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juvenile nephronophthisis

Monday 27 October 2003

Nephronophthisis comprises a group of autosomal recessive cystic kidney diseases, which constitute the most frequent genetic cause for end-stage renal failure in children and young adults.


- medullary cystic disease

  • renal medullary cysts
  • renal corticomedullary cysts
  • renal interstitial fibrosis
  • renal tubular atrophy
  • relatively spared glomeruli

- nephronophthisis-associated hepatic disease


- autosomal recessive form
- autosomal dominant form (MIM.174000)


Four gene loci for NPHP have been mapped:

NPHP1 2q13 NPHP1 nephrocystin MIM.256100
NPHP2 9q22 INVS inversin MIM.243305
NPHP3 3q22 NPHP3 nephrocystin-3 MIM.608002
NPHP4 1p36 NPHP4 nephrocystin-4 MIM.607215


- retinitis pigmentosa (Senior-Loken syndrome) (SLS) (NPHP4): mutations in the nephroretinin gene in 1p36 (12205563)
- hepatic fibrosis
- skeletal malformations
- central nervous system malformations


- cysts of 1-15 mm in diameter, located primarily at the corticomedullary junction (70%)
- chronic sclerosing tubulo-interstitial nephropathy


- In contrast to PKDs, renal cysts are mostly restricted to the corticomedullary border of the kidneys, and kidney size is normal or reduced. This finding might indicate that apoptosis is a more prominent feature of NPHP than proliferation. In PKD where the kidney is enlarged, hyperproliferation might prevail, although increased apoptosis has also been demonstrated in PKD (see below for further discussion on the cell cycle).

- Five NPHP-associated genes (NPHP1, NPHP2, NPHP3, NPHP4, NPHP5) (NPHP5 is also known as IQ motif containing B1, IQCB1), have been identified by positional cloning.

- Mutations in NPHP1 cause nephronophthisis type 1 (NPHP1). NPHP1 encodes a novel protein, nephrocystin-1, that interacts with components of cell-cell and cell-matrix signalling, such as breast cancer anti-oestrogen resistance 1 (BCAR1), protein tyrosine kinase 2b (PTK2B), tensin-46, filamin-A (FLNA) and filamin-B (FLNB). It also interacts with the products of other NPHP genes such as nephrocystin-2/inversin-12, nephrocystin-3 and nephrocystin-4. Nephrocystin-1 is localized at adherens junctions of renal epithelial cells.

- This finding, together with the fact that it directly interacts with the focal adhesion protein BCAR1, implicates nephrocystin-1 in signalling processes at adherens junctions and focal adhesions, which are involved in cell-cell and cell-basement membrane signalling, respectively.

- The renal cystic changes of infantile NPHP2 combine clinical features of NPHP and PKD51. NPHP2 has been mapped to chromosome 9q21-q22. Guided by the observations that a deletion of exons 3-11 of the Invs gene had been shown to cause a renal cystic phenotype in the inv/inv mouse mode, mutations in human INVS, which lies within the NPHP2 critical genetic interval, as the cause of infantile NPHP2 with and without situs inversus.

- Inversin interacts with nephrocystin-1 and beta-tubulin. As expected, given that beta-tubulin and beta-tubulin constitute the microtubule scaffold of primary cilia, nephrocystin-1 and inversin localize to primary cilia of renal tubular cells - the same subcellular compartment that was identified as central to the pathogenesis of PKD.

- The interaction and co-localization to cilia of nephrocystin 1, inversin, and -tubulin provides a link between the pathogenesis of NPHP, the pathogenesis of PKD, primary cilia function and left-right axis determination.

- Positional cloning in a large Venezuelan kindred identified mutations in NPHP3 as responsible for adolescent NPHP3. The same study showed that the spontaneous mouse mutant pcy, which has a renal cystic phenotype, is caused by mutations in the mouse orthologue Nphp3. The novel gene product nephrocystin-3 contains a signal peptide, a coiled-coil domain, a tubulin-tyrosine ligase domain, a stand domain, and a tetratricopeptide (TTC) domain. Coiled-coil and TTC domains are typically found in ciliary and centrosomal protein components.

- Mutations in NPHP4 were identified by homozygosity mapping and a total genome search for linkage. The nephrocystin-4/nephroretinin protein is in a complex with other proteins that are involved in cell adhesion and actin cytoskeleton organization, such as nephrocystin 1, BCAR1 and PTK2B. Nephrocystin 4/nephroretinin also co-localizes with the microtubule component beta-tubulin.

In polarized epithelial cells, it localizes to primary cilia, basal bodies and close to the cortical actin cytoskeleton, whereas in dividing cells it localizes to centrosomes. This distribution is reminiscent of what has been described for proteins that are mutated in BBS20.

More recently, we positionally cloned another novel evolutionarily conserved gene (NPHP5) that is mutated in nephronophthisis type 5 (NPHP5). All identified mutations were truncations of nephrocystin 5, and all patients had early-onset retinitis pigmentosa.

Nephrocystin-5 contains an IQ domain, which directly interacts with calmodulin, and is in a complex with the retinitis pigmentosa GTPase regulator (RPGR), which when defective causes X-linked retinitis pigmentosa. Both nephrocystin 5 and RPGR localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells.

Taken together these findings indicate that the nephrocystin proteins are involved in cell-cell and cell-matrix adhesion signalling events and in cell division.

See also

- nephronophthisis-associated ciliopathies


- Hildebrandt F, Zhou W. Nephronophthisis-Associated Ciliopathies.
J Am Soc Nephrol. 2007 May 18; PMID: 17513324

- Saunier S, Salomon R, Antignac C. Nephronophthisis. Curr Opin Genet Dev. 2005 Jun;15(3):324-31. PMID: 15917209

- Hildebrandt F, Omram H. Related New insights: nephronophthisis-medullary cystic kidney disease. Pediatr Nephrol. 2001 Feb;16(2):168-76. PMID: 11261687

- Hildebrandt F, Otto E. Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol. 2000 Sep;11(9):1753-61. PMID: 10966501