Abstract: PO1993
Genetic Causes for Congenital Nephrotic Syndrome: North American Mutations and the Contribution of Regulatory Factors
Session Information
- Pediatric Nephrology: Genetics, Kidney Stones, Quality Improvement, and Case Reports
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1700 Pediatric Nephrology
Authors
- Hefley, Shyanne, Texas Tech University Health Sciences Center, Amarillo, Texas, United States
- Greenbaum, Larry A., Emory University, Atlanta, Georgia, United States
- Constantinescu, Alexandru R., Joe DiMaggio Children's Hospital, Hollywood, Florida, United States
- Mattoo, Tej K., Wayne State University, Detroit, Michigan, United States
- Wenderfer, Scott E., Baylor College of Medicine, Houston, Texas, United States
- Twombley, Katherine, Medical University of South Carolina, Charleston, South Carolina, United States
- Vasylyeva, Tetyana L., Texas Tech University Health Sciences Center, Amarillo, Texas, United States
Background
Congenital Nephrotic Syndrome (CNS) is a debilitating disease that affects children within the first few months of life and is characterized by severe proteinuria and loss of kidney function. A majority of CNS cases are caused by mutation of the NPHS1 gene, particularly in other countries. Our first aim was to determine the specific genetic causes for CNS in North America (NA). Our second aim was to determine the contribution of FOXC1, FOXL1, and GATA3 to NPHS1 transcription and nephrin production, which could serve as potential drug targets for CNS therapy.
Methods
A retrospective chart review was performed to determine the prevalence of CNS mutations in NA. A survey was administered to members of the Pediatric Nephrology Research Consortium (PNRC) and consisted of 65 questions pertaining to CNS. A questionnaire was developed by a team of pediatric nephrologists and was administered to members of the Pediatric Nephrology Research Consortium (PNRC) via Qualtrics. In vitro studies to determine the impact of FOXC1, FOXL1, and GATA3 on NPHS1 were performed using mouse primary podocytes and siRNA knockdown was performed to determine the effect of these transcription factors on nephrin production.
Results
We found the average age of CNS diagnosis was 2.6 months, with 60.3% of patients being female. Sixty-eight percent of patients underwent genetic testing for their CNS and a majority of patients (65.1%) had NPHS1 mutations, whereas 11.6% had NPHS2 mutations. Interestingly, 7.0% had both NPHS1 and NPHS2 mutations and 11.6% had only WT1 mutations. The remaining 4.6% had inconclusive results. We noted that the average age of onset for NPHS1-only mutations was 2.1 months, whereas patients with only NPHS2 mutations had an average age of onset of 4.5 months. Interestingly, patients with either WT-1 mutations or a combination of NPHS1 and NPHS2 mutations had younger ages of onset of 1.35 months and 1.25 months, respectively. In our in vitro studies, siRNA knockdown of FOXC1, FOXL1, and GATA3 resulted in alterations in the expression of nephrin.
Conclusion
The results of this study not only demonstrate the distribution of genetic causes for CNS in North America, but also show that transcription factors may play a role in NPHS1 transcription.