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

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

In: J CLIN INVEST, Vol. 130, No. 1, 02.01.2020, p. 335-344.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Bedin, M, Boyer, O, Servais, A, Li, Y, Villoing-Gaudé, L, Tête, M-J, Cambier, A, Hogan, J, Baudouin, V, Krid, S, Bensman, A, Lammens, F, Louillet, F, Ranchin, B, Vigneau, C, Bouteau, I, Isnard-Bagnis, C, Mache, CJ, Schäfer, T, Pape, L, Gödel, M, Huber, TB, Benz, M, Klaus, G, Hansen, M, Latta, K, Gribouval, O, Morinière, V, Tournant, C, Grohmann, M, Kuhn, E, Wagner, T, Bole-Feysot, C, Jabot-Hanin, F, Nitschké, P, Ahluwalia, TS, Köttgen, A, Brix Folsted Andersen, C, Bergmann, C, Antignac, C & Simons, M 2020, 'Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function', J CLIN INVEST, vol. 130, no. 1, pp. 335-344. https://doi.org/10.1172/JCI129937

APA

Bedin, M., Boyer, O., Servais, A., Li, Y., Villoing-Gaudé, L., Tête, M-J., Cambier, A., Hogan, J., Baudouin, V., Krid, S., Bensman, A., Lammens, F., Louillet, F., Ranchin, B., Vigneau, C., Bouteau, I., Isnard-Bagnis, C., Mache, C. J., Schäfer, T., ... Simons, M. (2020). Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function. J CLIN INVEST, 130(1), 335-344. https://doi.org/10.1172/JCI129937

Vancouver

Bedin M, Boyer O, Servais A, Li Y, Villoing-Gaudé L, Tête M-J et al. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function. J CLIN INVEST. 2020 Jan 2;130(1):335-344. https://doi.org/10.1172/JCI129937

Bibtex

@article{84b18bf2bf804d01acd3bd5a05118a6b,
title = "Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function",
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-Gr{\"a}sbeck 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).",
author = "Mathilda Bedin and Olivia Boyer and Aude Servais and Yong Li and Laure Villoing-Gaud{\'e} and Marie-Josephe T{\^e}te and Alexandra Cambier and Julien Hogan and Veronique Baudouin and Saoussen Krid and Albert Bensman and Florie Lammens and Ferielle Louillet and Bruno Ranchin and Cecile Vigneau and Iseline Bouteau and Corinne Isnard-Bagnis and Mache, {Christoph J} and Tobias Sch{\"a}fer and Lars Pape and Markus G{\"o}del and Huber, {Tobias B} and Marcus Benz and G{\"u}nter Klaus and Matthias Hansen and Kay Latta and Olivier Gribouval and Vincent Morini{\`e}re and Carole Tournant and Maik Grohmann and Elisa Kuhn and Timo Wagner and Christine Bole-Feysot and Fabienne Jabot-Hanin and Patrick Nitschk{\'e} and Ahluwalia, {Tarunveer S} and Anna K{\"o}ttgen and {Brix Folsted Andersen}, Christian and Carsten Bergmann and Corinne Antignac and Matias Simons",
year = "2020",
month = jan,
day = "2",
doi = "10.1172/JCI129937",
language = "English",
volume = "130",
pages = "335--344",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

RIS

TY - JOUR

T1 - Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

AU - Bedin, Mathilda

AU - Boyer, Olivia

AU - Servais, Aude

AU - Li, Yong

AU - Villoing-Gaudé, Laure

AU - Tête, Marie-Josephe

AU - Cambier, Alexandra

AU - Hogan, Julien

AU - Baudouin, Veronique

AU - Krid, Saoussen

AU - Bensman, Albert

AU - Lammens, Florie

AU - Louillet, Ferielle

AU - Ranchin, Bruno

AU - Vigneau, Cecile

AU - Bouteau, Iseline

AU - Isnard-Bagnis, Corinne

AU - Mache, Christoph J

AU - Schäfer, Tobias

AU - Pape, Lars

AU - Gödel, Markus

AU - Huber, Tobias B

AU - Benz, Marcus

AU - Klaus, Günter

AU - Hansen, Matthias

AU - Latta, Kay

AU - Gribouval, Olivier

AU - Morinière, Vincent

AU - Tournant, Carole

AU - Grohmann, Maik

AU - Kuhn, Elisa

AU - Wagner, Timo

AU - Bole-Feysot, Christine

AU - Jabot-Hanin, Fabienne

AU - Nitschké, Patrick

AU - Ahluwalia, Tarunveer S

AU - Köttgen, Anna

AU - Brix Folsted Andersen, Christian

AU - Bergmann, Carsten

AU - Antignac, Corinne

AU - Simons, Matias

PY - 2020/1/2

Y1 - 2020/1/2

N2 - 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).

AB - 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).

U2 - 10.1172/JCI129937

DO - 10.1172/JCI129937

M3 - SCORING: Journal article

C2 - 31613795

VL - 130

SP - 335

EP - 344

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 1

ER -