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Kidney Week

Abstract: SA-PO613

NBL1 Correlates with Kidney Disease in a Mouse Model for Alport Syndrome, but Is Not Causal

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Willey, Courtney, The Jackson Laboratory, Bar Harbor, Maine, United States
  • Bufi, Rei, The Jackson Laboratory, Bar Harbor, Maine, United States
  • Brackett, Abigail, The Jackson Laboratory, Bar Harbor, Maine, United States
  • Sheehan, Susan Marie, The Jackson Laboratory, Bar Harbor, Maine, United States
  • Korstanje, Ron, The Jackson Laboratory, Bar Harbor, Maine, United States
Background

Alport syndrome (AS) is a rare genetic condition that often results in progressive loss of kidney function and end-stage kidney disease. Although the causal genes for AS are well characterized, individuals with AS still display a wide range of variation in kidney function and age of onset, suggesting the presence of modifiers. Recently, several studies identified levels of neuroblastoma suppressor of tumorigenicity 1 (NBL1) in the blood to be strongly and independently associated with more severe progression of diabetic nephropathy and IgA nephropathy. We decided to investigate the role of NBL1 in a genetically diverse population of Diversity Outbred (DO) mice with X-linked Alport Syndrome (DO-XLAS) and found a significant correlation between NBL1 and kidney function. However, it is still unclear whether NBL1 is causal or consequential to kidney disease.

Methods

To test causality, we created an NBL1 knockout (KO) mouse model and confirmed that heterozygous (HET) animals have significantly lower NBL1 levels in their blood compared to wildtype (WT). We then induced AS by breeding a mutated Col4a5 allele into our NBL1 KO mice and investigated differences in kidney function and damage.

Results

We did not find a difference in GFR or albuminuria between HET and WT animals, suggesting that NBL1 does not have a causal role in disease progression. We are performing a genetic analysis on 600 DO-XLAS mice to identify the drivers of increased plasma NBL1 levels and better understand the underlying mechanism and relationship with kidney disease.

Conclusion

NBL1 does not appear to have a causal role in disease progression and increased NBL1 levels are more likely to be a consequence of kidney disease. The exact role of NBL1 in kidney disease remains to be elucidated.

Funding

  • NIDDK Support