This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Donoviel, D. B.
Right arrow Articles by Powell, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Donoviel, D. B.
Right arrow Articles by Powell, D. R.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2001, p. 4829-4836, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4829-4836.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Proteinuria and Perinatal Lethality in Mice Lacking NEPH1, a Novel Protein with Homology to NEPHRIN

Dorit B. Donoviel,1,* Deon D. Freed,1 Hannes Vogel,2 David G. Potter,3 Edith Hawkins,2 James P. Barrish,2 Brian N. Mathur,3 C. Alexander Turner,3 Robert Geske,1 Charles A. Montgomery,1 Michael Starbuck,1 Mary Brandt,1 Anupma Gupta,1 Ramiro Ramirez-Solis,1 Brian P. Zambrowicz,3 and David R. Powell1

Pharmaceutical Biology1 and Genomics,3 Lexicon Genetics, Inc., The Woodlands, Texas 77381, and Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 770302

Received 26 February 2001/Returned for modification 2 April 2001/Accepted 18 April 2001

A high-throughput, retrovirus-mediated mutagenesis method based on gene trapping in embryonic stem cells was used to identify a novel mouse gene. The human ortholog encodes a transmembrane protein containing five extracellular immunoglobulin-like domains that is structurally related to human NEPHRIN, a protein associated with congenital nephrotic syndrome. Northern analysis revealed wide expression in humans and mice, with highest expression in kidney. Based on similarity to NEPHRIN and abundant expression in kidney, this protein was designated NEPH1 and embryonic stem cells containing the retroviral insertion in the Neph1 locus were used to generate mutant mice. Analysis of kidney RNA from Neph1-/- mice showed that the retroviral insertion disrupted expression of Neph1 transcripts. Neph1-/- pups were represented at the expected normal Mendelian ratios at 1 to 3 days of age but at only 10% of the expected frequency at 10 to 12 days after birth, suggesting an early postnatal lethality. The Neph1-/- animals that survived beyond the first week of life were sickly and small but without edema, and all died between 3 and 8 weeks of age. Proteinuria ranging from 300 to 2,000 mg/dl was present in all Neph1-/- mice. Electron microscopy demonstrated NEPH1 expression in glomerular podocytes and revealed effacement of podocyte foot processes in Neph1-/- mice. These findings suggest that NEPH1, like NEPHRIN, may play an important role in maintaining the structure of the filtration barrier that prevents proteins from freely entering the glomerular urinary space.

* Corresponding author. Mailing address: Division of Endocrinology, Pharmaceutical Biology, Lexicon Genetics, Inc., 4000 Research Forest Dr., The Woodlands, TX 77381. Phone: (281) 863-3059. Fax: (281) 419-9125. E-mail: ddonoviel{at}lexgen.com.

Molecular and Cellular Biology, July 2001, p. 4829-4836, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4829-4836.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Giardino, L., Armelloni, S., Corbelli, A., Mattinzoli, D., Zennaro, C., Guerrot, D., Tourrel, F., Ikehata, M., Li, M., Berra, S., Carraro, M., Messa, P., Rastaldi, M. P. (2009). Podocyte Glutamatergic Signaling Contributes to the Function of the Glomerular Filtration Barrier. J. Am. Soc. Nephrol. 20: 1929-1940 [Abstract] [Full Text]  
