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Abstract: FR-PO1017

A Novel Heterozygous Missense Mutation of Wilms’ Tumor 1 May Cause FSGS Through Dysregulated Expression of ARHGAP24

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Hall, Gentzon, Duke University Medical Center, Durham, North Carolina, United States
  • Sampson, Matt G., University of Michigan, Ann Arbor, Michigan, United States
  • Lane, Brandon M., Duke University, Durham, North Carolina, United States
  • Gregory, Olivia G., Duke University Medical Center, Durham, North Carolina, United States
  • Kovalik, Maria Eugenia, Duke University, Durham, North Carolina, United States
  • Wu, Guanghong, Duke university, Durham, North Carolina, United States
  • Chryst-Stangl, Megan, Duke Molecular Physiology Institute, Durham, North Carolina, United States
  • Wang, Liming, Duke University Medical Center, Durham, North Carolina, United States
  • Spurney, Robert F., Duke University Medical Center, Durham, North Carolina, United States
  • Gbadegesin, Rasheed A., Duke University Medical Center, Durham, North Carolina, United States

Mutations of the transcriptional regulator Wilms’ Tumor 1 are most commonly associated with syndromic disease but some mutations have been shown to cause renal-limited disease. We previously reported a novel heterozygous missense mutation (Exon 9; p.R458Q) of Wilms’ Tumor 1 that caused non-syndromic autosomal dominant FSGS in two Northern European kindreds. We now report a second novel WT1 mutation (Exon 8; p.R443G) as a cause of non-syndromic autosomal dominant FSGS in a 3-generation kindred from North-Central India.


Direct sequencing, lentivirus-mediated WT1 expression, immunoblot, immunofluorescence imaging, electrophoretic mobility shift assay (EMSA) and apoptosis assays.


A novel heterozygous missense mutation of WT1 (Exon 8; p.R443G) was identified by direct sequencing of the proband and an affected cousin in a North-Central Indian kindred with non-syndromic FSGS. An autosomal dominant pattern of inheritance was suggested by male-to-male transmission across three generations of the family. Substitution of the highly conserved arginine residue at position 443 was considered damaging by in-silico prediction. The R443G mutation impaired DNA-binding by EMSA and distorted the secondary structure of the transcription factor DNA-binding domain by in-silico modeling. WT1 was previously identified as a potential regulator of ARHGAP24; a known FSGS gene that regulates podocyte cytoskeletal dynamics and survival through modulation of Rac1 activity. ARHGAP24 protein expression was significantly upregulated in WT1R443G podocytes (p=0.003; n=3) relative to WT1WT podocytes. Consistent with the increase in ARHGAP24 expression, WT1R443G podocytes exhibited decreased motility (p=0.01; n=3) and increased apoptosis (p=0.04; n=5) accompanied by a significant decrease in STAT3 phosphorylation at Ser727 (p=0.02; n=3); a Rac1-mediated prosurvival post-translational modification. These findings suggest that WT1 functions as an inhibitor of ARHGAP24 expression and the R443G mutation impairs this inhibitory effect.


The novel WT1R443G mutation causes non-syndromic FSGS. The mutation induces an upregulation of ARHGAP24 expression and increases podocyte apoptosis probably through decreased Rac1-mediated prosurvival signaling.


  • NIDDK Support