A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal disease

Drash, Allan L.; Sherman, Frederick S.; Hartmann, William H.; Blizzard, Robert M.

doi:10.1016/s0022-3476(70)80409-7

Cited by 381 publications

(143 citation statements)

References 13 publications

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“…Heterozygous germline mutations in WT1 were described in two rare human conditions: Denys-Drash syndrome (DDS) with exon mutations in the zinc-finger region (7,8) and Frasier syndrome (FS) with mutations affecting the canonic donor KTS splice site of intron 9 (9,10). DDS includes steroid-resistant nephrotic syndrome rapidly progressing to ESRD, 46 XY disorder in sex development (DSD) with sex reversal and a high risk for WT (11,12). FS is defined by progressive glomerulopathy, gonadoblastoma, and 46 XY DSD with sex reversal (13).…”

Section: Introductionmentioning

confidence: 99%

Clinical and Molecular Characterization of Patients with Heterozygous Mutations in Wilms Tumor Suppressor Gene 1

Lehnhardt¹,

Karnatz²,

Ahlenstiel-Grunow³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT.Design, setting, participants & measurements Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012.Results Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P,0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR,.8]; P,0.001) and splice site mutations (12.3 [IQR,.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations.Conclusions Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.

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Section: Introductionmentioning

confidence: 99%

Clinical and Molecular Characterization of Patients with Heterozygous Mutations in Wilms Tumor Suppressor Gene 1

Lehnhardt¹,

Karnatz²,

Ahlenstiel-Grunow³

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…A role for WT1 in the process of MET, which results in nephron endowment, is implied both by WT1 upregulation during this event and the blastemal proliferation and arrested epithelialization seen in Wilms' tumours. Finally, Denys-Drash syndrome patients (Denys et al, 1967;Drash et al, 1970), who carry a single mutant copy of the WT1 gene constitutionally, suffer early onset nephropathy as a result of mesangial sclerosis suggesting that the ongoing expression of WT1 by the podocytes is essential for glomerular function after birth.…”

Section: Introductionmentioning

confidence: 99%

Anlaysis of complementary expression profiles following WT1 induction versus repression reveals the cholesterol/fatty acid synthetic pathways as a possible major target of WT1

et al. 2004

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“…D enys-Drash syndrome (DDS) is a rare urogenital disorder that is associated with male pseudohermaphroditism, a high risk for Wilms' tumors, and diffuse mesangial sclerosis, which presents before the age of 2 yr and progresses rapidly to end-stage renal failure (1)(2)(3). The disease is mainly caused by heterozygous germline missense mutations in exons 8 and 9 of the Wilms' tumor-1 (WT1) gene, encoding zinc finger 2 and 3 of the protein.…”

mentioning

confidence: 99%

Impaired Glomerular Maturation and Lack of VEGF165b in Denys-Drash Syndrome

Schumacher¹,

Jeruschke²,

Eitner³

et al. 2007

Journal of the American Society of Nephrology

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Individuals with Denys-Drash syndrome (DDS) develop diffuse mesangial sclerosis, ultimately leading to renal failure. The disease is caused by mutations that affect the zinc finger structure of the Wilms' tumor protein (WT1), but the mechanisms whereby these mutations result in glomerulosclerosis remain largely obscure. How WT1 regulates genes is likely to be complex, because it has multiple splice forms, binds both DNA and RNA, and associates with spliceosomes. Herein is described that in DDS podocytes, the ratio of both WT1 ؉KTS isoforms C to D differs considerably from that of normal child and adult control podocytes and more closely resembles fetal profiles. Aside from the delay in podocyte maturation, DDS glomeruli show swollen endothelial cells, reminiscent of endotheliosis, together with incompletely fused capillary basement membranes; a dramatic decrease in collagen ␣4(IV) and laminin ␤2 chains; and the presence of immature or activated mesangial cells that express ␣-smooth muscle actin. Because appropriate vascular endothelial growth factor A (VEGF-A) expression is known to be essential for the development and maintenance of glomerular architecture and function, this article addresses the question of whether VEGF-A expression is deregulated in DDS. The data presented here show that DDS podocytes express high levels of the proangiogenic isoform VEGF165, but completely lack the inhibitory isoform VEGF165b. The VEGF165/VEGF165b ratio in DDS resembles that of fetal S-shaped bodies, rather than that of normal child or adult control subjects. The alteration in VEGF-A expression presented here may provide a mechanistic insight into the pathogenesis of DDS.

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A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal disease

Cited by 381 publications

References 13 publications

Clinical and Molecular Characterization of Patients with Heterozygous Mutations in Wilms Tumor Suppressor Gene 1

Clinical and Molecular Characterization of Patients with Heterozygous Mutations in Wilms Tumor Suppressor Gene 1

Anlaysis of complementary expression profiles following WT1 induction versus repression reveals the cholesterol/fatty acid synthetic pathways as a possible major target of WT1

Impaired Glomerular Maturation and Lack of VEGF165b in Denys-Drash Syndrome

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