Nephronophthisis is the most common genetic cause of chronic renal failure in children. Mutations in three different loci contribute to this recessive phenotype, one of which, NPHP1 , encodes nephrocystin — a novel docking protein that is involved in cell adhesion. Now, Mollet et al. and Otto et al. report the characterization of a fourth locus, NPHP4 , that contributes to this disorder. Mollet et al. also show that its product interacts with nephrocystin, probably functioning in the same pathway.

Because of genetic heterogeneity of nephronophthisis, Mollet et al. and Otto et al. embarked on finding new loci that are linked with this disorder. To this end, both groups used genome-wide linkage and haplotype analysis in families in which there was no linkage between the disorder and the previously identified loci. The results implicated a small region on chromosome 1 that contained six candidate genes, so both groups screened affected individuals for mutations in a subset of candidates that were known to be expressed in the kidney. Collectively, the two groups found 16 mutations in one ORF that encodes a novel hydrophilic protein. Mollet et al. call this protein nephrocystin-4, whereas Otto et al. call it nephroretinin, to reflect the fact that the mutations in NPHP4 are found in some individuals who not only suffer from nephronophthisis but also retinitis pigmentosa.

The product of NPHP4 has been conserved during evolution — the mouse orthologue is 86% identical with the human protein at the amino-acid level, and there is also a previously uncharacterized worm orthologue. Although novel, the NPHP4 protein contains a proline-rich region with a consensus motif that is known to interact with SH3 domains, one of which is present in nephrocystin. Mollet et al. showed that NPHP4 interacts with nephrocystin, at least in vitro. But domains other than SH3 must also be involved in this interaction because it was not abolished by a mutation that disrupts the SH3 domain of nephrocystin.

Given that nephrocystin interacts with several proteins that are involved in cell adhesion, the authors speculate that the product of NPHP4 also affects the same process and that pathogenic changes that are associated with nephronophthisis result from the abnormal adhesion of cells in the renal tubules.

The results of both studies indicate the existence of a new cell-adhesion pathway that is important in the nephronophthisis disease process. But the pathway remains to be investigated in detail. The fact that Otto et al. failed to detect mutations in NPHP4 in some of the affected families indicates a greater genetic heterogeneity than expected for nephronophthisis that awaits additional studies.