Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 23 May 2003:
Vol. 300. no. 5623, pp. 1298 - 1300
DOI: 10.1126/science.1081068
Prev | Table of Contents | Next

Reports

CD2-Associated Protein Haploinsufficiency Is Linked to Glomerular Disease Susceptibility

Jeong M. Kim,1* Hui Wu,1* Gopa Green,1 Cheryl A. Winkler,3 Jeffrey B. Kopp,4 Jeffrey H. Miner,2 Emil R. Unanue,1 Andrey S. Shaw1{dagger}

Loss of CD2-associated protein (CD2AP), a component of the filtration complex in the kidney, causes death in mice at 6 weeks of age. Mice with CD2AP haploinsufficiency developed glomerular changes at 9 months of age and had increased susceptibility to glomerular injury by nephrotoxic antibodies or immune complexes. Electron microscopic analysis of podocytes revealed defects in the formation of multivesicular bodies, suggesting an impairment of the intracellular degradation pathway. Two human patients with focal segmental glomerulosclerosis had a mutation predicted to ablate expression of one CD2AP allele, implicating CD2AP as a determinant of human susceptibility to glomerular disease.

1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2 Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
3 Molecular Epidemiology Section, Laboratory of Genomic Diversity, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
4 Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.



* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: shaw{at}pathology.wustl.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology.
E. Machuca, G. Benoit, and C. Antignac (2009)
Hum. Mol. Genet. 18, R185-R194
   Abstract »    Full Text »    PDF »
T{beta}RI Independently Activates Smad- and CD2AP-Dependent Pathways in Podocytes.
S. Xavier, T. Niranjan, S. Krick, T. Zhang, W. Ju, A. S. Shaw, M. Schiffer, and E. P. Bottinger (2009)
J. Am. Soc. Nephrol. 20, 2127-2137
   Abstract »    Full Text »    PDF »
Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome.
G. Mollet, J. Ratelade, O. Boyer, A. O. Muda, L. Morisset, T. A. Lavin, D. Kitzis, M. J. Dallman, L. Bugeon, N. Hubner, et al. (2009)
J. Am. Soc. Nephrol. 20, 2181-2189
   Abstract »    Full Text »    PDF »
Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.
A. Pierides, K. Voskarides, Y. Athanasiou, K. Ioannou, L. Damianou, M. Arsali, M. Zavros, M. Pierides, V. Vargemezis, C. Patsias, et al. (2009)
Nephrol. Dial. Transplant. 24, 2721-2729
   Abstract »    Full Text »    PDF »
Wnt/{beta}-Catenin Signaling Promotes Podocyte Dysfunction and Albuminuria.
C. Dai, D. B. Stolz, L. P. Kiss, S. P. Monga, L. B. Holzman, and Y. Liu (2009)
J. Am. Soc. Nephrol. 20, 1997-2008
   Abstract »    Full Text »    PDF »
Activation of Canonical Wnt Signaling Meets with Podocytopathy.
A. Waters and A. Koziell (2009)
J. Am. Soc. Nephrol. 20, 1864-1866
   Full Text »    PDF »
Active vitamin D and its analogue, 22-oxacalcitriol, ameliorate puromycin aminonucleoside-induced nephrosis in rats.
I. Matsui, T. Hamano, K. Tomida, K. Inoue, Y. Takabatake, Y. Nagasawa, N. Kawada, T. Ito, H. Kawachi, H. Rakugi, et al. (2009)
Nephrol. Dial. Transplant. 24, 2354-2361
   Abstract »    Full Text »    PDF »
CD2AP mutations are associated with sporadic nephrotic syndrome and focal segmental glomerulosclerosis (FSGS).
M. Gigante, P. Pontrelli, E. Montemurno, L. Roca, F. Aucella, R. Penza, G. Caridi, E. Ranieri, G. M. Ghiggeri, and L. Gesualdo (2009)
Nephrol. Dial. Transplant. 24, 1858-1864
   Abstract »    Full Text »    PDF »
TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription.
J. Schlondorff, D. del Camino, R. Carrasquillo, V. Lacey, and M. R. Pollak (2009)
Am J Physiol Cell Physiol 296, C558-C569
   Abstract »    Full Text »    PDF »
Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis.
