Skip Navigation


Human Molecular Genetics Advance Access originally published online on October 21, 2003
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
12/24/3397    most recent
ddg360v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (66)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Huber, T. B.
Right arrow Articles by Benzing, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Huber, T. B.
Right arrow Articles by Benzing, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2003, Vol. 12, No. 24 3397-3405
DOI: 10.1093/hmg/ddg360
© 2003 Oxford University Press

Molecular basis of the functional podocin–nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains

Tobias B. Huber1,{dagger}, Matias Simons1,{dagger}, Björn Hartleben1, Leonie Sernetz1, Miriam Schmidts1, Enken Gundlach1, Moin A. Saleem2, Gerd Walz1 and Thomas Benzing1,*

1Renal Division, University Hospital Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany and 2Children's Renal Unit and Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol, UK

Received September 30, 2003; Accepted October 17, 2003

Hereditary nephrotic syndrome is a heterogeneous disease, characterized by heavy proteinuria and renal failure. Mutations of NPHS1 or NPHS2, the genes encoding for nephrin and podocin, lead to early onset of heavy proteinuria, and rapid progression to end-stage renal disease, suggesting that both proteins are essential for the integrity of the glomerular filter. Podocin is a stomatin protein family member with a predicted hairpin-like structure localizing to the insertion site of the slit diaphragm of podocytes, the visceral glomerular epithelial cells of the kidney. Here we investigate the pathomechanisms of different disease-causing podocin mutations. We show that wild-type podocin is targeted to the plasma membrane, and forms homo-oligomers involving the carboxy and amino terminal cytoplasmic domains. The association of podocin with specialized lipid raft microdomains of the plasma membrane was a prerequisite for recruitment of nephrin into rafts. In contrast, disease-causing mutations of podocin (R138Q and R138X) failed to recruit nephrin into rafts either because these mutants were retained in the endoplasmic reticulum (R138Q), or because they failed to associate with rafts (R138X) despite their presence in the plasma membrane. None of the mutants did augment nephrin signaling, suggesting that lipid raft targeting facilitates nephrin signaling. Our findings demonstrate that the failure of mutant podocin to recruit nephrin into lipid rafts may be essential for the pathogenesis of NPHS2.

* To whom correspondence should be addressed. Tel: +49 7612703559; Fax: +49 7612706362; Email: benzing{at}med1.ukl.uni-freiburg.de

