Abstract: FR-PO788
Recessive Mutations in Bassoon (BSN) Are a Potential New 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
- Onuchic-Whitford, Ana C., Boston Children's Hospital, Boston, Massachusetts, United States
- Klambt, Verena, Boston Children's Hospital, Boston, Massachusetts, United States
- Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
- Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
- Ashraf, Shazia, 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
- Lim, Tze Yin, Columbia University, New York, New York, United States
- Sanna-Cherchi, Simone, Columbia University, New York, New York, 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 most frequent cause of chronic kidney disease in children and young adults. Major insights into its pathogenesis came from discovery of ~60 monogenic causes, contributing to ~12-30% of SRNS with onset <25 years of age. However, a significant proportion remains without a genetic diagnosis.
Methods
To identify novel pathogenic genetic variants, we performed whole-exome sequencing (WES) in a world-wide cohort of >800 individuals from different families with SRNS. We evaluated potential pathogenicity of genetic variants by in-silico prediction scores, evolutionary conservation and allele frequency in public genome sequencing databases.
Results
We identified 6 individuals from different families with recessive deleterious mutations in the BSN gene (bassoon). Two individuals harbored different homozygous mutations (p.S1481T and p.P3888L), while 4 had compound heterozygous mutations (p.R519W / p.T2829M; p.R3664Q / p.R1193H; p.P620L / p.K2697E; and p.P2503Afs*15 / p.H3716N). Age of SRNS onset was 7 months to >21 years old. Of 4 patients who underwent renal biopsies, 3 had focal segmental glomerulosclerosis, and 1 had minimal change disease. Four patients had extra-renal manifestations (microcephaly, atrial septal defect, short stature, seizures, and intellectual disability). Bassoon is a scaffolding protein found in the neuronal presynaptic plasma membrane, involved in priming of synaptic vesicles, assembly of active zones and localization of voltage-gated calcium channels (Front Synaptic Neurosci 7:19, 2015). Podocytes have been shown to contain structures resembling synaptic vesicles. Bassoon was previously identified in cultured podocytes and in kidney glomeruli by Western blot and immunohistochemistry (FASEB J. 20(7):976, 2006).
Conclusion
By WES, we here identify recessive mutations of BSN in 6 affected individuals, revealing a potential novel monogenic cause of SRNS.
Funding
- NIDDK Support