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Gene Review

NPHP4  -  nephronophthisis 4

Homo sapiens

Synonyms: KIAA0673, Nephrocystin-4, Nephroretinin, POC10, SLSN4
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Disease relevance of NPHP4


High impact information on NPHP4

  • The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped [2].
  • Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 (ref. 14) [3].
  • Mutations in NPHP4 are associated with nephronophthisis and a combination of nephronophthisis and retinitis pigmentosa called Senior-Løken syndrome (SLSN) [4].
  • Their interaction is disrupted by either mutations in RPGRIP1, found in patients with LCA, or by mutations in NPHP4, found in patients with nephronophthisis or SLSN [4].
  • Through yeast two-hybrid screening of a retinal cDNA library, we found this C2 domain to specifically bind to nephrocystin-4, encoded by NPHP4 [4].

Biological context of NPHP4

  • We here report identification of the gene (NPHP4) causing NPHP type 4, by use of high-resolution haplotype analysis and by demonstration of nine likely loss-of-function mutations in six affected families [5].
  • In one family with NPHP4, extensive genealogical studies were conducted, revealing consanguinity during the 17th century [6].
  • To determine the frequency of NPHP4 mutations, we performed mutational analysis by direct sequencing of all 30 NPHP4 exons in 250 different patients with isolated NPH, SLS, or Cogan syndrome ascertained worldwide over 14 years [7].
  • The allele frequencies of the TMPRSS4 c.4-7A>G, NPHP4 c.2818-2A>T, and ORCTL4 c.517-2A>C polymorphisms in a Japanese population were determined to be 0.42, 0.10, and 0.27, respectively, by PCR-SSCP analysis [8].
  • These data suggest that nephrocystin and nephrocystin-4 belong to a multifunctional complex localized in actin- and microtubule-based structures involved in cell-cell and cell-matrix adhesion signaling as well as in cell division [1].

Anatomical context of NPHP4

  • However, the co-localization of nephrocystin-4 with the microtubules is not restricted to the primary cilia, as nephrocystin-4 was also detected at the centrosomes of dividing cells and close to the cortical actin cytoskeleton in polarized cells [1].
  • In this study, we demonstrated that nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies, and associates with microtubule component alpha-tubulin, suggesting a common role for the nephrocystin proteins in ciliary function [1].

Other interactions of NPHP4

  • We also detected p130Cas and Pyk2 in the nephrocystin-4-containing complex, confirming the role of the nephrocystin proteins in cell-cell and cell-matrix adhesion signaling events [1].


  1. Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes. Mollet, G., Silbermann, F., Delous, M., Salomon, R., Antignac, C., Saunier, S. Hum. Mol. Genet. (2005) [Pubmed]
  2. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Otto, E.A., Schermer, B., Obara, T., O'Toole, J.F., Hiller, K.S., Mueller, A.M., Ruf, R.G., Hoefele, J., Beekmann, F., Landau, D., Foreman, J.W., Goodship, J.A., Strachan, T., Kispert, A., Wolf, M.T., Gagnadoux, M.F., Nivet, H., Antignac, C., Walz, G., Drummond, I.A., Benzing, T., Hildebrandt, F. Nat. Genet. (2003) [Pubmed]
  3. The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Mollet, G., Salomon, R., Gribouval, O., Silbermann, F., Bacq, D., Landthaler, G., Milford, D., Nayir, A., Rizzoni, G., Antignac, C., Saunier, S. Nat. Genet. (2002) [Pubmed]
  4. Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations. Roepman, R., Letteboer, S.J., Arts, H.H., van Beersum, S.E., Lu, X., Krieger, E., Ferreira, P.A., Cremers, F.P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  5. A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Otto, E., Hoefele, J., Ruf, R., Mueller, A.M., Hiller, K.S., Wolf, M.T., Schuermann, M.J., Becker, A., Birkenhäger, R., Sudbrak, R., Hennies, H.C., Nürnberg, P., Hildebrandt, F. Am. J. Hum. Genet. (2002) [Pubmed]
  6. Mapping of gene loci for nephronophthisis type 4 and Senior-Løken syndrome, to chromosome 1p36. Schuermann, M.J., Otto, E., Becker, A., Saar, K., Rüschendorf, F., Polak, B.C., Ala-Mello, S., Hoefele, J., Wiedensohler, A., Haller, M., Omran, H., Nürnberg, P., Hildebrandt, F. Am. J. Hum. Genet. (2002) [Pubmed]
  7. Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis. Hoefele, J., Sudbrak, R., Reinhardt, R., Lehrack, S., Hennig, S., Imm, A., Muerb, U., Utsch, B., Attanasio, M., O'Toole, J.F., Otto, E., Hildebrandt, F. Hum. Mutat. (2005) [Pubmed]
  8. Effect of splice-site polymorphisms of the TMPRSS4, NPHP4 and ORCTL4 genes on their mRNA expression. Yamada, H., Shinmura, K., Tsuneyoshi, T., Sugimura, H. J. Genet. (2005) [Pubmed]
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