  • Aya, K., Shimizu, J., Ohtomo, Y., Satomura, K., Suzuki, H., Yan, K., Sado, Y., Morishima, T., Tanaka, H. (2009). NPHS1 gene mutation in Japanese patients with congenital nephrotic syndrome. Nephrol Dial Transplant 24: 2411-2414 [Abstract] [Full Text]  
  • Zhuang, S., Shao, H., Guo, F., Trimble, R., Pearce, E., Abmayr, S. M. (2009). Sns and Kirre, the Drosophila orthologs of Nephrin and Neph1, direct adhesion, fusion and formation of a slit diaphragm-like structure in insect nephrocytes. Development 136: 2335-2344 [Abstract] [Full Text]  
  • Fukasawa, H., Bornheimer, S., Kudlicka, K., Farquhar, M. G. (2009). Slit Diaphragms Contain Tight Junction Proteins. J. Am. Soc. Nephrol. 20: 1491-1503 [Abstract] [Full Text]  
  • Harita, Y., Kurihara, H., Kosako, H., Tezuka, T., Sekine, T., Igarashi, T., Ohsawa, I., Ohta, S., Hattori, S. (2009). Phosphorylation of Nephrin Triggers Ca2+ Signaling by Recruitment and Activation of Phospholipase C-{gamma}1. J. Biol. Chem. 284: 8951-8962 [Abstract] [Full Text]  
  • Wagner, M. C., Rhodes, G., Wang, E., Pruthi, V., Arif, E., Saleem, M. A., Wean, S. E., Garg, P., Verma, R., Holzman, L. B., Gattone, V., Molitoris, B. A., Nihalani, D. (2008). Ischemic Injury to Kidney Induces Glomerular Podocyte Effacement and Dissociation of Slit Diaphragm Proteins Neph1 and ZO-1. J. Biol. Chem. 283: 35579-35589 [Abstract] [Full Text]  
  • Otaki, Y., Miyauchi, N., Higa, M., Takada, A., Kuroda, T., Gejyo, F., Shimizu, F., Kawachi, H. (2008). Dissociation of NEPH1 from nephrin is involved in development of a rat model of focal segmental glomerulosclerosis. Am. J. Physiol. Renal Physiol. 295: F1376-F1387 [Abstract] [Full Text]  
  • Hartleben, B., Schweizer, H., Lubben, P., Bartram, M. P., Moller, C. C., Herr, R., Wei, C., Neumann-Haefelin, E., Schermer, B., Zentgraf, H., Kerjaschki, D., Reiser, J., Walz, G., Benzing, T., Huber, T. B. (2008). Neph-Nephrin Proteins Bind the Par3-Par6-Atypical Protein Kinase C (aPKC) Complex to Regulate Podocyte Cell Polarity. J. Biol. Chem. 283: 23033-23038 [Abstract] [Full Text]  
  • Duner, F., Patrakka, J., Xiao, Z., Larsson, J., Vlamis-Gardikas, A., Pettersson, E., Tryggvason, K., Hultenby, K., Wernerson, A. (2008). Dendrin expression in glomerulogenesis and in human minimal change nephrotic syndrome. Nephrol Dial Transplant 23: 2504-2511 [Abstract] [Full Text]  
  • Ratelade, J., Lavin, T. A., Muda, A. O., Morisset, L., Mollet, G., Boyer, O., Chen, D. S., Henger, A., Kretzler, M., Hubner, N., Thery, C., Gubler, M.-C., Montagutelli, X., Antignac, C., Esquivel, E. L. (2008). Maternal Environment Interacts with Modifier Genes to Influence Progression of Nephrotic Syndrome. J. Am. Soc. Nephrol. 19: 1491-1499 [Abstract] [Full Text]  
  • Guo, J., Ananthakrishnan, R., Qu, W., Lu, Y., Reiniger, N., Zeng, S., Ma, W., Rosario, R., Yan, S. F., Ramasamy, R., D'Agati, V., Marie Schmidt, A. (2008). RAGE Mediates Podocyte Injury in Adriamycin-induced Glomerulosclerosis. J. Am. Soc. Nephrol. 19: 961-972 [Abstract] [Full Text]  
  • Harita, Y., Kurihara, H., Kosako, H., Tezuka, T., Sekine, T., Igarashi, T., Hattori, S. (2008). Neph1, a Component of the Kidney Slit Diaphragm, Is Tyrosine-phosphorylated by the Src Family Tyrosine Kinase and Modulates Intracellular Signaling by Binding to Grb2. J. Biol. Chem. 283: 9177-9186 [Abstract] [Full Text]  
  • Quaggin, S. E., Kreidberg, J. A. (2008). Development of the renal glomerulus: good neighbors and good fences. Development 135: 609-620 [Abstract] [Full Text]  
