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

被引：70

作者：

Bedin, Mathilda ^{[1
]}

Boyer, Olivia ^{[2
,3
]}

Servais, Aude ^{[2
,4
]}

Li, Yong ^{[5
,6
]}

Villoing-Gaude, Laure ^{[1
]}

Tete, Marie-Josephe ^{[2
]}

Cambier, Alexandra ^{[7
]}

Hogan, Julien ^{[7
]}

Baudouin, Veronique ^{[7
]}

Krid, Saoussen ^{[3
]}

Bensman, Albert ^{[3
]}

Lammens, Florie ^{[8
]}

Louillet, Ferielle ^{[9
]}

Ranchin, Bruno ^{[10
]}

Vigneau, Cecile ^{[11
]}

Bouteau, Iseline ^{[12
]}

Isnard-Bagnis, Corinne ^{[13
]}

Mache, Christoph J. ^{[14
]}

Schaefer, Tobias ^{[15
]}

Pape, Lars ^{[16
]}

Goedel, Markus ^{[17
]}

Huber, Tobias B. ^{[17
]}

Benz, Marcus ^{[18
]}

Klaus, Guenter ^{[19
]}

Hansen, Matthias ^{[20
]}

Latta, Kay ^{[19
]}

Gribouval, Olivier ^{[2
]}

Moriniere, Vincent ^{[21
]}

Tournant, Carole ^{[21
]}

Grohmann, Maik ^{[22
,23
]}

Kuhn, Elisa ^{[22
]}

Wagner, Timo ^{[22
]}

Bole-Feysot, Christine ^{[24
,25
]}

Jabot-Hanin, Fabienne ^{[24
,25
]}

Nitschke, Patrick ^{[24
,25
]}

Ahluwalia, Tarunveer S. ^{[26
]}

Koettgen, Anna ^{[5
,6
]}

Andersen, Christian Brix Folsted ^{[27
]}

Bergmann, Carsten ^{[22
,23
,28
]}

Antignac, Corinne ^{[2
,21
]}

Simons, Matias ^{[1
]}

机构：

[1] Univ Paris, Imagine Inst, INSERM, U1163,Lab Epithelial Biol & Dis, Paris, France

[2] Univ Paris, Imagine Inst, INSERM, U1163,Lab Hereditary Kidney Dis, Paris, France

[3] Hop Necker Enfants Malad, AP HP, Dept Pediat Nephrol, Paris, France

[4] Hop Necker Enfants Malad, AP HP, Dept Nephrol, Paris, France

[5] Univ Freiburg, Fac Med, Inst Genet Epidemiol, Freiburg, Germany

[6] Univ Freiburg, Med Ctr, Freiburg, Germany

[7] Robert Debre Hosp, AP HP, Dept Pediat Nephrol & Transplantat, Paris, France

[8] CHRU Lille, Lille, France

[9] CHRU Rouen, Rouen, France

[10] Hosp Civils Lyon, Dept Pediat Nephrol, Bron, France

[11] CHU Rennes, INSERM, U1085, IRSET 9, Rennes, France

[12] CHU Poitiers, Poitiers, France

[13] Hop La Pitie Salpetriere, Dept Nephrol, Paris, France

[14] Med Univ Graz, Childrens Hosp, Graz, Austria

[15] Univ Med Ctr Freiburg, Div Renal, Freiburg, Germany

[16] Hannover Med Sch, Dept Pediat Kidney Liver & Metab Dis, Hannover, Germany

[17] Univ Med Ctr Hamburg Eppendorf, Dept Med, Hamburg, Germany

[18] Kindernephrol Dachau, Dachau, Germany

[19] Univ Med Ctr Marburg Giessen, Dept Child & Adolescent Med, Marburg, Germany

[20] Kinderhosp, KfH Nierenzentrum Kinder & Jugendl & Clementine, Frankfurt, Germany

[21] Hop Necker Enfants Malad, AP HP, Dept Genet, Paris, France

[22] Bioscientia, Ctr Human Genet, Ingelheim, Germany

[23] Ctr Human Genet, Mainz, Germany

[24] INSERM, Inst Imagine, UMR 1163, Bioinformat Platform, Paris, France

[25] Univ Paris, Bioinformat Core Facil, Struct Federat Rech Necker, INSERM,US24,CNRS,UMS3633, Paris, France

