Loss or oncogenic mutation of DROSHA impairs kidney development and function, but is not sufficient for Wilms tumor formation

2018 ◽  
Vol 144 (6) ◽  
pp. 1391-1400 ◽  
Author(s):  
Philip Kruber ◽  
Oguzhan Angay ◽  
Anja Winkler ◽  
Michael R. Bösl ◽  
Susanne Kneitz ◽  
...  
Keyword(s):  
Kidney Development ◽  
Wilms Tumor ◽  
Tumor Formation ◽  
Oncogenic Mutation ◽  
And Function

Abstract 094: Pappa2 is Important for Determining the Nephron Number

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Vikash Kumar ◽  
Chun Yang ◽  
Aron M Geurts ◽  
Mingyu Liang ◽  
Allen W Cowley
Keyword(s):  
Mrna Expression ◽  
Kidney Development ◽  
Brown Norway ◽  
Ureteric Bud ◽  
Induced Hypertension ◽  
Allele Variant ◽  
Rat Strain ◽  
Nephron Development ◽  
And Function ◽  
Igfbp 3

Pappa2 is a metalloproteinase which specifically cleaves IGFBP-3 and IGFBP-5 and in turn releases IGF-1. Recently, we have shown that a subcongenic Dahl salt-sensitive (SS) rat strain containing a 0.71 Mbp of chromosome 13 which includes Pappa2 gene from salt-insensitive Brown Norway (26-P strain) is protected significantly (24 mmHg) from salt-induced hypertension (Cowley et al., 2016). Although it is recognized that Pappa2 modulates development of bone size, cranial cartilage and angiogenesis, its role in kidney development and function is unknown. The present study determined the contribution of Pappa2 to nephron development by comparing SS and 26-P rat strains. It was found that Pappa2 mRNA expression was 5-fold higher in embryonic kidney (day 20.5) of the salt-resistant 26-P rats compared with age-matched SS rats. Pappa2 mRNA expression significantly increased with age of kidney reaching a maximum at postnatal day 5 in both strains. Pappa2 mRNA expression at postnatal day 15 was found to be 9-fold higher in the kidney of 26-P compared with SS strain. Immunohistochemistry studies revealed that Pappa2 co-localized with IGFBP-5 in the ureteric bud indicating that Pappa2 could be important for ureteric branching and nephron endowment. Glomerulus/mm 2 was therefore determined by counting total number of glomeruli in kidney sections from pups starting from P0 to P20. The salt-resistant 26-P congenic strain exhibited significantly greater nephron density 9.03 and 7.07 glo/mm 2 compared to 6.89 and 4.85 glo/mm 2 in SS rat at day P15 and P20, respectively. It appears that the Brown Norway pappa2 allele variant prevents the reduced nephron numbers observed in SS rats and thereby protects these congenic rats from salt-induced hypertension.

scholarly journals MicroRNA-27a-5p inhibits proliferation, migration and invasion and promotes apoptosis of Wilms tumor cell by targeting PBOV1

2021 ◽  
Author(s):  
zhengtuan guo ◽  
qiang yv ◽  
chunlin miao ◽  
wenan ge ◽  
peng li
Keyword(s):  
Tumor Cells ◽  
Wilms Tumor ◽  
Suppressive Effect ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tumor Tissues ◽  
And Function ◽  
Tumor Suppressive Effect

Wilms tumor is the most common type of renal tumor in children. MicroRNAs (miRNA) are small non-coding RNAs that play crucial regulatory roles in tumorigenesis. We aimed to study the expression profile and function of miR-27a-5p in Wilms tumor. MiR-27a-5p expression was downregulated in human Wilms tumor tissues. Functionally, overexpression of miR-27a-5p promoted cell apoptosis of Wilms tumor cells. Furthermore, upregulated miR-27a-5p delayed xenograft Wilms tumor tumorigenesis in vivo. Bioinformatics analysis predicted miR-27-5p directly targeted to the 3’-untranslated region (UTR) of PBOV1 and luciferase reporter assay confirmed the interaction between miR-27a-5p and PBOV1. The function of PBOV1 in Wilms tumor was evaluated in vitro and knockdown of PBOV1 dampened cell migration. In addition, overexpression of PBOV1 antagonized the tumor-suppressive effect of miR-27a-5p in Wilms tumor cells. Collectively, our findings reveal the regulatory axis of miR-27-5p/PBOV1 in Wilms tumor and miR-27a-5p might serve as a novel therapeutic target in Wilms tumor.

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.

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.

The excretory system of young chickens experiencing mercury toxicity—effects on kidney development, morphology, and function

1978 ◽  
Vol 7 (1) ◽  
pp. 257-271 ◽  
Author(s):  
Patricia Y. Hester ◽  
John Brake ◽  
Charles V. Sikes ◽  
Paul Thaxton ◽  
Samuel L. Pardue
Keyword(s):  
Kidney Development ◽  
Excretory System ◽  
Mercury Toxicity ◽  
And Function ◽  
Toxicity Effects

scholarly journals Amine Oxidase Copper-containing 1 (AOC1) Is a Downstream Target Gene of the Wilms Tumor Protein, WT1, during Kidney Development

2014 ◽  
Vol 289 (35) ◽  
pp. 24452-24462 ◽  
Author(s):  
Karin M. Kirschner ◽  
Julian F.W. Braun ◽  
Charlotte L. Jacobi ◽  
Lucas J. Rudigier ◽  
Anja Bondke Persson ◽  
...  
Keyword(s):  
Target Gene ◽  
Kidney Development ◽  
Wilms Tumor ◽  
Amine Oxidase ◽  
Downstream Target ◽  
Downstream Target Gene

Chromatin dynamics in kidney development and function

2014 ◽  
Vol 356 (3) ◽  
pp. 601-608 ◽  
Author(s):  
Wibke Bechtel-Walz ◽  
Tobias B. Huber
Keyword(s):  
Kidney Development ◽  
Chromatin Dynamics ◽  
And Function

scholarly journals Organic anion and cation transporter expression and function during embryonic kidney development and in organ culture models

2006 ◽  
Vol 69 (5) ◽  
pp. 837-845 ◽  
Author(s):  
D.H. Sweet ◽  
S.A. Eraly ◽  
D.A. Vaughn ◽  
K.T. Bush ◽  
S.K. Nigam
Keyword(s):  
Organ Culture ◽  
Kidney Development ◽  
Organic Anion ◽  
Culture Models ◽  
And Function ◽  
Transporter Expression

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.

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