M. Lowik, E. Levtchenko, D. Westra, P. Groenen, E. Steenbergen, J. Weening, M. Lilien, L. Monnens, and L. v. d. Heuvel (2008)
Nephrol. Dial. Transplant. 23, 3146-3151
   Abstract »    Full Text »    PDF »
CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction.
C. C. Tsui and B. A. Pierchala (2008)
J. Neurosci. 28, 8789-8800
   Abstract »    Full Text »    PDF »
Selective Loss of Podoplanin Protein Expression Accompanies Proteinuria and Precedes Alterations in Podocyte Morphology in a Spontaneous Proteinuric Rat Model.
K. Koop, M. Eikmans, M. Wehland, H. Baelde, D. Ijpelaar, R. Kreutz, H. Kawachi, D. Kerjaschki, E. de Heer, and J. A. Bruijn (2008)
Am. J. Pathol. 173, 315-326
   Abstract »    Full Text »    PDF »
Differential requirements for Alix and ESCRT-III in cytokinesis and HIV-1 release.
J. G. Carlton, M. Agromayor, and J. Martin-Serrano (2008)
PNAS 105, 10541-10546
   Abstract »    Full Text »    PDF »
Epithelial-to-Mesenchymal Transition Is a Potential Pathway Leading to Podocyte Dysfunction and Proteinuria.
Y. Li, Y. S. Kang, C. Dai, L. P. Kiss, X. Wen, and Y. Liu (2008)
Am. J. Pathol. 172, 299-308
   Abstract »    Full Text »    PDF »
COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy.
K. Voskarides, L. Damianou, V. Neocleous, I. Zouvani, S. Christodoulidou, V. Hadjiconstantinou, K. Ioannou, Y. Athanasiou, C. Patsias, E. Alexopoulos, et al. (2007)
J. Am. Soc. Nephrol. 18, 3004-3016
   Abstract »    Full Text »    PDF »
The homophilic adhesion molecule sidekick-1 contributes to augmented podocyte aggregation in HIV-associated nephropathy.
L. Kaufman, G. Yang, K. Hayashi, J. R. Ashby, L. Huang, M. J. Ross, M. E. Klotman, and P. E. Klotman (2007)
FASEB J 21, 1367-1375
   Abstract »    Full Text »    PDF »
Early endosomes associated with dynamic F-actin structures are required for late trafficking of H. pylori VacA toxin.
N. C. Gauthier, P. Monzo, T. Gonzalez, A. Doye, A. Oldani, P. Gounon, V. Ricci, M. Cormont, and P. Boquet (2007)
J. Cell Biol. 177, 343-354
   Abstract »    Full Text »    PDF »
Nephrotic Syndrome in the First Year of Life: Two Thirds of Cases Are Caused by Mutations in 4 Genes (NPHS1, NPHS2, WT1, and LAMB2).
B. G. Hinkes, B. Mucha, C. N. Vlangos, R. Gbadegesin, J. Liu, K. Hasselbacher, D. Hangan, F. Ozaltin, M. Zenker, F. Hildebrandt, et al. (2007)
Pediatrics 119, e907-e919
   Abstract »    Full Text »    PDF »
Recessive NPHS2 (Podocin) Mutations Are Rare in Adult-Onset Idiopathic Focal Segmental Glomerulosclerosis.
N. He, A. Zahirieh, Y. Mei, B. Lee, S. Senthilnathan, B. Wong, B. Mucha, F. Hildebrandt, D. E. Cole, D. Cattran, et al. (2007)
Clin. J. Am. Soc. Nephrol. 2, 31-37
   Abstract »    Full Text »    PDF »
Immuotactoid Glomerulopathy (Fibrillary Glomerulonephritis).
S. M. Korbet, M. M. Schwartz, and E. J. Lewis (2006)
Clin. J. Am. Soc. Nephrol. 1, 1351-1356
   Full Text »    PDF »
HIV-1 Genes vpr and nef Synergistically Damage Podocytes, Leading to Glomerulosclerosis.
