PortalPublikationenMolecular basis of the functional podocin-nephrin complex

Molecular basis of the functional podocin-nephrin complex

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Molecular basis of the functional podocin-nephrin complex : mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. / Huber, Tobias B; Simons, Matias; Hartleben, Björn; Sernetz, Leonie; Schmidts, Miriam; Gundlach, Enken; Saleem, Moin A; Walz, Gerd; Benzing, Thomas.

in: HUM MOL GENET, Jahrgang 12, Nr. 24, 15.12.2003, S. 3397-405.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Huber, TB, Simons, M, Hartleben, B, Sernetz, L, Schmidts, M, Gundlach, E, Saleem, MA, Walz, G & Benzing, T 2003, 'Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains', HUM MOL GENET, Jg. 12, Nr. 24, S. 3397-405. https://doi.org/10.1093/hmg/ddg360

APA

Huber, T. B., Simons, M., Hartleben, B., Sernetz, L., Schmidts, M., Gundlach, E., Saleem, M. A., Walz, G., & Benzing, T. (2003). Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. HUM MOL GENET, 12(24), 3397-405. https://doi.org/10.1093/hmg/ddg360

Vancouver

Huber TB, Simons M, Hartleben B, Sernetz L, Schmidts M, Gundlach E et al. Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. HUM MOL GENET. 2003 Dez 15;12(24):3397-405. https://doi.org/10.1093/hmg/ddg360

Bibtex

@article{12596d952bac4e169e60d2e40e4a49b7,
title = "Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains",
abstract = "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.",
keywords = "Cell Membrane, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mutation, Nephrotic Syndrome, Plasmids, Proteins, Signal Transduction, Transfection, Journal Article, Research Support, Non-U.S. Gov't",
author = "Huber, {Tobias B} and Matias Simons and Bj{\"o}rn Hartleben and Leonie Sernetz and Miriam Schmidts and Enken Gundlach and Saleem, {Moin A} and Gerd Walz and Thomas Benzing",
year = "2003",
month = dec,
day = "15",
doi = "10.1093/hmg/ddg360",
language = "English",
volume = "12",
pages = "3397--405",
journal = "HUM MOL GENET",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "24",

}

RIS

TY - JOUR

T1 - Molecular basis of the functional podocin-nephrin complex

T2 - mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains

AU - Huber, Tobias B

AU - Simons, Matias

AU - Hartleben, Björn

AU - Sernetz, Leonie

AU - Schmidts, Miriam

AU - Gundlach, Enken

AU - Saleem, Moin A

AU - Walz, Gerd

AU - Benzing, Thomas

PY - 2003/12/15

Y1 - 2003/12/15

N2 - 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.

AB - 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.

KW - Cell Membrane

KW - HeLa Cells

KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - Membrane Proteins

KW - Mutation

KW - Nephrotic Syndrome

KW - Plasmids

KW - Proteins

KW - Signal Transduction

KW - Transfection

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/hmg/ddg360

DO - 10.1093/hmg/ddg360

M3 - SCORING: Journal article

C2 - 14570703

VL - 12

SP - 3397

EP - 3405

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 24

ER -