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Abstract: FR-OR062

High Prevalence of C-Terminal CUBN Variants Associated with Chronic Proteinuria and Normal Renal Function in Humans

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Simons, Matias, Institut Imagine, Paris, France
  • Bedin, Mathilda, Institut Imagine, Paris, France
  • Boyer, Olivia, Imagine Institute/Laboratory of Hereditary Kidney Diseases, Paris, France
  • Servais, Aude, Necker University Hospital, Paris, France
  • Li, Yong, Medical Center - University of Freiburg, Freiburg, Germany
  • Ahluwalia, Tarunveer S., Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Kottgen, Anna, Medical Center - University of Freiburg, Freiburg, Germany
  • Bergmann, Carsten, Medical Center - University of Freiburg, Freiburg, Germany
  • Antignac, Corinne, Imagine Institute/Laboratory of Hereditary Kidney Diseases, Paris, France
Background

Proteinuria is considered as an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear if all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS) featured by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.

Methods

We used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling and epidemiological methods.

Results

We identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene are associated with chronic isolated proteinuria with childhood onset. Since the proteinuria displayed a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and proteinuria-lowering treatments. Yet, renal function was normal in all cases. By contrast, we did not find any biallelic pathogenic CUBN variants in patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 out of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. By structural modeling, we further demonstrate that all these C-terminal variants affect stability or ligand binding of CUB domains. Finally, we show that four C-terminal CUBN variants are associated with albuminuria and significantly higher eGFR in meta-analyses of large population-based cohorts.

Conclusion

Collectively, our data suggest an important role for the C-terminal half of cubilin in renal protein reabsorption. Defective reabsorption could be an unexpectedly common benign condition that does not require any treatment and may even have renoprotective effects. Therefore, cubilin can be defined as a safe drug target in human renal disease.

Funding

  • Government Support - Non-U.S.