Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

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DOI

  • Mathilda Bedin, Institut National de la Santé et de la Recherche Médicale (INSERM)
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  • Olivia Boyer, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker-Enfants Malades
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  • Aude Servais, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker-Enfants Malades
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  • Yong Li, University of Freiburg
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  • Laure Villoing-Gaudé, Institut National de la Santé et de la Recherche Médicale (INSERM)
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  • Marie Josephe Tête, Institut National de la Santé et de la Recherche Médicale (INSERM)
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  • Alexandra Cambier, Hopital Robert-Debre AP-HP
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  • Julien Hogan, Hopital Robert-Debre AP-HP
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  • Veronique Baudouin, Hopital Robert-Debre AP-HP
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  • Saoussen Krid, Institut Necker-Enfants Malades
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  • Albert Bensman, Institut Necker-Enfants Malades
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  • Florie Lammens, Université de Lille
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  • Ferielle Louillet, CHU Hopitaux de Rouen
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  • Bruno Ranchin, Hospices Civils de Lyon
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  • Cecile Vigneau, University Hospital of Pontchaillou
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  • Iseline Bouteau, Centre Hospitalier Universitaire de Poitiers
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  • Corinne Isnard-Bagnis, Sorbonne Université
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  • Christoph J. MacHe, Medical University of Graz
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  • Tobias Schäfer, University of Freiburg
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  • Lars Pape, Hannover Medical School
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  • Markus Gödel, University Medical Center Hamburg-Eppendorf
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  • Tobias B. Huber, University Medical Center Hamburg-Eppendorf
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  • Marcus Benz, Kindernephrologie Dachau
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  • Günter Klaus, Philipps-Universität Marburg
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  • Matthias Hansen, KfH-Nierenzentrum fur Kinder und Jugendliche und Clementine-Kinderhospital
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  • Kay Latta, KfH-Nierenzentrum fur Kinder und Jugendliche und Clementine-Kinderhospital
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  • Olivier Gribouval, Institut National de la Santé et de la Recherche Médicale (INSERM)
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  • Vincent Morinière, Institut Necker-Enfants Malades
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  • Carole Tournant, Institut Necker-Enfants Malades
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  • Maik Grohmann, Bioscientia Institut für Medizinische Diagnostik GmbH, Center for Human Genetics
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  • Elisa Kuhn, Bioscientia Institut für Medizinische Diagnostik GmbH
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  • Timo Wagner, Bioscientia Institut für Medizinische Diagnostik GmbH
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  • Christine Bole-Feysot, Institut National de la Santé et de la Recherche Médicale (INSERM), CNRS
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  • Fabienne Jabot-Hanin, Institut National de la Santé et de la Recherche Médicale (INSERM), CNRS
  • ,
  • Patrick Nitschké, Institut National de la Santé et de la Recherche Médicale (INSERM), CNRS
  • ,
  • Tarunveer S. Ahluwalia, Steno Diabetes Center
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  • Anna Köttgen, University of Freiburg
  • ,
  • Christian Brix Folsted Andersen
  • Carsten Bergmann, Bioscientia Institut für Medizinische Diagnostik GmbH, Center for Human Genetics, University of Freiburg
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  • Corinne Antignac, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker-Enfants Malades
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  • Matias Simons, Institut National de la Santé et de la Recherche Médicale (INSERM)

BACKGROUND. Proteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized 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 were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had 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 the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR 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 albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Investigation
Vol/bind130
Nummer1
Sider (fra-til)335-344
Antal sider10
ISSN0021-9738
DOI
StatusUdgivet - 2020

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