ArticleJournal of the American Society of Nephrology : JASN2015
A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS.
Article in Journal of the American Society of Nephrology : JASN, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 50 citations in OpenAlex.
- Molecular Genetics Solves the Conundrum of Two Brothers Affected With Proteinuria Coming With a Very Different Flavor: A Case Report.Kidney medicine · 2025Article
- Multiplexed bulk and single-cell RNA-seq hybrid enables cost-efficient disease modeling with chimeric organoids.Nature communications · 2024Article
- β-Arrestin pathway activation by selective ATR1 agonism promotes calcium influx in podocytes, leading to glomerular damage.Clinical science (London, England : 1979) · 2023Article
- Modeling Podocyte Ontogeny and Podocytopathies with the Zebrafish.Journal of developmental biology · 2023Review
- Alteration in DNA-binding affinity of Wilms tumor 1 protein due to WT1 genetic variants associated with steroid - resistant nephrotic syndrome in children.Scientific reports · 2022Article
- Article
- Spectrum of Clinical Manifestations in Children WithFrontiers in pediatrics · 2022Article
- Exonic WT1 pathogenic variants in 46,XY DSD associated with gonadoblastoma.Endocrine connections · 2021Article
- Review
- Case Report: A Pathogenic Missense Variant ofFrontiers in medicine · 2021Article
- Nephrotic syndrome in a dish: recent developments in modeling in vitro.Pediatric nephrology (Berlin, Germany) · 2020Review
- Disease Modeling To Understand the Pathomechanisms of Human Genetic Kidney Disorders.Clinical journal of the American Society of Nephrology : CJASN · 2020Review
- The Human FSGS-CausingJournal of the American Society of Nephrology : JASN · 2018Article
- Recent advances of animal model of focal segmental glomerulosclerosis.Clinical and experimental nephrology · 2018Review
- Whole exome sequencing: a state-of-the-art approach for defining (and exploring!) genetic landscapes in pediatric nephrology.Pediatric nephrology (Berlin, Germany) · 2018Review
- Clinical and pathological phenotype of genetic causes of focal segmental glomerulosclerosis in adults.Clinical kidney journal · 2018Article
- Zebrafish as a Model for Drug Screening in Genetic Kidney Diseases.Frontiers in pediatrics · 2018Review
- Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population.Frontiers in pediatrics · 2018Article
- Genetic mutational testing of Chinese children with familial hematuria with biopsy‑proven FSGS.Molecular medicine reports · 2018Article
- Hereditary Podocytopathies in Adults: The Next Generation.Kidney diseases (Basel, Switzerland) · 2017Review
Corrections and comments
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Authors and funding
18 authors at 5 institutions in 2 countries.
Funding
Abstract
FSGS is a clinical disorder characterized by focal scarring of the glomerular capillary tuft, podocyte injury, and nephrotic syndrome. Although idiopathic forms of FSGS predominate, recent insights into the molecular and genetic causes of FSGS have enhanced our understanding of disease pathogenesis. Here, we report a novel missense mutation of the transcriptional regulator Wilms' Tumor 1 (WT1) as the cause of nonsyndromic, autosomal dominant FSGS in two Northern European kindreds from the United States. We performed sequential genome-wide linkage analysis and whole-exome sequencing to evaluate participants from family DUK6524. Subsequently, whole-exome sequencing and direct sequencing were performed on proband DNA from family DUK6975. We identified multiple suggestive loci on chromosomes 6, 11, and 13 in family DUK6524 and identified a segregating missense mutation (R458Q) in WT1 isoform D as the cause of FSGS in this family. The identical mutation was found in family DUK6975. The R458Q mutation was not found in 1600 control chromosomes and was predicted as damaging by in silico simulation. We depleted wt1a in zebrafish embryos and observed glomerular injury and filtration defects, both of which were rescued with wild-type but not mutant human WT1D mRNA. Finally, we explored the subcellular mechanism of the mutation in vitro. WT1(R458Q) overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells and impaired focal contact formation in podocytes. Taken together, these data suggest that the WT1(R458Q) mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.