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

Mathilda Bedin 1 Olivia Boyer 2 Aude Servais 3 Yong Li 4 Laure Villoing-Gaudé Marie-Josèphe Tête 5 Alexandra Cambier Julien Hogan 6 Véronique Baudouin 7 Saoussen Krid Albert Bensman 8 Florie Lammens 9 Ferielle Louillet Bruno Ranchin 10 Cécile Vigneau 11, 12 Iseline Bouteau Corinne Isnard-Bagnis 13 Christoph Mache Tobias Schäfer Lars Pape 14 Markus Gödel Tobias Huber 15 Marcus Benz Günter Klaus Matthias Hansen Kay Latta Olivier Gribouval 2 Vincent Morinière 16 Carole Tournant Maik Grohmann Elisa Kuhn Timo Wagner Christine Bôle-Feysot 17 Fabienne Jabot-Hanin 18 Patrick Nitschke 19 Tarunveer S Ahluwalia 20 Anna Köttgen Christian Brix Folsted Andersen Carsten Bergmann Corinne Antignac 2 Matias Simons 1, * 
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).
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Submitted on : Monday, January 20, 2020 - 10:13:48 AM
Last modification on : Friday, August 5, 2022 - 12:35:05 PM

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Mathilda Bedin, Olivia Boyer, Aude Servais, Yong Li, Laure Villoing-Gaudé, et al.. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function. Journal of Clinical Investigation, American Society for Clinical Investigation, 2020, 130 (1), pp.335-344. ⟨10.1172/JCI129937⟩. ⟨hal-02445305⟩



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