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Gene Review

NPHS2  -  nephrosis 2, idiopathic, steroid-resistant...

Homo sapiens

Synonyms: PDCN, Podocin, SRN1
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Disease relevance of NPHS2

  • NPHS2 was recently identified as a gene whose mutations cause autosomal recessive steroid-resistant nephrotic syndrome [1].
  • We sequenced NPHS2 promoter region from -628 to ATG in a large cohort of 260 nephrotic patients (161 with FSGS) who were presenting proteinuria from moderate to severe and were receiving or had received modular therapies according to their sensitivity to steroids and other immune modulators [2].
  • Using a positional cloning approach, our group identified a gene, NPHS2, involved in a specific entity of familial SRNS characterized by early onset, complete steroid-resistance, rapid progression to ESRD and no recurrence after renal transplantation [3].
  • Podocin (NPHS2) expression in podocytes is associated with variable degrees of proteinuria and progression to renal failure in different glomerular diseases that suggests different expression profiles in NPHS2 promoter [4].
  • In conclusion, NPHS2 gene mutations are not a major cause of chronic renal insufficiency caused by sporadic SRNS or heavy proteinuria in Japanese children [5].

High impact information on NPHS2


Chemical compound and disease context of NPHS2


Biological context of NPHS2


Anatomical context of NPHS2


Associations of NPHS2 with chemical compounds

  • Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains [18].
  • Mutations in both podocin gene (NPHS2) alleles lead to a wide range of human disease, from childhood-onset steroid-resistant FSGS and minimal change disease to adult-onset FSGS [20].
  • None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS [21].
  • Inaugural Article: Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels [22].
  • Photostimulated reactions of vinyl phosphate esters with triorganostannides. evidence for an SRN1 vinylic mechanism [23].

Regulatory relationships of NPHS2

  • USF1 was identified as the transcriptional factor regulating NPHS2 at this site [2].

Other interactions of NPHS2

  • In mutant kidneys, NPHS1 and NPHS2 were only moderately downregulated (25 to 30%) at birth but not at 2 or 4 months [24].
  • We have excluded linkage with candidate regions for nephrin, CD2AP, WT1, and podocin in this sample [25].
  • CONCLUSIONS: In this study, we exhaustively analyzed the NPHS2 and the exon 8 of the ACTN4 genes in a series of sporadic 'adult-onset' FSGS patients [26].
  • Secondary changes in the distribution of nephrin, CD2AP, and alpha-actinin are additional evidences for the scaffolding role of podocin in the organization of the slit diaphragm [27].
  • METHODS: Using renal biopsies of six patients, we analyzed the in vivo consequences of different types of NPHS2 mutations on (1) the podocyte expression and distribution of podocin using in situ hybridization and immunohistology and (2) the distribution of related podocyte proteins and glomerular extracellular matrix components [27].

Analytical, diagnostic and therapeutic context of NPHS2

  • Our findings provide the first evidence for a functional inter-relationship between NPHS1 and NPHS2 in human nephrotic disease, thus underscoring their critical role in the regulation of glomerular filtration [12].
  • The whole coding region, all intron/exon boundaries and flanking intronic regions of NPHS2 gene and the exon 8, i.e. hot-spot mutations of the ACTN4 gene, were analyzed in all patients by denaturing high-performance liquid chromatography (DHPLC) to search disease-causing defects [26].
  • Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation [28].
  • Direct sequencing was performed after PCR amplification of all 29 and 8 exons of the NPHS1 and NPHS2 genes, respectively [29].
  • Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups [30].


