NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome

A Correction to this article was published on 01 May 2000


Familial idiopathic nephrotic syndromes represent a heterogeneous group of kidney disorders, and include autosomal recessive steroid-resistant nephrotic syndrome, which is characterized by early childhood onset of proteinuria, rapid progression to end-stage renal disease and focal segmental glomerulosclerosis. A causative gene for this disease, NPHS2, was mapped to 1q25–31 and we report here its identification by positional cloning. NPHS2 is almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli, and encodes a new integral membrane protein, podocin, belonging to the stomatin protein family. We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Map of the NPHS2 region.
Figure 2: Tissue distribution and relative expression of NPHS2 in human tissues.
Figure 3: Detection of NPHS2 mutations.
Figure 4: Amino-acid sequence comparison of human podocin, human stomatin and C. elegans MEC-2.
Figure 5: In situ hybridization of antisense (ad) and sense (e) NPHS2 riboprobes labelled with digoxigenin ( a,b) or [35S]UTP (ce).

Accession codes




  1. 1

    Olson, J.L. & Schwartz, M.M. The nephrotic syndrome: minimal change disease, focal segmental glomerulosclerosis, and miscellaneous causes . in Heptinstall's Pathology of the Kidney (eds Jennette, J.C., Olson, J.L. & Silva, F.G.) 187–257 (Lippincott-Raven, Philadelphia, 1998).

    Google Scholar 

  2. 2

    Broyer, M., Meyrier, A., Niaudet, P. & Habib, R. Minimal changes and focal segmental glomerular sclerosis. in Oxford Textbook of Clinical Nephrology (eds Davison, A.M. et al.) 493– 535 (Oxford University Press, Oxford, 1998).

    Google Scholar 

  3. 3

    Kestilä, M. et al. Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol. Cell 1, 575–582 (1998).

    Article  Google Scholar 

  4. 4

    Ruotsalainen, V. et al. Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc. Natl Acad. Sci. USA 96, 7962–7967 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Holthofer, H. et al. Nephrin localizes at the podocyte filtration slit area and is characteristically spliced in the human kidney. Am. J. Pathol. 155, 1681–1687 ( 1999).

    CAS  Article  Google Scholar 

  6. 6

    Holzman, L.B. et al. Nephrin localizes to the slit pore of the glomerular epithelial cell. Kidney Int. 56, 1481– 1491 (1999).

    Article  Google Scholar 

  7. 7

    Mathis, B.J. et al. A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13. Kidney Int. 53, 282 –286 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Winn, M.P. et al. Linkage of a gene causing familial focal segmental glomerulosclerosis to chromosome 11 and further evidence of genetic heterogeneity. Genomics 58, 113–120 ( 1999).

    CAS  Article  Google Scholar 

  9. 9

    Fuchshuber, A. et al. Mapping a gene (SRN1) to chromosome 1q25–q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. Hum. Mol. Genet. 4, 2155– 2158 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152– 154 (1996).

    CAS  Article  Google Scholar 

  11. 11

    Kozak, M. Interpreting cDNA sequences: some insights from studies on translation. Mamm. Genome 7, 563–574 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Prestridge, D.S. Predicting Pol II promoter sequences using transcription factor binding sites. J. Mol. Biol. 249, 923– 932 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Bairoch, A., Bucher, P. & Hofmann, K. The PROSITE database, its status in 1995. Nucleic Acids Res. 24, 189–196 (1996).

    CAS  Article  Google Scholar 

  14. 14

    Nakai, K. & Kanehisa, M. A knowledge base for predicting protein localization sites in eukaryotic cells. Genomics 14, 897–911 (1992).

    CAS  Article  Google Scholar 

  15. 15

    Snyers, L., Umlauf, E. & Prohaska, R. Cysteine 29 is the major palmitoylation site on stomatin. FEBS Lett. 449, 101–104 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Stewart, G.W. et al. Isolation of cDNA coding for an ubiquitous membrane protein deficient in high Na+, low K+ stomatocytic erythrocytes. Blood 79, 1593–1601 (1992).

    CAS  PubMed  Google Scholar 

  17. 17

    Huang, M., Gu, G., Ferguson, E.L. & Chalfie, M. A stomatin-like protein necessary for mechanosensation in C. elegans. Nature 378, 292–295 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Mannsfeldt, A.G., Carroll, P., Stucky, C.L. & Lewin, G.R. Stomatin, a MEC-2 like protein, is expressed by mammalian sensory neurons. Mol. Cell. Neurosci. 13, 391– 404 (1999).

    CAS  Article  Google Scholar 

  19. 19

    Salzer, U., Ahorn, H. & Prohaska, R. Identification of the phosphorylation site on human erythrocyte band 7 integral membrane protein: implications for a monotopic protein structure. Biochim. Biophys. Acta. 1151, 149–152 (1993).