Y. Zuo, T. Matsusaka, J. Zhong, J. Ma, L.-j. Ma, Z. Hanna, P. Jolicoeur, A. B. Fogo, and I. Ichikawa (2006)
J. Am. Soc. Nephrol. 17, 2832-2843
   Abstract »    Full Text »    PDF »
CFBP Is a Novel Tyrosine-phosphorylated Protein That Might Function as a Regulator of CIN85/CD2AP.
H. Konishi, K. Tashiro, Y. Murata, H. Nabeshi, E. Yamauchi, and H. Taniguchi (2006)
J. Biol. Chem. 281, 28919-28931
   Abstract »    Full Text »    PDF »
Non-optimal TATA Elements Exhibit Diverse Mechanistic Consequences.
J. J. Stewart, J. A. Fischbeck, X. Chen, and L. A. Stargell (2006)
J. Biol. Chem. 281, 22665-22673
   Abstract »    Full Text »    PDF »
Essential Role of Integrin-Linked Kinase in Podocyte Biology: Bridging the Integrin and Slit Diaphragm Signaling.
C. Dai, D. B. Stolz, S. I. Bastacky, R. St.-Arnaud, C. Wu, S. Dedhar, and Y. Liu (2006)
J. Am. Soc. Nephrol. 17, 2164-2175
   Abstract »    Full Text »    PDF »
Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP.
F. Guan, G. Villegas, J. Teichman, P. Mundel, and A. Tufro (2006)
Am J Physiol Renal Physiol 291, F422-F428
   Abstract »    Full Text »    PDF »
An Ancestral Haplotype Defines Susceptibility to Doxorubicin Nephropathy in the Laboratory Mouse.
Z. Zheng, P. Pavlidis, S. Chua, V. D. D'Agati, and A. G. Gharavi (2006)
J. Am. Soc. Nephrol. 17, 1796-1800
   Abstract »    Full Text »    PDF »
Hereditary proteinuria syndromes and mechanisms of proteinuria..
K. Tryggvason, J. Patrakka, and J. Wartiovaara (2006)
N. Engl. J. Med. 354, 1387-1401
   Full Text »    PDF »
Genetic factors in progressive renal disease: the good ones, the bad ones and the ugly ducklings.
M. Eikmans, J. A. Aben, K. Koop, H. J. Baelde, E. de Heer, and J. A. Bruijn (2006)
Nephrol. Dial. Transplant. 21, 257-260
   Full Text »    PDF »
Activation of G{alpha}q-Coupled Signaling Pathways in Glomerular Podocytes Promotes Renal Injury.
L. Wang, T. A. Fields, K. Pazmino, Q. Dai, J. L. Burchette, D. N. Howell, T. M. Coffman, and R. F. Spurney (2005)
J. Am. Soc. Nephrol. 16, 3611-3622
   Abstract »    Full Text »    PDF »
Association of CD2AP with dynamic actin on vesicles in podocytes.
T. Welsch, N. Endlich, G. Gokce, E. Doroshenko, J. C. Simpson, W. Kriz, A. S. Shaw, and K. Endlich (2005)
Am J Physiol Renal Physiol 289, F1134-F1143
   Abstract »    Full Text »    PDF »
CD2-associated Protein (CD2AP) Expression in Podocytes Rescues Lethality of CD2AP Deficiency.
J. A. Grunkemeyer, C. Kwoh, T. B. Huber, and A. S. Shaw (2005)
J. Biol. Chem. 280, 29677-29681
   Abstract »    Full Text »    PDF »
Clues to CD2-associated Protein Involvement in Cytokinesis.
P. Monzo, N. C. Gauthier, F. Keslair, A. Loubat, C. M. Field, Y. Le Marchand-Brustel, and M. Cormont (2005)
Mol. Biol. Cell 16, 2891-2902
   Abstract »    Full Text »    PDF »
Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population.
M. S. Orloff, S. K. Iyengar, C. A. Winkler, K. A. B. Goddard, R. A. Dart, T. S. Ahuja, M. Mokrzycki, W. A. Briggs, S. M. Korbet, P. L. Kimmel, et al. (2005)
Physiol Genomics 21, 212-221
   Abstract »    Full Text »    PDF »
Genetic Engineering of Glomerular Sclerosis in the Mouse via Control of Onset and Severity of Podocyte-Specific Injury.