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
M. Mairhofer, M. Steiner, U. Salzer, and R. Prohaska
Stomatin-like Protein-1 Interacts with Stomatin and Is Targeted to Late Endosomes
J. Biol. Chem., October 16, 2009; 284(42): 29218 - 29229.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
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.
Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome
J. Am. Soc. Nephrol., October 1, 2009; 20(10): 2181 - 2189.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
M. R. Pollak
Surprising Results following Conditional Podocyte Inactivation
J. Am. Soc. Nephrol., October 1, 2009; 20(10): 2086 - 2088.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
B. Schermer and T. Benzing
Lipid-Protein Interactions along the Slit Diaphragm of Podocytes
J. Am. Soc. Nephrol., March 1, 2009; 20(3): 473 - 478.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
A. Philippe, F. Nevo, E. L. Esquivel, D. Reklaityte, O. Gribouval, M.-J. Tete, C. Loirat, J. Dantal, M. Fischbach, C. Pouteil-Noble, et al.
Nephrin Mutations Can Cause Childhood-Onset Steroid-Resistant Nephrotic Syndrome
J. Am. Soc. Nephrol., October 1, 2008; 19(10): 1871 - 1878.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
M. P. Winn
2007 Young Investigator Award: TRP'ing into a New Era for Glomerular Disease
J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1071 - 1075.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
B. Hinkes, C. Vlangos, S. Heeringa, B. Mucha, R. Gbadegesin, J. Liu, K. Hasselbacher, F. Ozaltin, F. Hildebrandt, and and Members of the APN Study Group
Specific Podocin Mutations Correlate with Age of Onset in Steroid-Resistant Nephrotic Syndrome
J. Am. Soc. Nephrol., February 1, 2008; 19(2): 365 - 371.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
L. De Petris, K. A. Hruska, S. Chiechio, and H. Liapis
Bone morphogenetic protein-7 delays podocyte injury due to high glucose
Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3442 - 3450.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
L. M. McKenzie, S. L. Hendrickson, W. A. Briggs, R. A. Dart, S. M. Korbet, M. H. Mokrzycki, P. L. Kimmel, T. S. Ahuja, J. S. Berns, E. E. Simon, et al.
NPHS2 Variation in Sporadic Focal Segmental Glomerulosclerosis
J. Am. Soc. Nephrol., November 1, 2007; 18(11): 2987 - 2995.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
A. Shono, H. Tsukaguchi, E. Yaoita, M. Nameta, H. Kurihara, X.-S. Qin, T. Yamamoto, and T. Doi
Podocin Participates in the Assembly of Tight Junctions between Foot Processes in Nephrotic Podocytes
J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2525 - 2533.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
H. Holthofer
Molecular architecture of the glomerular slit diaphragm: lessons learnt for a better understanding of disease pathogenesis
Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2124 - 2128.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. M. P. Pearce, Y. Wang, G. G. Kelley, and R. J. H. Wojcikiewicz
SPFH2 Mediates the Endoplasmic Reticulum-associated Degradation of Inositol 1,4,5-Trisphosphate Receptors and Other Substrates in Mammalian Cells
J. Biol. Chem., July 13, 2007; 282(28): 20104 - 20115.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
B. G. Hinkes, B. Mucha, C. N. Vlangos, R. Gbadegesin, J. Liu, K. Hasselbacher, D. Hangan, F. Ozaltin, M. Zenker, F. Hildebrandt, et al.
Nephrotic Syndrome in the First Year of Life: Two Thirds of Cases Are Caused by Mutations in 4 Genes (NPHS1, NPHS2, WT1, and LAMB2)
Pediatrics, April 1, 2007; 119(4): e907 - e919.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
T. B. Huber, B. Schermer, R. U. Muller, M. Hohne, M. Bartram, A. Calixto, H. Hagmann, C. Reinhardt, F. Koos, K. Kunzelmann, et al.
Inaugural Article: Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels
PNAS, November 14, 2006; 103(46): 17079 - 17086.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Umlauf, M. Mairhofer, and R. Prohaska
Characterization of the Stomatin Domain Involved in Homo-oligomerization and Lipid Raft Association
J. Biol. Chem., August 18, 2006; 281(33): 23349 - 23356.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
K. Tryggvason, J. Patrakka, and J. Wartiovaara
Hereditary proteinuria syndromes and mechanisms of proteinuria.
N. Engl. J. Med., March 30, 2006; 354(13): 1387 - 1401.
[Full Text] [PDF]

Home page
 Exp Biol MedHome page
R. Ma, J. Du, S. Sours, and M. Ding
Store-Operated Ca2+ Channel in Renal Microcirculation and Glomeruli
Exp Biol Med, February 1, 2006; 231(2): 145 - 153.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
M. P. Winn, N. Daskalakis, R. F. Spurney, and J. P. Middleton
Unexpected Role of TRPC6 Channel in Familial Nephrotic Syndrome: Does It Have Clinical Implications?
J. Am. Soc. Nephrol., February 1, 2006; 17(2): 378 - 387.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
Y. Frishberg, S. Feinstein, C. Rinat, R. Becker-Cohen, I. Lerer, A. Raas-Rothschild, B. Ferber, and A. Nir
The Heart of Children with Steroid-Resistant Nephrotic Syndrome: Is It All Podocin?
J. Am. Soc. Nephrol., January 1, 2006; 17(1): 227 - 231.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
C. M. Meyers, M. Geanacopoulos, L. B. Holzman, and D. J. Salant
Glomerular Disease Workshop
J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3472 - 3476.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
G. Walz
Slit or pore? A mutation of the ion channel TRPC6 causes FSGS
Nephrol. Dial. Transplant., September 1, 2005; 20(9): 1777 - 1779.
[Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
A. Meyrier
Nephrotic focal segmental glomerulosclerosis in 2004: an update
Nephrol. Dial. Transplant., October 1, 2004; 19(10): 2437 - 2444.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
X. L. Liu, S. C. Done, K. Yan, P. Kilpelainen, T. Pikkarainen, and K. Tryggvason
Defective Trafficking of Nephrin Missense Mutants Rescued by a Chemical Chaperone
J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1731 - 1738.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
T. Benzing
Signaling at the Slit Diaphragm
J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1382 - 1391.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
P. Niaudet
Podocin and Nephrotic Syndrome: Implications for the Clinician
J. Am. Soc. Nephrol., March 1, 2004; 15(3): 832 - 834.
[Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.