  • He, L., Sun, Y., Takemoto, M., Norlin, J., Tryggvason, K., Samuelsson, T., Betsholtz, C. (2008). The Glomerular Transcriptome and a Predicted Protein-Protein Interaction Network. J. Am. Soc. Nephrol. 19: 260-268 [Abstract] [Full Text]  
  • Garg, P., Verma, R., Nihalani, D., Johnstone, D. B., Holzman, L. B. (2007). Neph1 Cooperates with Nephrin To Transduce a Signal That Induces Actin Polymerization. Mol. Cell. Biol. 27: 8698-8712 [Abstract] [Full Text]  
  • Garrett, M. R., Gunning, W. T., Radecki, T., Richard, A. (2007). Dissection of a genetic locus influencing renal function in the rat and its concordance with kidney disease loci on human chromosome 1q21. Physiol. Genomics 30: 322-334 [Abstract] [Full Text]  
  • Holthofer, H. (2007). Molecular architecture of the glomerular slit diaphragm: lessons learnt for a better understanding of disease pathogenesis. Nephrol Dial Transplant 22: 2124-2128 [Full Text]  
  • Desai, U., Lee, E-C., Chung, K., Gao, C., Gay, J., Key, B., Hansen, G., Machajewski, D., Platt, K. A., Sands, A. T., Schneider, M., Van Sligtenhorst, I., Suwanichkul, A., Vogel, P., Wilganowski, N., Wingert, J., Zambrowicz, B. P., Landes, G., Powell, D. R. (2007). Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice. Proc. Natl. Acad. Sci. USA 104: 11766-11771 [Abstract] [Full Text]  
  • Jefferson, J. A., Shankland, S. J. (2007). Familial nephrotic syndrome: PLCE1 enters the fray. Nephrol Dial Transplant 22: 1849-1852 [Full Text]  
  • Asanuma, K., Campbell, K. N., Kim, K., Faul, C., Mundel, P. (2007). Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes. Proc. Natl. Acad. Sci. USA 104: 10134-10139 [Abstract] [Full Text]  
  • Patrakka, J., Xiao, Z., Nukui, M., Takemoto, M., He, L., Oddsson, A., Perisic, L., Kaukinen, A., Szigyarto, C. A.-K., Uhlen, M., Jalanko, H., Betsholtz, C., Tryggvason, K. (2007). Expression and Subcellular Distribution of Novel Glomerulus-Associated Proteins Dendrin, Ehd3, Sh2d4a, Plekhh2, and 2310066E14Rik. J. Am. Soc. Nephrol. 18: 689-697 [Abstract] [Full Text]  
  • Dandapani, S. V., Sugimoto, H., Matthews, B. D., Kolb, R. J., Sinha, S., Gerszten, R. E., Zhou, J., Ingber, D. E., Kalluri, R., Pollak, M. R. (2007). {alpha}-Actinin-4 Is Required for Normal Podocyte Adhesion. J. Biol. Chem. 282: 467-477 [Abstract] [Full Text]  
  • Moeller, M. J. (2007). Dynamics at the slit diaphragm--is nephrin actin'?. Nephrol Dial Transplant 22: 37-39 [Full Text]  
  • Kitamura, A., Tsukaguchi, H., Iijima, K., Araki, J., Hattori, M., Ikeda, M., Honda, M., Nozu, K., Nakazato, H., Yoshikawa, N., Kagami, S., Muramatsu, M., Choi, Y., Cheong, H. I., Doi, T. (2006). Genetics and clinical features of 15 Asian families with steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 21: 3133-3138 [Full Text]  
  • Miyauchi, N., Saito, A., Karasawa, T., Harita, Y., Suzuki, K., Koike, H., Han, G. D., Shimizu, F., Kawachi, H. (2006). Synaptic Vesicle Protein 2B Is Expressed in Podocyte, and Its Expression Is Altered in Proteinuric Glomeruli. J. Am. Soc. Nephrol. 17: 2748-2759 [Abstract] [Full Text]  
  • Moriguchi, T., Hamada, M., Morito, N., Terunuma, T., Hasegawa, K., Zhang, C., Yokomizo, T., Esaki, R., Kuroda, E., Yoh, K., Kudo, T., Nagata, M., Greaves, D. R., Engel, J. D., Yamamoto, M., Takahashi, S. (2006). MafB Is Essential for Renal Development and F4/80 Expression in Macrophages. Mol. Cell. Biol. 26: 5715-5727 [Abstract] [Full Text]  
  • Tryggvason, K., Patrakka, J., Wartiovaara, J. (2006). Hereditary proteinuria syndromes and mechanisms of proteinuria.. NEJM 354: 1387-1401 [Full Text]  