[26] Steno Diabet Ctr Copenhagen, Gentofte, Denmark

[27] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[28] Univ Hosp Freiburg, Dept Med, Div Renal, Freiburg, Germany

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2020年 / 130卷 / 01期

关键词：

GENOME-WIDE ASSOCIATION; FACTOR-VITAMIN B-12; TUBULAR PROTEINURIA; KIDNEY-DISEASE; COLLABORATIVE METAANALYSIS; HIGHER ALBUMINURIA; DEFICIENT PATIENTS; DONNAI-BARROW; FOLLOW-UP; CUBILIN;

D O I：

10.1172/JCI129937

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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-Grasbeck 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.

引用

页码：335 / 344

页数：10

共 58 条

[1] How does proteinuria cause progressive renal damage? [J].

Abbate, Mauro ;

Zoja, Carla ;

Remuzzi, Giuseppe .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2006, 17 (11) :2974-2984

[2] A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria [J].

Ahluwalia, Tarunveer S. ;

Schulz, Christina-Alexandra ;

Waage, Johannes ;

Skaaby, Tea ;

Sandholm, Niina ;

van Zuydam, Natalie ;

Charmet, Romain ;

Bork-Jensen, Jette ;

Almgren, Peter ;

Thuesen, Betina H. ;

Bedin, Mathilda ;

Brandslund, Ivan ;

Christensen, Cramer K. ;

Linneberg, Allan ;

Ahlqvist, Emma ;

Groop, Per-Henrik ;

Hadjadj, Samy ;

Tregouet, David-Alexandre ;

Jorgensen, Marit E. ;

Grarup, Niels ;

Pedersen, Oluf ;

Simons, Matias ;

Groop, Leif ;

Orho-Melander, Marju ;

McCarthy, Mark I. ;

Melander, Olle ;

Rossing, Peter ;

Kilpelainen, Tuomas O. ;

Hansen, Torben .

DIABETOLOGIA, 2019, 62 (02) :292-305

[3] Factors influencing the course and the response to treatment in primary focal segmental glomerulosclerosis [J].

Alexopoulos, E ;

Stangou, M ;

Papagianni, A ;

Pantzaki, A ;

Papadimitriou, M .

NEPHROLOGY DIALYSIS TRANSPLANTATION, 2000, 15 (09) :1348-1356

[4] Cubilin Is Essential for Albumin Reabsorption in the Renal Proximal Tubule [J].

Amsellem, Sabine ;

Gburek, Jakub ;

Hamard, Ghislaine ;

Nielsen, Rikke ;

Willnow, Thomas E. ;

Devuyst, Olivier ;

Nexo, Ebba ;

Verroust, Pierre J. ;

Christensen, Erik I. ;

Kozyraki, Renata .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2010, 21 (11) :1859-1867

[5] Structural basis for receptor recognition of vitamin-B12-intrinsic factor complexes [J].

Andersen, Christian Brix Folsted ;

Madsen, Mette ;

Storm, Tina ;

Moestrup, Soren K. ;

Andersen, Gregers R. .

NATURE, 2010, 464 (7287) :445-U147

[6] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[7] Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts [J].

Astor, Brad C. ;

Matsushita, Kunihiro ;

Gansevoort, Ron T. ;

van der Velde, Marije ;

Woodward, Mark ;

Levey, Andrew S. ;

de Jong, Paul E. ;

Coresh, Josef .

KIDNEY INTERNATIONAL, 2011, 79 (12) :1331-1340

[8] Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children [J].

