A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS

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

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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. WT1R458Q 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 WT1R458Q mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS.

Original languageEnglish
Pages (from-to)831-843
Number of pages13
JournalJournal of the American Society of Nephrology
Issue number4
StatePublished - Apr 1 2015


Dive into the research topics of 'A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS'. Together they form a unique fingerprint.

Cite this