597 - Clinical Spectrum and Molecular Mechanisms of WT1-related Glomerulopathy

Publication Number: 597.4429

Leah Bolsius, Boston Children's Hospital, Cambridge, MA, United States; Nina Mann, Boston Children's Hospital, Boston, MA, United States; Rebecca Nelson, Boston Children's Hospital, Allston, MA, United States; Lily Hiltebeitel, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Friedhelm Hildebrandt, Boston Children's Hospital, Boston, MA, United States

Background: The transcription factor Wilms’ Tumor 1 (WT1) is essential for nephrogenesis and podocyte maintenance. Beyond Denys-Drash and Frasier syndrome, WT1 variants can cause non-syndromic glomerulopathy with variable severity and age of onset.

Objective: This study aims to explore the phenotypic spectrum of WT1-related glomerulopathy and the molecular mechanisms by which WT1 variants cause disease.

Design/Methods: We performed a retrospective chart review of patients with WT1-related glomerular disease who were cared for at a single center between 2004 and 2024, alongside a systematic literature review. Immortalized hsPodocyte cell lines stably expressing WT1 patient variants were generated to assess cellular localization and transcriptional activity.

Results: We identified 13 individuals with proteinuric kidney disease and pathogenic WT1 variants. Seven individuals had missense variants, two had truncating variants, and four had splice site variants. Notably, two individuals with a WT1 p.Arg467Gln variant presented with neonatal onset, while two individuals with a different amino acid change at the same locus, p.Arg467Trp, had a later disease onset and slower progression. A systematic literature review corroborated these findings with a median age of kidney failure of 1.2 months for the p.Arg467Gln variant (n=15) and 21.6 months for the p.Arg467Trp variant (n=40). In vitro, both variants localize to discrete nuclear subdomains instead of diffusely within the nucleus like the wild-type WT1 protein, and both fail to activate transcription.
While most pathogenic WT1 missense variants are located within the protein’s C-terminal zinc finger domains, one patient had a previously reported N-terminal variant, p.Val167Asp. In vitro, this variant remains diffusely localized within the nucleus and increases transcriptional activity twofold compared to the wild-type WT1 protein.

Conclusion(s): There is a broad spectrum of diseases associated with WT1-related kidney disease. The WT1 p.Arg467Gln variant appears to cause more severe, early-onset disease than the p.Arg467Trp variant despite similar functional consequences of both amino acid changes. Further studies will be needed to determine the mechanism by which the p.Arg467Gln causes more severe disease. The rare N-terminal p.Val167Asp variant increases WT1 transcriptional activity and acts via a gain-of-function mechanism. Our future studies are focused on applying proximity labeling techniques to better characterize the nuclear subdomains to which the p.Arg467 mutant proteins localize and the mechanisms by which the p.Val167Asp variant exerts its gain-of-function effects.

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