Azukaitis, Karolis ;

Ju, Wenjun ;

Kirchner, Marietta ;

Nair, Viji ;

Smith, Michelle ;

Fang, Zhiyin ;

Thurn-Valsassina, Daniela ;

Bayazit, Aysun ;

Niemirska, Anna ;

Canpolat, Nur ;

Bulut, Ipek Kaplan ;

Yalcinkaya, Fatos ;

Paripovic, Dusan ;

Harambat, Jerome ;

Cakar, Nilgun ;

Alpay, Harika ;

Lugani, Francesca ;

Mencarelli, Francesca ;

Civilibal, Mahmut ;

Erdogan, Hakan ;

Gellermann, Jutta ;

Vidal, Enrico ;

Tabel, Yilmaz ;

Gimpel, Charlotte ;

Ertan, Pelin ;

Yavascan, Onder ;

Melk, Anette ;

Querfeld, Uwe ;

Wuehl, Elke ;

Kretzler, Matthias ;

Schaefer, Franz ;

Arbeiter, Klaus ;

Rosales, Alejandra ;

Dusek, Jiri ;

Zaloszyc, Ariane ;

Liebau, Max ;

Weber, Lutz ;

Muschiol, Evelin ;

Buescher, Rainer ;

Oh, Jun ;

Thurn-Valassina, Daniela ;

Haffner, Dieter ;

John, Ulrike ;

Wygoda, Simone ;

Jeck, Nikola ;

Wigger, Marianne ;

Testa, Sara ;

Murer, Luisa ;

Matteucci, Chiara ;

Jankauskiene, Augustina .

KIDNEY INTERNATIONAL, 2019, 96 (01) :214-221

[9] Observations of a large Dent disease cohort [J].

Blanchard, Anne ;

Curis, Emmanuel ;

Guyon-Roger, Tiphaine ;

Kahila, Diana ;

Treard, Cyrielle ;

Baudouin, Veronique ;

Berard, Etienne ;

Champion, Gerard ;

Cochat, Pierre ;

Dubourg, Julie ;

de la Faille, Renaud ;

Devuyst, Olivier ;

Deschenes, Georges ;

Fischbach, Michel ;

Harambat, Jerome ;

Houillier, Pascal ;

Karras, Alexandre ;

Knebelmann, Bertrand ;

Lavocat, Marie-Pierre ;

Loirat, Chantal ;

Merieau, Elodie ;

Niaudet, Patrick ;

Nobili, Francois ;

Novo, Robert ;

Salomon, Remi ;

Ulinski, Tim ;

Jeunemaitre, Xavier ;

Vargas-Poussou, Rosa .

KIDNEY INTERNATIONAL, 2016, 90 (02) :430-439

[10] CUBN Is a Gene Locus for Albuminuria [J].

Boeger, Carsten A. ;

Chen, Ming-Huei ;

Tin, Adrienne ;

Olden, Matthias ;

Koettgen, Anna ;

de Boer, Ian H. ;

Fuchsberger, Christian ;

O'Seaghdha, Conall M. ;

Pattaro, Cristian ;

Teumer, Alexander ;

Liu, Ching-Ti ;

Glazer, Nicole L. ;

Li, Man ;

O'Conne, Jeffrey R. ;

Tanaka, Toshiko ;

Peralta, Carmen A. ;

Kutalik, Zoltan ;

Luan, Jian'an ;

Zhao, Jing Hua ;

Hwang, Shih-Jen ;

Akylbekova, Ermeg ;

Kramer, Holly ;

van der Harst, Pim ;

Smith, Albert V. ;

Lohman, Kurt ;

de Andrade, Mariza ;

Hayward, Caroline ;

Kollerits, Barbara ;

Toenjes, Anke ;

Aspelund, Thor ;

Ingelsson, Erik ;

Eiriksdottir, Gudny ;

Launer, Lenore J. ;

Harris, Tamara B. ;

Shuldiner, Alan R. ;

Mitchell, Braxton D. ;

Arking, Dan E. ;

Franceschini, Nora ;

Boerwinkle, Eric ;

Egan, Josephine ;

Hernandez, Dena ;

Reilly, Muredach ;

Townsend, Raymond R. ;

Lumley, Thomas ;

Siscovick, David S. ;

Psaty, Bruce M. ;

Kestenbaum, Bryan ;

Haritunians, Talin ;

Bergmann, Sven ;

Vollenweider, Peter .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2011, 22 (03) :555-570

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