Abstract: TH-PO475
Molecular Mechanisms of Neonatal-Onset WT1-Related Glomerulopathy
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Hiltebeitel, Lily, Boston Children's Hospital, Boston, Massachusetts, United States
- Yang, Jie, The University of Texas MD Anderson Cancer Center Children's Cancer Hospital, Houston, Texas, United States
- Cao, Yu, The University of Texas MD Anderson Cancer Center Children's Cancer Hospital, Houston, Texas, United States
- Zhang, Xing, The University of Texas MD Anderson Cancer Center Children's Cancer Hospital, Houston, Texas, United States
- Cheng, Xiaodong, The University of Texas MD Anderson Cancer Center Children's Cancer Hospital, Houston, Texas, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
Background
Human mutations in WT1, or Wilms’ tumor 1, lead to severe, progressive glomerulopathy marked by heavy proteinuria and progression to end-stage renal disease (ESRD). A subset of patients with WT1 variants present at birth with rapid progression to renal failure. We sought to determine the genotypic spectrum and molecular mechanisms causing neonatal onset WT1-related disease.
Methods
We performed a systematic literature review of neonatal-onset (<1 month of age) WT1-related glomerulopathy and of all cases with the WT1 p.Arg467Trp or p.Arg467Gln variants. Cell biological techniques were utilized to assess the cellular localization, DNA binding, and transcriptional activity of wild type and mutant WT1 proteins.
Results
We identified 21 cases with pathogenic WT1 variants who had disease onset by 1 month of age and ESRD by 6 months. 17/21 (80%) cases had mutations at one of two DNA-binding residues: p.Arg439 (n=10) and p.Arg467 (n=7). Notably, there was enrichment for the p.Arg467Gln variant (n=6) and no cases with the p.Arg467Trp variant, which is a common mutational hot-spot. We found that nearly all individuals with the p.Arg467Gln variant developed early onset renal failure (median age at ESRD 1.2 months, n=15), while those with the p.Arg467Trp variant had a more variable disease course (median age at ESRD 21.6 months, n=40). In vitro studies showed that the wild type WT1 protein (in the -KTS isoform) localized diffusely within the cell nucleus, while both the p.Arg467Gln and p.Arg467Trp mutant proteins (in the -KTS isoform) localized to nuclear subdomains and failed to activate transcription. The p.Arg467Gln and p.Arg467Trp mutant proteins also have significantly reduced DNA binding, suggesting that these mutations do not function in a dominant manner via activation of aberrant transcriptional pathways.
Conclusion
WT1 mutations at the p.Arg439 and p.Arg467 loci are associated with neonatal-onset disease and early progression to ESRD. The p.Arg467Gln variant leads to more severe disease than the p.Arg467Trp variant but there was no functional difference between the two mutant proteins with regards to cellular localization or DNA binding. Further studies will be needed to better elucidate the mechanisms of neonatal-onset WT1-related glomerulopathy.
Funding
- NIDDK Support