  1. Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. Schwarz, K., Simons, M., Reiser, J., Saleem, M.A., Faul, C., Kriz, W., Shaw, A.S., Holzman, L.B., Mundel, P. J. Clin. Invest. (2001) [Pubmed]
  2. Rare functional variants of podocin (NPHS2) promoter in patients with nephrotic syndrome. Oleggini, R., Bertelli, R., Di Donato, A., Di Duca, M., Caridi, G., Sanna-Cherchi, S., Scolari, F., Murer, L., Allegri, L., Coppo, R., Emma, F., Camussi, G., Perfumo, F., Ghiggeri, G.M. Gene Expr. (2006) [Pubmed]
  3. Molecular basis of steroid-resistant nephrotic syndrome. Antignac, C. Nefrología : publicación oficial de la Sociedad Española Nefrologia. (2005) [Pubmed]
  4. Cis and trans regulatory elements in NPHS2 promoter: Implications in proteinuria and progression of renal diseases. Di Duca, M., Oleggini, R., Sanna-Cherchi, S., Pasquali, L., Di Donato, A., Parodi, S., Bertelli, R., Caridi, G., Frasca, G., Cerullo, G., Amoroso, A., Schena, F.P., Scolari, F., Ghiggeri, G.M. Kidney Int. (2006) [Pubmed]
  5. NPHS2 mutations in sporadic steroid-resistant nephrotic syndrome in Japanese children. Maruyama, K., Iijima, K., Ikeda, M., Kitamura, A., Tsukaguchi, H., Yoshiya, K., Hoshii, S., Wada, N., Uemura, O., Satomura, K., Honda, M., Yoshikawa, N. Pediatr. Nephrol. (2003) [Pubmed]
  6. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Boute, N., Gribouval, O., Roselli, S., Benessy, F., Lee, H., Fuchshuber, A., Dahan, K., Gubler, M.C., Niaudet, P., Antignac, C. Nat. Genet. (2000) [Pubmed]
  7. The LIM-homeodomain transcription factor Lmx1b plays a crucial role in podocytes. Rohr, C., Prestel, J., Heidet, L., Hosser, H., Kriz, W., Johnson, R.L., Antignac, C., Witzgall, R. J. Clin. Invest. (2002) [Pubmed]
  8. Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation. Miner, J.H., Morello, R., Andrews, K.L., Li, C., Antignac, C., Shaw, A.S., Lee, B. J. Clin. Invest. (2002) [Pubmed]
  9. NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. Tsukaguchi, H., Sudhakar, A., Le, T.C., Nguyen, T., Yao, J., Schwimmer, J.A., Schachter, A.D., Poch, E., Abreu, P.F., Appel, G.B., Pereira, A.B., Kalluri, R., Pollak, M.R. J. Clin. Invest. (2002) [Pubmed]
  10. Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome. Sako, M., Nakanishi, K., Obana, M., Yata, N., Hoshii, S., Takahashi, S., Wada, N., Takahashi, Y., Kaku, Y., Satomura, K., Ikeda, M., Honda, M., Iijima, K., Yoshikawa, N. Kidney Int. (2005) [Pubmed]
  11. Plasma membrane targeting of podocin through the classical exocytic pathway: effect of NPHS2 mutations. Roselli, S., Moutkine, I., Gribouval, O., Benmerah, A., Antignac, C. Traffic (2004) [Pubmed]
  12. Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Koziell, A., Grech, V., Hussain, S., Lee, G., Lenkkeri, U., Tryggvason, K., Scambler, P. Hum. Mol. Genet. (2002) [Pubmed]
  13. Two gene fragments that direct podocyte-specific expression in transgenic mice. Moeller, M.J., Sanden, S.K., Soofi, A., Wiggins, R.C., Holzman, L.B. J. Am. Soc. Nephrol. (2002) [Pubmed]
  14. Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Huber, T.B., Hartleben, B., Kim, J., Schmidts, M., Schermer, B., Keil, A., Egger, L., Lecha, R.L., Borner, C., Pavenstädt, H., Shaw, A.S., Walz, G., Benzing, T. Mol. Cell. Biol. (2003) [Pubmed]
  15. Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. Karle, S.M., Uetz, B., Ronner, V., Glaeser, L., Hildebrandt, F., Fuchshuber, A. J. Am. Soc. Nephrol. (2002) [Pubmed]
  16. Nephrotic plasma alters slit diaphragm-dependent signaling and translocates nephrin, Podocin, and CD2 associated protein in cultured human podocytes. Coward, R.J., Foster, R.R., Patton, D., Ni, L., Lennon, R., Bates, D.O., Harper, S.J., Mathieson, P.W., Saleem, M.A. J. Am. Soc. Nephrol. (2005) [Pubmed]