  • Slebos, R. J.C., Yi, Y., Ely, K., Carter, J., Evjen, A., Zhang, X., Shyr, Y., Murphy, B. M., Cmelak, A. J., Burkey, B. B., Netterville, J. L., Levy, S., Yarbrough, W. G., Chung, C. H. (2006). Gene Expression Differences Associated with Human Papillomavirus Status in Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res. 12: 701-709 [Abstract] [Full Text]  
  • Lehtonen, S., Ryan, J. J., Kudlicka, K., Iino, N., Zhou, H., Farquhar, M. G. (2005). Cell junction-associated proteins IQGAP1, MAGI-2, CASK, spectrins, and {alpha}-actinin are components of the nephrin multiprotein complex. Proc. Natl. Acad. Sci. USA 102: 9814-9819 [Abstract] [Full Text]  
  • Bussolati, B., Deregibus, M. C., Fonsato, V., Doublier, S., Spatola, T., Procida, S., Di Carlo, F., Camussi, G. (2005). Statins Prevent Oxidized LDL-Induced Injury of Glomerular Podocytes by Activating the Phosphatidylinositol 3-Kinase/AKT-Signaling Pathway. J. Am. Soc. Nephrol. 16: 1936-1947 [Abstract] [Full Text]  
  • Gerke, P., Sellin, L., Kretz, O., Petraschka, D., Zentgraf, H., Benzing, T., Walz, G. (2005). NEPH2 Is Located at the Glomerular Slit Diaphragm, Interacts with Nephrin and Is Cleaved from Podocytes by Metalloproteinases. J. Am. Soc. Nephrol. 16: 1693-1702 [Abstract] [Full Text]  
  • Tryggvason, K., Wartiovaara, J. (2005). How Does the Kidney Filter Plasma?. Physiology 20: 96-101 [Abstract] [Full Text]  
  • Lahdenkari, A.-T., Lounatmaa, K., Patrakka, J., Holmberg, C., Wartiovaara, J., Kestila, M., Koskimies, O., Jalanko, H. (2004). Podocytes Are Firmly Attached to Glomerular Basement Membrane in Kidneys with Heavy Proteinuria. J. Am. Soc. Nephrol. 15: 2611-2618 [Abstract] [Full Text]  
  • Reiser, J., Mundel, P. (2004). Danger Signaling by Glomerular Podocytes Defines a Novel Function of Inducible B7-1 in the Pathogenesis of Nephrotic Syndrome. J. Am. Soc. Nephrol. 15: 2246-2248 [Full Text]  
  • Korstanje, R., DiPetrillo, K. (2004). Unraveling the genetics of chronic kidney disease using animal models. Am. J. Physiol. Renal Physiol. 287: F347-F352 [Abstract] [Full Text]  
  • Reiser, J., Oh, J., Shirato, I., Asanuma, K., Hug, A., Mundel, T. M., Honey, K., Ishidoh, K., Kominami, E., Kreidberg, J. A., Tomino, Y., Mundel, P. (2004). Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and {alpha}3 Integrin. J. Biol. Chem. 279: 34827-34832 [Abstract] [Full Text]  
  • Kojima, K., Davidovits, A., Poczewski, H., Langer, B., Uchida, S., Nagy-Bojarski, K., Hovorka, A., Sedivy, R., Kerjaschki, D. (2004). Podocyte Flattening and Disorder of Glomerular Basement Membrane Are Associated with Splitting of Dystroglycan-Matrix Interaction. J. Am. Soc. Nephrol. 15: 2079-2089 [Abstract] [Full Text]  
  • Benzing, T. (2004). Signaling at the Slit Diaphragm. J. Am. Soc. Nephrol. 15: 1382-1391 [Full Text]  
  • Roselli, S., Heidet, L., Sich, M., Henger, A., Kretzler, M., Gubler, M.-C., Antignac, C. (2004). Early Glomerular Filtration Defect and Severe Renal Disease in Podocin-Deficient Mice. Mol. Cell. Biol. 24: 550-560 [Abstract] [Full Text]  
  • 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: 3397-3405 [Abstract] [Full Text]  
  • Khoshnoodi, J., Sigmundsson, K., Ofverstedt, L.-G., Skoglund, U., Obrink, B., Wartiovaara, J., Tryggvason, K. (2003). Nephrin Promotes Cell-Cell Adhesion through Homophilic Interactions. Am. J. Pathol. 163: 2337-2346 [Abstract] [Full Text]  
