Abstract: FR-PO789
Recessive Mutations in TNS1 Are a Potential Novel Cause of Nephrotic Syndrome
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
- Kitzler, Thomas Michael, 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
- Mao, Youying, Boston Children's Hospital , Boston, Massachusetts, United States
- Ashraf, Shazia, Boston Children's Hospital , Boston, Massachusetts, United States
- Klambt, Verena, Boston Children's Hospital , Boston, Massachusetts, United States
- Majmundar, Amar J., Boston Children's Hospital , Boston, Massachusetts, United States
- Buerger, Florian, 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
- Cifuentes, Iliana M., Fundación para El Niño Enfermo Renal (FUNDANIER), Quetzaltenango, Guatemala
- Lou-Meda, Randall M., Fundación para El Niño Enfermo Renal (FUNDANIER), Quetzaltenango, Guatemala
- Aguilar, Angie Lizet, Fundación para El Niño Enfermo Renal (FUNDANIER), Quetzaltenango, Guatemala
- Soliman, Neveen, Cairo University, Cairo, Egypt
- Bagga, Arvind, All India Institute of Medical Sciences, New Delhi, India
- 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. Using WES, we demonstrated that mutations in one of the 59 known SRNS genes can be identified in 25% of patients (NDT, 2019 doi: 10.1093/ndt/gfz028).
Methods
To discover additional monogenic causes of NS, we performed WES in a cohort of 600 families with childhood onset SRNS.
Results
We identified rare compound heterozygous missense mutations in the TNS1 gene in five individuals from four unrelated families with NS: family B2014: p.R1198Q and p.R940Y; A1226: p.I224N and p.D66V; A4619: p.S1098R and S920C, A4580: p.T218I and p.A1685T. TNS1 is known to interact with actin, to bind to β1-integrin and serve as a scaffold for adhesion-related signaling. Specifically, it enhances RhoA activity in a DLC1-dependent manner through its multiple domains (BBA 1853:3258, 2015). We found that the p.T218I (PTEN_C2 domain) and p.A1685T (PTB domain) mutations are predicted to reduce overall protein domain stability, while the highly conserved p.D66V mutation is predicted to destabilize the PTEN_C2 domain (http://cupsat.tu-bs.de/). The two siblings in our index family (B2014) presented with a history of proteinuria. In addition, sibling B2014_21 had renal hypoplasia and lack of corticomedullary differentiation on renal ultrasound, while B2014_22 had increased renal echogenicity with prominence of the renal papillae. Notably, tensin-/- mice have renal failure, proximal tubule cysts with disrupted cell-matrix junctions in non-cystic areas, tubulointerstitial nephritis, glomerulosclerosis, and abnormal renal papillae (JCB 136:1349, 1997). Employing immunofluorescence in sections of healthy rat glomeruli, we demonstrated primarily mesangial localization of TNS1, which is corroborated by single-cell RNA expression data in mice glomeruli (JASN 29:2060, 2018).
Conclusion
We identified likely disease-causing mutations in TNS1 in four unrelated families with NS, revealing a novel monogenic cause of human glomerular disease.
Funding
- NIDDK Support