Abstract: PO1664
Rare Variants in RCAN1-3 Genes Are Enriched in Patients with CKD
Session Information
- Podocyte Injury in Human Disease: Pathomechanism, Diagnosis, and Therapy
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Lane, Brandon M., Duke University Department of Pediatrics, Durham, North Carolina, United States
- Benson, Katherine A., Royal College of Surgeons in Ireland, Dublin, Ireland
- Murray, Susan Louise, Duke University School of Medicine, Durham, North Carolina, United States
- Chryst-Stangl, Megan, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
- Wu, Guanghong, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
- Wang, Liming, Duke University Hospital, Durham, North Carolina, United States
- Elhassan, Elhussein Aamir Elzein, Beaumont Hospital, Dublin, Ireland
- Howell, David Noble, Duke University Department of Pathology, Durham, North Carolina, United States
- Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
- Spurney, Robert F., Duke University Hospital, Durham, North Carolina, United States
- Gbadegesin, Rasheed A., Duke University Department of Pediatrics, Durham, North Carolina, United States
Background
We recently identified rare variants in the gene encoding Regulator of Calcineurin Type 1 (RCAN1) as a novel cause of FSGS/SRNS. Cells expressing mutant RCAN1 and human podocytes with reduced RCAN1 displayed increased CN activity that resulted in increased susceptibility to apoptosis compared to WT RCAN1. There are two additional proteins in the RCAN family, RCAN2 and RCAN3, both of which are capable of regulating CN activity. To further elucidate the role of pathogenic variants in RCAN genes in the etiology and pathogenesis of chronic kidney disease, we screened patients with CKD for rare variants in RCAN1-3 genes. In addition, we performed kinase screening to identify compounds that can rescue the phenotype induced by defective RCAN1.
Methods
In collaboration with the Genome England Consortium, we examined associations between potentially pathogenic variants in RCAN1-3 genes and kidney disease in the large multi-ethnic National Health Service database. We compared the percentage of patients with rare (MAF <0.01), functional RCAN1-3 variants in patients with CKD (renal and urinary tract disorders) and patients with neurological disorders. We also used target kinase inhibition to examine additional potential RCAN1 regulatory kinases.
Results
Of the 4,153 patients in the UK National Health Service data set with CKD, 39 (0.94%) had rare functional RCAN 1-3 variants compared to 87 (0.57%) of the 15,141 patients with neurological disorders, revealing a significant enrichment of rare pathogenic variants in RCAN1-3 genes in patients with kidney disease compared to those without (p=0.0006). Pharmacological inhibition of additional RCAN regulatory kinases including DYRK1A (Harmine) or BMK1 (Ax15836 and XMD8-85) could rescue the elevated CN activity (p =0.4946. 0.3980 and 0.0912 respectively) and reduced viability (p>0.05) in disease causing mutant RCAN1 expressing cells compared to WT controls.
Conclusion
This data suggests that not only are RCAN1-3 likely single gene causes of NS/FSGS, but functional variants in the genes may also act as susceptibility or modifier genes that contribute to development of CKD. Our findings also highlight the therapeutic potential of targeting RCAN1 regulatory molecules in the treatment of FSGS.
Funding
- Commercial Support –