Abstract: TH-PO0359
Altered Lipid Handling and Cytoskeletal Dynamics in RCAN1-Associated Nephrotic Syndrome
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Lane, Brandon M., Duke University School of Medicine, Durham, North Carolina, United States
- Chryst-Stangl, Megan, Duke University School of Medicine, Durham, North Carolina, United States
- Ebo, Christian Marlo, University of Miami Miller School of Medicine, Miami, Florida, United States
- Harkins, Scott P., University of Miami Miller School of Medicine, Miami, Florida, United States
- El Saghir, Jamal, University of Michigan, Ann Arbor, Michigan, United States
- Helmuth, Margaret, University of Michigan, Ann Arbor, Michigan, United States
- Fermin, Damian, University of Michigan, Ann Arbor, Michigan, United States
- Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
- Harder, Jennifer L., University of Michigan, Ann Arbor, Michigan, United States
- Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
- Ali, Hassan, University of Miami Miller School of Medicine, Miami, Florida, United States
- Gbadegesin, Rasheed A., Duke University School of Medicine, Durham, North Carolina, United States
Background
We previously identified variants in the the gene encoding Regulator of Calcinuerin Type 1 (RCAN1) as a cause of nephrotic syndrome. While increased calcineurin activity and apoptosis have been observed in RCAN1-deficient cells, the mechanisms driving podocyte injury remain unclear.
Methods
To define mechanisms of RCAN1-mediated podocyte dysfunction, we evaluated disease phenotypes in CRISPR-edited human immortalized podocytes harboring a pathogenic RCAN1 I162T variant. We also created RCAN1 knockout (KO) podocytes to model general loss of function variants. Findings were validated in iPSC-derived podocytes generated from two affected individuals with RCAN1 I162T and an unaffected familial control, with two independent clones analyzed per subject.
Results
Live-cell imaging demonstrated that both RCAN1 I162T and KO podocytes exhibit increased apoptosis (cleaved caspase-3 activity), increased focal adhesion (Paxillin-GFP), and reduced motility (scratch wound assay), indicating shared injury phenotypes. In contrast, lipid accumulation was observed exclusively in RCAN1 I162T podocytes. This variant-specific phenotype was associated with reduced membrane-localized ABCG1 despite preserved transcript levels, along with compensatory upregulation of ABCA1. Increased lipid accumulation was confirmed in RCAN1 I162T patient-derived iPSC podocytes compared to unaffected controls .
Conclusion
RCAN1 variants drive shared podocyte injury characterized by reduced viability and altered cytoskeletal dynamics, but the I162T variant additionally confers a distinct lipid dysregulation phenotype. These findings identify impaired ABCG1 membrane trafficking as a potential variant-specific mechanism of disease and highlight a targetable pathway for therapeutic intervention.
Funding
- NIDDK Support