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NPHS1

MIM.602716 19q13.1

Wednesday 7 March 2007

Nephrin (NPHS1) is a kidney glomerular filtration barrier protein that is an essential component of the interpodocyte-spanning slit diaphragm (podocyte slit diaphragn).

Nephrin (NPHS1), Neph1 (KIRREL) and podocin (NPHS2) seem to form a multifunctional receptor complex at the podocyte slit diaphragm. Nephrin is a central component of the glomerular ultrafilter, with both structural and signaling functions.

The extracellular domain of nephrin and other components of the slit diaphragm seem to form a porous molecular sieve. The intracellular domain of nephrin is associated with linker proteins, such as CD2-associated protein and Nck proteins that can connect nephrin to the actin cytoskeleton.

Since the discovery of nephrin, the first integral component of the slit diaphragm to be identified, the podocyte slit pore has become a major focus in research concerning the glomerular filtration barrier.

Most of the other components of the podocyte slit diaphragm interact directly with this complex, in many cases coupling slit diaphragm components to the podocyte’s actin cytoskeleton.

Alterations in nephrin interactions with other proteins during development or injury can lead to complex signaling reactions aimed at establishing or restoring the filter function.

Pathology

- germline mutations in the nephrin gene are associated with congenital nephrotic syndrome (MIM.256300)

  • Finnish type congenital nephrotic syndrome (Finnish type congenital nephrosis 1) (MIM.256300)

- A growing number of molecules that function at the podocyte slit diaphragm (PSD) have been identified in patients with inherited and sporadic nephrotic syndromes. Genetic deletion of nearly all of these molecules results in proteinuria and effacement of foot processes.

See also

- NPHSs: NPHS1, NPHS2

References

- Patrakka J, Tryggvason K. Nephrin—a unique structural and signaling protein of the kidney filter. Trends Mol Med. 2007 Sep;13(9):396-403. PMID: 17766183

- Johnstone DB, Holzman LB. Clinical impact of research on the podocyte slit diaphragm. Nat Clin Pract Nephrol. 2006 May;2(5):271-82. PMID: 16932440

- Aya, K.; Tanaka, H.; Seino, Y. : Novel mutation in the nephrin gene of a Japanese patient with congenital nephrotic syndrome of the Finnish type. Kidney Int. 57: 401-404, 2000. PubMed ID : 10652016

- Beltcheva, O.; Martin, P.; Lenkkeri, U.; Tryggvason, K. : Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome. Hum. Mutat. 17: 368-373, 2001. PubMed ID : 11317351

- Koziell, A.; Grech, V.; Hussain, S.; Lee, G.; Lenkkeri, U.; Tryggvason, K.; Scambler, P. : Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum. Molec. Genet. 11: 379-388, 2002. PubMed ID : 11854170

- Lenkkeri, U.; Mannikko, M.; McCready, P.; Lamerdin, J.; Gribouval, O.; Niaudet, P.; Antignac, C.; Kashtan, C. E.; Holmberg, C.; Olsen, A.; Kestila, M.; Tryggvason, K. : Structure of the gene for congenital nephrotic syndrome of the Finnish type (NPHS1) and characterization of mutations. Am. J. Hum. Genet. 64: 51-61, 1999. PubMed ID : 9915943