Kidney Week

Abstract: SA-PO618

Pathogenic Variants in NFATC1 and NFATC3 Can Cause Nephrotic Syndrome

Session Information

• Genetic Kidney Diseases: Models, Mechanisms, and Therapies
  October 26, 2024 | Location: Exhibit Hall, 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

• Zhang, Sue, Duke University, Durham, North Carolina, United States

Sue Zhang

• Peters, Hariel G., Duke University, Durham, North Carolina, United States

Hariel G. Peters

• Chryst-Stangl, Megan, Duke University, Durham, North Carolina, United States

Megan Chryst-Stangl

• Wu, Guanghong, Duke University, Durham, North Carolina, United States

Guanghong Wu

• Gbadegesin, Rasheed A., Duke University, Durham, North Carolina, United States

Rasheed A. Gbadegesin, MD, MBBS, FASN

• Lane, Brandon M., Duke University, Durham, North Carolina, United States

Brandon M. Lane, PhD

Background

Nephrotic syndrome (NS) is a kidney condition that is characterized by disruption of the glomerular filtration barrier leading to proteinuria and progressive kidney damage. While dysregulation of the calcineurin (CN) signaling pathway has been implicated in the pathogenesis of NS, the role of pathogenic variants in calcineurin signaling pathway (CNP) genes in the etiology of genetic NS remains unclear. To address this, we performed whole exome sequencing on >500 children with nephrotic syndrome and performed targeted analysis of 67 CNP genes.

Methods

We carried out whole exome sequencing in >500 children with NS and use previously published filtering algorithm to identify pathogenic variants in CNP genes in these children. To determine the pathogenicity of the variants on podocyte homeostasis, we used lentiviral shRNA and plasmid transduction to modulate NFATC1 and NFATC3 gene expression in immortalized podocyte cell lines and examined changes in cell migration using automated live-cell imaging.

Results

We identified two variants in NFAT genes (NFATC1 c.insC2463; p.G821fs and NFATC3 c.G1519A; p.A507T) in two families with steroid resistant nephrotic syndrome (SRNS). The two variants segregate with disease in the family. Knockdown of NFATC1 and NFATC3 in immortalized human podocyte cell lines reduces podocyte motility and disruption of cytoskeleton regulation.

Conclusion

Our data suggests that NFATC1 and NFATC3 are new candidate genes for nephrotic syndrome.

Funding

• NIDDK Support