A Novel Missense Mutation of Wilms’ Tumor 1 Causes Autosomal Dominant FSGS

Hall, Gentzon; Gbadegesin, Rasheed; Lavin, Peter; Wu, Guanghong; Liu, Yangfan; Oh, Edwin C.; Wang, Liming; Spurney, Robert F.; Eckel, Jason; Lindsey, Thomas; Homstad, Alison; Malone, Andrew F.; Phelan, Paul J.; Shaw, Andréy S.; Howell, David N.; Conlon, Peter J.; Katsanis, Nicholas; Winn, Michelle P.

doi:10.1681/asn.2013101053

Cited by 46 publications

(44 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…WT1 (R458Q) overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells, and impaired focal contact formation in podocytes. This mutation can alter the regulation of podocyte homeostasis and causes non-syndromic FSGS [79] ( Table 2; Fig. 1).…”

Section: Wilms Tumormentioning

confidence: 99%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

View full text Add to dashboard Cite

In the last decade, great advances have been made in understanding the genetic basis for focal segmental glomerulosclerosis (FSGS). Animal models using specific gene disruption of the slit diaphragm and cytoskeleton of the foot process mirror the etiology of the human disease. Many animal models have been developed to understand the complex pathophysiology of FSGS. Therefore, we need to know the usefulness and exact methodology of creating animal models. Here, we review classic animal models and newly developed genetic animal models. Classic animal models of FSGS involve direct podocyte injury and indirect podocyte injury due to adaptive responses. However, the phenotype depends on the animal background. Renal ablation and direct podocyte toxin (PAN, adriamycin) models are leading animal models for FSGS, which have some limitations depending on mice background. A second group of animal models were developed using combinations of genetic mutation and toxin, such as NEP25, diphtheria toxin, and Thy1.1 models, which specifically injure podocytes. A third group of animal models involves genetic engineering techniques targeting podocyte expression molecules, such as podocin, CD2-associated protein, and TRPC6 channels. More detailed information about podocytopathy and FSGS can be expected in the coming decade. Different animal models should be used to study FSGS depending on the specific aim and sometimes should be used in combination.

show abstract

Section: Wilms Tumormentioning

confidence: 99%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

View full text Add to dashboard Cite

show abstract

“…[122][123][124] In particular, its inhibitory effect on Wnt/β-catenin signaling has gained much interest because it might represent a potential drugable target for future therapeutic interventions to treat proteinuric kidney diseases (for review 9 ).…”

Section: Wt1 and Wnt/b-catenin Signalingmentioning

confidence: 99%

Live or Let Die: Is There any Cell Death in Podocytes?

Braun

Becker

Brinkkoetter

2016

Seminars in Nephrology

View full text Add to dashboard Cite

“…Genetic testing should be considered in proteinuric girls even if they are not nephrotic. In familial cases of late-onset proteinuria without WT or XY DSD, dominant inheritance of WT1 mutations should be considered (24,25).…”

Section: Proteinuriamentioning

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

View full text Add to dashboard Cite

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.

show abstract

A Novel Missense Mutation of Wilms’ Tumor 1 Causes Autosomal Dominant FSGS

Cited by 46 publications

References 47 publications

Recent advances of animal model of focal segmental glomerulosclerosis

Recent advances of animal model of focal segmental glomerulosclerosis

Live or Let Die: Is There any Cell Death in Podocytes?

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

Contact Info

Product

Resources

About