Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Let-7a induces metabolic reprogramming in breast cancer cells via targeting mitochondrial encoded ND4

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Cardiovascular autonomic neuropathy and the impact on progression of diabetic kidney disease in type 1 diabetes

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Genetic association study of childhood aggression across raters, instruments, and age

    Research output: Contribution to journalJournal articleResearchpeer-review

  • 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
View graph of relations

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).

Original languageEnglish
JournalThe Journal of clinical investigation
Volume130
Issue number1
Pages (from-to)335-344
Number of pages10
ISSN0021-9738
DOIs
Publication statusPublished - 2 Jan 2020

    Research areas

  • Albuminuria/epidemiology, Anemia, Megaloblastic/epidemiology, Female, Humans, Kidney Tubules, Proximal/metabolism, Malabsorption Syndromes/epidemiology, Male, Mutation, Proteinuria/epidemiology, Receptors, Cell Surface/genetics, Vitamin B 12 Deficiency/epidemiology

ID: 61378500