T. Matsusaka, J. Xin, S. Niwa, K. Kobayashi, A. Akatsuka, H. Hashizume, Q.-c. Wang, I. Pastan, A. B. Fogo, and I. Ichikawa (2005)
J. Am. Soc. Nephrol. 16, 1013-1023
   Abstract »    Full Text »    PDF »
The Wt1+/R394W Mouse Displays Glomerulosclerosis and Early-Onset Renal Failure Characteristic of Human Denys-Drash Syndrome.
F. Gao, S. Maiti, G. Sun, N. G. Ordonez, M. Udtha, J. M. Deng, R. R. Behringer, and V. Huff (2004)
Mol. Cell. Biol. 24, 9899-9910
   Abstract »    Full Text »    PDF »
Podocytes Are Firmly Attached to Glomerular Basement Membrane in Kidneys with Heavy Proteinuria.
A.-T. Lahdenkari, K. Lounatmaa, J. Patrakka, C. Holmberg, J. Wartiovaara, M. Kestila, O. Koskimies, and H. Jalanko (2004)
J. Am. Soc. Nephrol. 15, 2611-2618
   Abstract »    Full Text »    PDF »
A Novel Role for the Adaptor Molecule CD2-associated Protein in Transforming Growth Factor-{beta}-induced Apoptosis.
M. Schiffer, P. Mundel, A. S. Shaw, and E. P. Bottinger (2004)
J. Biol. Chem. 279, 37004-37012
   Abstract »    Full Text »    PDF »
Podocyte Flattening and Disorder of Glomerular Basement Membrane Are Associated with Splitting of Dystroglycan-Matrix Interaction.
K. Kojima, A. Davidovits, H. Poczewski, B. Langer, S. Uchida, K. Nagy-Bojarski, A. Hovorka, R. Sedivy, and D. Kerjaschki (2004)
J. Am. Soc. Nephrol. 15, 2079-2089
   Abstract »    Full Text »    PDF »
E3 Ligases in T Cell Anergy--Turning Immune Responses into Tolerance.
V. Heissmeyer and A. Rao (2004)
Sci. STKE 2004, pe29
   Abstract »    Full Text »    PDF »
Familial Glomerulonephropathy in the Bullmastiff.
M. L. Casal, D. M. Dambach, T. Meister, P. F. Jezyk, D. F. Patterson, and P. S. Henthorn (2004)
Vet. Pathol. 41, 319-325
   Abstract »    Full Text »    PDF »
Signaling at the Slit Diaphragm.
T. Benzing (2004)
J. Am. Soc. Nephrol. 15, 1382-1391
   Full Text »    PDF »
A WT1 Co-regulator Controls Podocyte Phenotype by Shuttling between Adhesion Structures and Nucleus.
M. B. Srichai, M. Konieczkowski, A. Padiyar, D. J. Konieczkowski, A. Mukherjee, P. S. Hayden, S. Kamat, M. A. El-Meanawy, S. Khan, P. Mundel, et al. (2004)
J. Biol. Chem. 279, 14398-14408
   Abstract »    Full Text »    PDF »
Podocin and Nephrotic Syndrome: Implications for the Clinician.
P. Niaudet (2004)
J. Am. Soc. Nephrol. 15, 832-834
   Full Text »    PDF »
Early Glomerular Filtration Defect and Severe Renal Disease in Podocin-Deficient Mice.
S. Roselli, L. Heidet, M. Sich, A. Henger, M. Kretzler, M.-C. Gubler, and C. Antignac (2004)
Mol. Cell. Biol. 24, 550-560
   Abstract »    Full Text »    PDF »
The Immunological Synapse Balances T Cell Receptor Signaling and Degradation.
K.-H. Lee, A. R. Dinner, C. Tu, G. Campi, S. Raychaudhuri, R. Varma, T. N. Sims, W. R. Burack, H. Wu, J. Wang, et al. (2003)
Science 302, 1218-1222
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)