Abstract: PO1672
Recessive Mutations in SEMA3G as a Potential Novel Cause of Nephrotic Syndrome
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
- Klambt, Verena, Boston Children's Hospital, Boston, Massachusetts, United States
- Onuchic-Whitford, Ana C., Boston Children's Hospital, Boston, Massachusetts, United States
- Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
- Deutsch, Konstantin, Boston Children's Hospital, Boston, Massachusetts, United States
- Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
- 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. The identification of monogenic causes of SRNS has revealed ~60 single-gene etiologies. While in 12-30% of patients with SRNS a causative mutation may be detected, many remain without a molecular diagnosis (Sadowski JASN 26:1279, 2015). These genes are predominantly expressed in glomerular podocytes and the encoded proteins merge onto molecular complexes and pathways that are essential to podocyte development or homeostasis.
Methods
To identify novel monogenic causes of NS, we performed whole exome sequencing (WES) in an international cohort of 1,382 NS patients.
Results
We identified homozygous mutations in SEMA3G in 3 unrelated children with nephrotic syndrome, 1 nonsense mutation (c.1078C>T, p.Arg360*), 1 essential splice site mutation (c.460-2A>G, predicted to lead to skipping of exon 5 and thus causing a frame-shift and truncation of the protein) and 1 missense mutation (c.2225G>A, p.Arg742Gln). SEMA3G is a secreted protein that has been implicated in cell migration and axon guidance, and shown to protect podocytes from inflammatory kidney disease in a mouse model (Ishibashi Sci Rep 6:25955, 2016). We evaluated publicly available kidney single-cell RNA sequencing datasets and found SEMA3G to be predominantly expressed in podocytes (Karaiskos JASN 29:2060, 2018). We then performed co-immunofluorescence staining in adult rat kidney sections for Sema3g and established markers of podocytes (nephrin), endothelial cells (CD31), and mesangial cells (αSMA). The Sema3g signal was strongest in podocyte foot processes as indicated by partial overlap with nephrin but lack of overlap with CD31, or αSMA signal.
Conclusion
We, here, identified recessive mutations in SEMA3G as a potential novel cause of nephrotic syndrome in children.
Funding
- NIDDK Support