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

Mathilda Bedin, Olivia Boyer, Aude Servais, Yong Li, Laure Villoing-Gaudé, Marie-Josephe Tête, Alexandra Cambier, Julien Hogan, Veronique Baudouin, Saoussen Krid, Albert Bensman, Florie Lammens, Ferielle Louillet, Bruno Ranchin, Cecile Vigneau, Iseline Bouteau, Corinne Isnard-Bagnis, Christoph J Mache, Tobias Schäfer, Lars Pape, Markus Gödel, Tobias B Huber, Marcus Benz, Günter Klaus, Matthias Hansen, Kay Latta, Olivier Gribouval, Vincent Morinière, Carole Tournant, Maik Grohmann, Elisa Kuhn, Timo Wagner, Christine Bole-Feysot, Fabienne Jabot-Hanin, Patrick Nitschké, Tarunveer S Ahluwalia, Anna Köttgen, Christian Brix Folsted Andersen, Carsten Bergmann, Corinne Antignac, Matias Simons

Journal: The Journal of clinical investigation 2020;130(1):335-344

PMID: 31613795

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Abstract

BACKGROUNDProteinuria 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.METHODSWe 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.RESULTSWe 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.CONCLUSIONCollectively, 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.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).

Address: Laboratory of Epithelial Biology and Disease and.; Laboratory of Hereditary Kidney Disease, Imagine Institute, INSERM U1163, Université de Paris, Paris, France.; Department of Pediatric Nephrology and.; Laboratory of Hereditary Kidney Disease, Imagine Institute, INSERM U1163, Université de Paris, Paris, France.; Department of Nephrology, Necker Hospital, Assistance Publique Hôpitaux de Paris (APHP), Paris, France.; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.; Laboratory of Hereditary Kidney Disease, Imagine Institute, INSERM U1163, Université de Paris, Paris, France.; Department of Pediatric Nephrology and Transplantation, Robert-Debré Hospital, APHP, Paris, France.; Department of Pediatric Nephrology and.; Centre Hospitalier Régional Universitaire de Lille, Lille, France.; Centre Hospitalier Universitaire de Rouen, Rouen, France.; Department of Pediatric Nephrology, Hospices Civils de Lyon, Bron, France.; Centre Hospitalier Universitaire de Rennes, INSERM U1085 IRSET-9, Rennes, France.; Centre Hospitalier Universitaire de Poitiers, Poitiers, France.; Department of Nephrology, Pitié Salpetrière Hospital, Paris, France.; Children's Hospital, Medical University Graz, Graz, Austria.; Renal Division, University Medical Center Freiburg, Freiburg, Germany.; Department of Pediatric Kidney, Liver and Metabolic Disease, Hannover Medical School, Hannover, Germany.; Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Kindernephrologie Dachau, Dachau, Germany.; Department of Child and Adolescent Medicine, University Medical Center Marburg-Giessen, Marburg, Germany.; KfH-Nierenzentrum für Kinder und Jugendliche und Clementine-Kinderhospital, Frankfurt, Germany.; Department of Genetics, Necker Hospital, APHP, Paris, France.; Center for Human Genetics, Bioscientia, Ingelheim, Germany.; Center for Human Genetics, Mainz, Germany.; Center for Human Genetics, Bioscientia, Ingelheim, Germany.; Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, Paris, France.; Bioinformatics Core Facility, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Université de Paris, Paris, France.; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; Department of Biomedicine, Aarhus University, Aarhus, Denmark.; Center for Human Genetics, Bioscientia, Ingelheim, Germany.; Center for Human Genetics, Mainz, Germany.; Renal Division, Department of Medicine, University Hospital Freiburg, Freiburg, Germany.; Laboratory of Hereditary Kidney Disease, Imagine Institute, INSERM U1163, Université de Paris, Paris, France.; Department of Genetics, Necker Hospital, APHP, Paris, France.

DOI: 10.1172/JCI129937

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MeSH Terms: Albuminuria, Anemia, Megaloblastic, Female, Humans, Kidney Tubules, Proximal, Malabsorption Syndromes, Male, Mutation, Proteinuria, Receptors, Cell Surface, Vitamin B 12 Deficiency