  17. Disease-causing missense mutations in NPHS2 gene alter normal nephrin trafficking to the plasma membrane. Nishibori, Y., Liu, L., Hosoyamada, M., Endou, H., Kudo, A., Takenaka, H., Higashihara, E., Bessho, F., Takahashi, S., Kershaw, D., Ruotsalainen, V., Tryggvason, K., Khoshnoodi, J., Yan, K. Kidney Int. (2004) [Pubmed]
  18. Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Huber, T.B., Simons, M., Hartleben, B., Sernetz, L., Schmidts, M., Gundlach, E., Saleem, M.A., Walz, G., Benzing, T. Hum. Mol. Genet. (2003) [Pubmed]
  19. Co-localization of nephrin, podocin, and the actin cytoskeleton: evidence for a role in podocyte foot process formation. Saleem, M.A., Ni, L., Witherden, I., Tryggvason, K., Ruotsalainen, V., Mundel, P., Mathieson, P.W. Am. J. Pathol. (2002) [Pubmed]
  20. The genetic basis of FSGS and steroid-resistant nephrosis. Pollak, M.R. Semin. Nephrol. (2003) [Pubmed]
  21. Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. Ruf, R.G., Lichtenberger, A., Karle, S.M., Haas, J.P., Anacleto, F.E., Schultheiss, M., Zalewski, I., Imm, A., Ruf, E.M., Mucha, B., Bagga, A., Neuhaus, T., Fuchshuber, A., Bakkaloglu, A., Hildebrandt, F. J. Am. Soc. Nephrol. (2004) [Pubmed]
  22. Inaugural Article: Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels. Huber, T.B., Schermer, B., M??ller, R.U., H??hne, M., Bartram, M., Calixto, A., Hagmann, H., Reinhardt, C., Koos, F., Kunzelmann, K., Shirokova, E., Krautwurst, D., Harteneck, C., Simons, M., Pavenst??dt, H., Kerjaschki, D., Thiele, C., Walz, G., Chalfie, M., Benzing, T. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  23. Photostimulated reactions of vinyl phosphate esters with triorganostannides. evidence for an SRN1 vinylic mechanism. Chopa, A.B., Dorn, V.B., Badajoz, M.A., Lockhart, M.T. J. Org. Chem. (2004) [Pubmed]
  24. The Wt1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys-Drash syndrome. Gao, F., Maiti, S., Sun, G., Ordonez, N.G., Udtha, M., Deng, J.M., Behringer, R.R., Huff, V. Mol. Cell. Biol. (2004) [Pubmed]
  25. Linkage analysis of candidate loci for end-stage renal disease due to diabetic nephropathy. Iyengar, S.K., Fox, K.A., Schachere, M., Manzoor, F., Slaughter, M.E., Covic, A.M., Orloff, S.M., Hayden, P.S., Olson, J.M., Schelling, J.R., Sedor, J.R. J. Am. Soc. Nephrol. (2003) [Pubmed]
  26. Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis. Aucella, F., De Bonis, P., Gatta, G., Muscarella, L.A., Vigilante, M., di Giorgio, G., D'Errico, M., Zelante, L., Stallone, C., Bisceglia, L. Nephron. Clinical practice [electronic resource]. (2005) [Pubmed]
  27. In vivo expression of podocyte slit diaphragm-associated proteins in nephrotic patients with NPHS2 mutation. Zhang, S.Y., Marlier, A., Gribouval, O., Gilbert, T., Heidet, L., Antignac, C., Gubler, M.C. Kidney Int. (2004) [Pubmed]
  28. NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Weber, S., Gribouval, O., Esquivel, E.L., Morinière, V., Tête, M.J., Legendre, C., Niaudet, P., Antignac, C. Kidney Int. (2004) [Pubmed]
  29. NPHS1 and NPHS2 gene mutations in Chinese children with sporadic nephrotic syndrome. Mao, J., Zhang, Y., Du, L., Dai, Y., Gu, W., Liu, A., Shang, S., Liang, L. Pediatr. Res. (2007) [Pubmed]
  30. NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review. Franceschini, N., North, K.E., Kopp, J.B., McKenzie, L., Winkler, C. Genet. Med. (2006) [Pubmed]
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