Abstract: FR-PO0719
DACH2: Potential Candidate Gene for Monogenic Steroid-Resistant Nephrotic Syndrome
Session Information
- Pediatric Nephrology: CKD, ESKD, and Glomerular Diseases
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1900 Pediatric Nephrology
Authors
- Prakash, Chiranth M, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Yousef, Kirollos, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Schneider, Ronen, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Majmundar, Amar J., Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Zahoor, Muhammad Y., Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Nelson, Becca, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Lemberg, Katharina, Boston Children’s Hospital, HMS, Boston, United States
- Buerger, Florian, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Weber, Lutz Thorsten, University of Cologne, Cologne, Germany
- Fathy, Hanan, University of Alexandria, Al Farwaniyah, Kuwait
- Saida, Ken, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Marchuk, Daniel, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Riedhammer, Korbinian M., Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Lomjansook, Kraisoon, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Zion, Elena, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Franken, Gijs A.C., Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Shril, Shirlee, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Widmeier, Eugen, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Kolvenbach, Caroline Maria, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Sayer, John Andrew, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children’s Hospital, HMS, Boston, Massachusetts, United States
Background
Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of pediatric end-stage kidney disease. SRNS presents as proteinuria, steroid resistance, and often FSGS on biopsy. In steroid-resistant cases, prognosis and therapy selection remain uncertain.
Single-gene variants in SRNS have offered initial insights into its mechanisms. Yet, in most cases, the cause remains elusive. DACH2, on the X-chromosome, the protein contains two characteristic Dachshund domains: N-terminal DNA domain and C-terminal interaction region.
We report four distinct likely deleterious hemizygous variants. DACH2 variants in individuals with nephrotic syndrome from unrelated families. We present evidence of the alleles’ deleterious nature, revealing a novel gene for monogenic SRNS.
Methods
To identify novel monogenic causes of NS, exome sequencing (ES) was performed as part of our worldwide nephrotic syndrome cohort of ~1,300 families. We investigated hemizygous likely deleterious DACH2 variants in individuals from unrelated families. Computational tools assessed structural and stability changes pre- and post-mutation.
Further, we assessed the localization of DACH2 protein in podocytes within rat kidney sections, and in vitro using overexpression systems in undifferentiated human podocytes.
Results
ES revealed hemizygous missense variants in DACH2 in four unrelated males with nephrotic syndrome: p.(Ser397Ile), p.(Arg539His), p.(Leu466Pro), and p.(*600Argext*8). All variants were predicted as likely deleterious and absent in homozygous/hemizygous state when in silico modeling predicted 3D-protein disruption. Nuclear localization studies showed DACH2 in podocyte nuclei of rat kidney sections. Moreover, DACH2 expression was observed in cytoplasm in undifferentiated human podocytes which shifted to the nucleus upon differentiation.
Conclusion
The data indicate that X-linked hemizygous DACH2 missense variants impair podocyte function, thus manifesting significant proteinuria. We hereby propose those hemizygous variants in DACH2 as a likely novel cause of SRNS.