    CAS  Article  Google Scholar 

  20. 20

    Snyers, L., Umlauf, E. & Prohaska, R. Oligomeric nature of the integral membrane protein stomatin. J. Biol. Chem. 273, 17221– 17226 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Engelman, J.A., Zhang, X.L., Razani, B., Pestell, R.G. & Lisanti, M.P. p42/44 MAP kinase-dependent and -independent signaling pathways regulate caveolin-1 gene expression. J. Biol. Chem. 274, 32333–32341 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Shih, N.Y. et al. Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286, 312– 315 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Kirsch, K.H., Georgescu, M.M., Ishimaru, S. & Hanafusa, H. CMS: an adapter molecule involved in cytoskeletal rearrangements. Proc. Natl Acad. Sci. USA 96, 6211– 6216 (1999).

    CAS  Article  Google Scholar 

  24. 24

    Noakes, P.G. et al. The renal glomerulus of mice lacking s-laminin/laminin β2: nephrosis despite molecular compensation by laminin β1. Nature Genet. 10, 400–406 ( 1995).

    CAS  Article  Google Scholar 

  25. 25

    Parving, H.H. et al. Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int. 41, 758– 762 (1992).

    CAS  Article  Google Scholar 

  26. 26

    Connolly, J.O., Weston, C.E. & Hendry, B.M. HIV-associated renal disease in London hospitals. Q. J. Med. 88, 627–634 (1995).

    CAS  Google Scholar 

  27. 27

    Verani, R.R. Obesity-associated focal segmental glomerulosclerosis: pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia. Am. J. Kidney Dis. 20, 629–634 (1992).

    CAS  Article  Google Scholar 

  28. 28

    Ioannou, P.A. et al. A new bacteriophage P1-derived vector for the propagation of large human DNA fragments. Nature Genet. 6, 84–89 (1994).

    CAS  Article  Google Scholar 

  29. 29

    Trask, B.J. et al. Characterization of somatic cell hybrids by bivariate flow karyotyping and fluorescence in situ hybridization. Somat. Cell Mol. Genet. 17, 117–136 (1991).

    CAS  Article  Google Scholar 

  30. 30

    Town, M. et al. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nature Genet. 18, 319–324 (1998).

    CAS  Article  Google Scholar 

  31. 31

    Li, B.L. et al. Human acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) gene organization and evidence that the 4.3-kilobase ACAT-1 mRNA is produced from two different chromosomes. J. Biol. Chem. 274, 11060– 11071 (1999).

    CAS  Article  Google Scholar 

  32. 32

    Brandenberger, A.W., Tee, M.K., Lee, J.Y., Chao, V. & Jaffe, R.B. Tissue distribution of estrogen receptors α (ER-α) and β (ER-β) mRNA in the midgestational human fetus. J. Clin. Endocrinol. Metab. 82, 3509– 3512 (1997).

    CAS  PubMed  Google Scholar 

  33. 33

    Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 ( 1990).

    CAS  Article  Google Scholar 

  34. 34

    Thompson, J.D., Higgins, D.G. & Gibson, T.J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994).

    CAS  Article  Google Scholar 

  35. 35

    Fuchshuber, A. et al. Presymptomatic diagnosis of familial steroid-resistant nephrotic syndrome. Lancet 347, 1050– 1051 (1996).

    CAS  Article  Google Scholar 

  36. 36

    Sibony, M., Commo, F., Callard, P. & Gasc, J.M. Enhancement of mRNA in situ hybridization signal by microwave heating. Lab. Invest. 73, 586–591 (1995).

    CAS  PubMed  Google Scholar 

  37. 37

    Kalatzis, V., Sahly, I., El-Amraoui, A. & Petit, C. Eya1 expression in the developing ear and kidney: towards the understanding of the pathogenesis of branchio-oto-renal (BOR) syndrome. Dev. Dyn. 213, 486–499 ( 1998).

    CAS  Article  Google Scholar 

  38. 38

    Heidet, L. et al. Diffuse leiomyomatosis associated with X-linked Alport syndrome: extracellular matrix study using immunohistochemistry and in situ hybridization. Lab. Invest. 76, 233–243 (1997).

    CAS  PubMed  Google Scholar 

  39. 39

    Antonarakis, S.E. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum. Mutat. 11, 1– 3 (1998).

    CAS  Article  Google Scholar 

  40. 40

    Kaplan, J.M. et al. Mutations in ACTN4, encoding a-actinin 4, cause familial focal segmental glomerulosclerosis. Nature Genet. 64, 251–256 (2000).

    Article  Google Scholar 

Download references


We thank the patients and their families for participation; E. Al-Sabban, L. Alsford, J.L. André, F. Bouissou, S. Caliskan, E. Kuwertz-Bröcking, B. Lange, J. Nauta and W. Proesmans for referring patients; V. Kalatzis and L. Heidet for critical reading of the manuscript; V. Chauvet for help with in situ hybridization; and Y. Deris for assistance with figure preparation. This study was supported in part by the Association pour l'Utilisation du Rein Artificiel and the Fondation pour la Recherche Médicale. N.B. was supported by grants from the Association Française contre les Myopathies and, subsequently, the Programme Hospitalier de Recherche Clinique.

Author information



Corresponding author

Correspondence to Corinne Antignac.

Additional information

Note added in proof:

During the publishing process, J. Kaplan et al. have shown that mutations in ACTN4, mapped to 19q13 and encoding a-actinin-4, an actin-filament cross linking protein, cause autosomal FSGS (ref. 40).

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Boute, N., Gribouval, O., Roselli, S. et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24, 349–354 (2000).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing