage produces the yellow fluorescent protein (YFP), allowing for colocalization with differentiation markers. Wt1cre-YFP cells were very abundant from the origin of the lung buds to postnatal stages, contributing significantly to pulmonary endothelial and smooth muscle cells, bronchial musculature, tracheal and bronchial cartilage, as well as CD34+ fibroblast-like interstitial cells. Thus Wt1cre-YFP mesenchymal cells show the very same differentiation potential as the splanchnopleural mesenchyme surrounding the lung buds. FSP1+ fibroblast-like cells were always YFP−; they expressed the common leukocyte antigen CD45 and were apparently recruited from circulating progenitors. We have also found defects in pulmonary development in Wt1−/− embryos, which showed abnormally fused lung lobes, round-shaped and reduced pleural cavities, and diaphragmatic hernia. Our results suggest a novel role for the embryonic mesothelium-derived cells in lung morphogenesis and involve the Wilms' tumor suppressor gene in the development of this organ.

scholarly journals Wilms' Tumor Suppressor GeneWT1

2000 ◽  
Vol 11 (suppl 2) ◽  
pp. S106-S115 ◽  
Author(s):  
CHRISTIAN MROWKA ◽  
ANDREAS SCHEDL
Keyword(s):  
Tumor Suppressor ◽  
Rna Editing ◽  
Kidney Development ◽  
Wilms Tumor ◽  
Suppressor Gene ◽  
Structural Features ◽  
Genomic Locus ◽  
Developmental Abnormalities ◽  
Complex Process

Abstract.Normal development of the kidney is a highly complex process that requires precise orchestration of proliferation, differentiation, and apoptosis. In the past few years, a number of genes that regulate these processes, and hence play pivotal roles in kidney development, have been identified. The Wilms' tumor suppressor geneWT1has been shown to be one of these essential regulators of kidney development, and mutations in this gene result in the formation of tumors and developmental abnormalities such as the Denys-Drash and Frasier syndromes. A fascinating aspect of theWT1gene is the multitude of isoforms produced from its genomic locus. In this review, our current understanding of the structural features ofWT1, how they modulate the transcriptional and post-transcriptional activities of the protein, and how mutations affecting individual isoforms can lead to diseased kidneys is summarized. In addition, results from transgenic experiments, which have yielded important findings regarding the function of WT1in vivo, are discussed. Finally, data on the unusual feature of RNA editing ofWT1transcripts are presented, and the relevance of RNA editing for the normal functioning of the WT1 protein in the kidney is discussed.

Analysis of the 11p13 Wilms' Tumor Suppressor Gene (WTI) in Ovarian Tumors

1993 ◽  
Vol 11 (4) ◽  
pp. 393-399 ◽  
Author(s):  
Wendy Bruening ◽  
Philippe Gros ◽  
Takaaki Sato ◽  
Jerry Stanimir ◽  
Yusuke Nakamura ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Wilms Tumor ◽  
Suppressor Gene ◽  
Ovarian Tumors

WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

2021 ◽  
pp. 1-9
Author(s):  
Maria T.M. Ferrari ◽  
Andreia Watanabe ◽  
Thatiane E. da Silva ◽  
Nathalia L. Gomes ◽  
Rafael L. Batista ◽  
...  
Keyword(s):  
Kidney Development ◽  
Wilms Tumor ◽  
Genetic Diagnosis ◽  
Germ Cell Tumors ◽  
Disorders Of Sex Development ◽  
Medical Attention ◽  
Primary Amenorrhea ◽  
Normal Female ◽  
Sex Development ◽  
Pathogenic Variants

Wilms’ tumor suppressor gene 1 (<i>WT1</i>) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of <i>WT1</i> have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between <i>WT1</i> disorders has been frequently observed. New <i>WT1</i> variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic <i>WT1</i> variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of <i>WT1</i> between exons 9 and 10. Two pathogenic missense <i>WT1</i> variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were &#x3c;1 year of age at the time of diagnosis. A novel <i>WT1</i> variant<i>,</i> c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with <i>WT1</i> variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

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