Abstract: FR-PO790
Recessive Mutations in SYNPO2 May Cause Nephrotic Syndrome via Mesangial Cell Dysfunction
Session Information
- Genetic Diseases of the Kidney - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Mao, Youying, Boston Children's Hospital, Boston, Massachusetts, United States
- Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
- Ashraf, Shazia, Boston Children's Hospital, Boston, Massachusetts, United States
- Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
- Klambt, Verena, Boston Children's Hospital, Boston, Massachusetts, United States
- Kitzler, Thomas Michael, Boston Children's Hospital, Boston, Massachusetts, United States
- Nakayama, Makiko, Boston Children's Hospital, Boston, Massachusetts, United States
- Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
- Deutsch, Konstantin, Boston Children's Hospital, Boston, Massachusetts, United States
- Onuchic-Whitford, Ana C., Brigham and Women's Hospital / Boston Children's Hospital, Boston, Massachusetts, United States
- Shamseldin, Hanan Elfadil, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
- Alkuraya, Fowzan S., King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
- Fathy, Hanan, El Shatty Children’s Hospital, Alexandria, Egypt
- Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background
Steroid resistant nephrotic syndrome (SRNS) is the second leading cause of chronic kidney disease in the first three decades of life. So far mutations in 60 genes were identified to cause steroid resistant nephrotic syndrome (SRNS).
Methods
To identify novel monogenic causes of NS we performed whole exome sequencing (WES) in a cohort of 1,200 NS patients. To study the functional significance of mutations found, podocyte migration rate (PMR) and active Rac1 GLISA assay were performed in a human podocyte cell line.
Results
In 3 unrelated patients with childhood onset nephrotic syndrome (NS) we discovered 1 homozygous truncating and 2 homozygous missense mutations in SYNPO2 (p.K1124*, p.G413S, and p.A1134T). From the 3 types of renal glomerular cells, the SYNPO2 transcript is expressed 10 fold higher in mesangial cells than in podocytes or endothelial cells (JASN 29: 2060, 2018). Accordingly, by immunofluorescence (IF) in adult rat sections, SYNPO2 localized most strongly to mesangial cells. By IF, on the subcellular level, SYNPO2 colocalizes with F-actin. Upon overexpression in podocytes, SYNPO2 colocalizes also with ACTN4, a gene that is mutated in autosomal dominant SRNS in humans. SYNPO2 shRNA knockdown reduced podocyte migration rate (PMR) in a human podocyte cell line. PMR was rescued by transfection of wild type mouse SYNPO2 cDNA but not by cDNA representing any of the 3 mutations from patients with NS. SYNPO2 shRNA knockdown in the podocyte cell line decreased active Rac1, which was rescued by transfection of wild type SYNPO2 cDNA but not by cDNA representing any of the 3 mutations from patients with NS.
Conclusion
We here discovered recessive SYNPO2 mutations as a novel monogenic cause of nephrotic syndrome, leading to mesangial cell dysfunction through Rac1-GTPase dysregulation.
Funding
- Other NIH Support