  • Li, B., Dedman, J. R., Kaetzel, M. A. (2003). Intron Disruption of the Annexin IV Gene Reveals Novel Transcripts. J. Biol. Chem. 278: 43276-43283 [Abstract] [Full Text]  
  • Ahola, H., Heikkila, E., Astrom, E., Inagaki, M., Izawa, I., Pavenstadt, H., Kerjaschki, D., Holthofer, H. (2003). A Novel Protein, Densin, Expressed by Glomerular Podocytes. J. Am. Soc. Nephrol. 14: 1731-1737 [Abstract] [Full Text]  
  • Gubler, M.-C. (2003). Podocyte Differentiation and Hereditary Proteinuria/Nephrotic Syndromes. J. Am. Soc. Nephrol. 14: S22-26 [Abstract] [Full Text]  
  • Barletta, G.-M., Kovari, I. A., Verma, R. K., Kerjaschki, D., Holzman, L. B. (2003). Nephrin and Neph1 Co-localize at the Podocyte Foot Process Intercellular Junction and Form cis Hetero-oligomers. J. Biol. Chem. 278: 19266-19271 [Abstract] [Full Text]  
  • Michaud, J.-L., Lemieux, L. I., Dube, M., Vanderhyden, B. C., Robertson, S. J., Kennedy, C. R.J. (2003). Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant {alpha}-Actinin-4. J. Am. Soc. Nephrol. 14: 1200-1211 [Abstract] [Full Text]  
  • Huber, T. B., Schmidts, M., Gerke, P., Schermer, B., Zahn, A., Hartleben, B., Sellin, L., Walz, G., Benzing, T. (2003). The Carboxyl Terminus of Neph Family Members Binds to the PDZ Domain Protein Zonula Occludens-1. J. Biol. Chem. 278: 13417-13421 [Abstract] [Full Text]  
  • Gerke, P., Huber, T. B., Sellin, L., Benzing, T., Walz, G. (2003). Homodimerization and Heterodimerization of the Glomerular Podocyte Proteins Nephrin and NEPH1. J. Am. Soc. Nephrol. 14: 918-926 [Abstract] [Full Text]  
  • Bugeon, L., Danou, A., Carpentier, D., Langridge, P., Syed, N., Dallman, M. J. (2003). Inducible Gene Silencing in Podocytes: A New Tool for Studying Glomerular Function. J. Am. Soc. Nephrol. 14: 786-791 [Abstract] [Full Text]  
  • Kreidberg, J. A. (2003). Podocyte Differentiation and Glomerulogenesis. J. Am. Soc. Nephrol. 14: 806-814 [Full Text]  
  • Pavenstadt, H., Kriz, W., Kretzler, M. (2003). Cell Biology of the Glomerular Podocyte. Physiol. Rev. 83: 253-307 [Abstract] [Full Text]  
  • Mundel, P., Shankland, S. J. (2002). Podocyte Biology and Response to Injury. J. Am. Soc. Nephrol. 13: 3005-3015 [Full Text]  
  • Pollak, M. R. (2002). Inherited Podocytopathies: FSGS and Nephrotic Syndrome from a Genetic Viewpoint. J. Am. Soc. Nephrol. 13: 3016-3023 [Full Text]  
  • Reiser, J., von Gersdorff, G., Simons, M., Schwarz, K., Faul, C., Giardino, L., Heider, T., Loos, M., Mundel, P. (2002). Novel concepts in understanding and management of glomerular proteinuria. Nephrol Dial Transplant 17: 951-955 [Full Text]  
  • Finch, R. A., Donoviel, D. B., Potter, D., Shi, M., Fan, A., Freed, D. D., Wang, C.-y., Zambrowicz, B. P., Ramirez-Solis, R., Sands, A. T., Zhang, N. (2002). mdmx Is a Negative Regulator of p53 Activity in Vivo. Cancer Res. 62: 3221-3225 [Abstract] [Full Text]  
  • Koziell, A., Grech, V., Hussain, S., Lee, G., Lenkkeri, U., Tryggvason, K., Scambler, P. (2002). Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet 11: 379-388 [Abstract] [Full Text]  
  • Miner, J. H. (2002). Focusing on the Glomerular Slit Diaphragm : Podocin Enters the Picture. Am. J. Pathol. 160: 3-5 [Full Text]  
  • Roselli, S., Gribouval, O., Boute, N., Sich, M., Benessy, F., Attie, T., Gubler, M.-C., Antignac, C. (2002). Podocin Localizes in the Kidney to the Slit Diaphragm Area. Am. J. Pathol. 160: 131-139 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»