NPHS2

The NPHS2 gene encodes an integral membrane protein that they named podocin.

Podocin is a critical component of the glomerular slit diaphragm, and genetic mutations lead to both familial and sporadic forms of steroid-resistant nephrotic syndrome.

Models

 In mice, constitutive absence of podocin leads to rapidly progressive renal disease characterized by mesangiolysis and/or mesangial sclerosis and nephrotic syndrome.

In the adult mouse kidney in a podocyte-specific manner, progressive loss of podocin in the glomerulus recapitulated albuminuria, hypercholesterolemia, hypertension, and renal failure seen in nephrotic syndrome in humans. Lesions of FSGS appeared after 4 wk, with subsequent development of diffuse glomerulosclerosis and tubulointerstitial damage.

Interestingly, conditional inactivation of podocin at birth resulted in a gradient of glomerular lesions, including mesangial proliferation, demonstrating a developmental stage dependence of renal histologic patterns of injury.

The development of significant albuminuria in this model occurred only after early and focal foot process effacement had progressed to diffuse involvement, with complete absence of podocin immunolabeling at the slit diaphragm.

Pathology

 germline mutations in steroid-resistant nephrotic syndrome (MIM.600995)

See also

 NPHSs

• NPHS2

References

 Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome. Mollet G, Ratelade J, Boyer O, Muda AO, Morisset L, Lavin TA, Kitzis D, Dallman MJ, Bugeon L, Hubner N, Gubler MC, Antignac C, Esquivel EL. J Am Soc Nephrol. 2009 Aug 27. PMID: 19713307

 Boute, N.; Gribouval, O.; Roselli, S.; Benessy, F.; Lee, H.; Fuchshuber, A.; Dahan, K.; Gubler, M.-C.; Niaudet, P.; Antignac, C. : NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nature Genet. 24: 349-354, 2000. PubMed ID : 10742096

 Fuchshuber, A.; Jean, G.; Gribouval, O.; Gubler, M.-C.; Broyer, M.; Beckmann, J. S.; Niaudet, P.; Antignac, C. : Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. Hum. Molec. Genet. 4: 2155-2158, 1995. PubMed ID : 8589695

 Huber, T. B.; Simons, M.; Hartleben, B.; Sernetz, L.; Schmidts, M.; Gundlach, E.; Saleem, M. A.; Walz, G.; Benzing, T. : Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum. Molec. Genet. 12: 3397-3405, 2003. PubMed ID : 14570703