Abstract: FR-OR064
De Novo Truncating TRIM8 Mutations Cause a Novel Pediatric Neuro-Renal Syndrome and Abrogate Protein Localization to Nuclear Bodies
Session Information
- Genetic Diseases and the Kidneys
November 08, 2019 | Location: 144, Walter E. Washington Convention Center
Abstract Time: 05:06 PM - 05:18 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
- Weng, Patricia L., UCLA, Los Angeles, California, United States
- Khan, Kamal, Duke University Medical Center, Durham, North Carolina, United States
- Lim, Tze Yin, Columbia University, New York, New York, United States
- Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
- Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
- Jin, Gina ying, Columbia University, New York, New York, United States
- Musgrove, John L., Duke University Medical Center, Durham, North Carolina, United States
- Aggarwal, Vimla, CUIMC, New york, New York, United States
- Onuchic-Whitford, Ana C., Boston Children's Hospital / Brigham and Women's Hospital, Boston, Massachusetts, United States
- Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
- Beck, Bodo B., University of Cologne Medical Center, Cologne, Germany
- Benz, Marcus R., Pediatric Nephrology Dachau, Dachau, Germany
- Hoefele, Julia, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
- D'Agati, Vivette D., Columbia University, New York, New York, United States
- Davis, Erica, Duke University Medical Center, Durham, North Carolina, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
Background
Genetic forms of pediatric focal segmental glomerulosclerosis (FSGS) are usually caused by recessive mutations. The contribution of dominant de novo mutations (DNMs) to this trait is unknown.
Methods
We performed genetic studies using exome sequencing (ES) in 43,146 individuals. We conducted studies in tissue and human podocytes transfected with TRIM8 cDNA constructs.
Results
A 4 year old child with epilepsy presented with FSGS. ES in the patient and unaffected parents identified a novel DNM in TRIM8 (p.Q459*). To establish a link between TRIM8 and FSGS, we conducted ES at Columbia University and Boston Children Hospital. We identified 6 additional TRIM8 truncating mutations in 2,051 FSGS children as compared to 0/35,885 controls (P=2.5x10-8). Parental data was available for 4/6 cases and in all instances the mutations were de novo (P=2.6x10-10), establishing TRIM8 as a novel FSGS gene. Review of clinical data showed that all 6 cases also had epilepsy, indicating that TRIM8 DNMs define a novel neuro-renal syndrome. Consistent with this, we identified additional TRIM8 mutations in 2/5,209 epilepsy patients. TRIM8 spans 551 amino acids. All mutations clustered between amino acid positions 410-460 in the last exon, predicted to escape non-sense mediated decay. TRIM8 was strongly expressed in podocytes and while overexpressed wildtype TRIM8 localized to nuclear bodies, constructs harboring patient-specific mutations (p.Q411* and p.Q459*) localized diffusely to the nucleoplasm.
Conclusion
Dominant TRIM8 DNMs cause a novel pediatric neuro-renal syndrome due to its aberrant nuclear localization, implicating nuclear bodies in FSGS pathogenesis. Work in zebrafish and mouse is ongoing.
Funding
- NIDDK Support