Nephronophthisis (NPHP) is a form of cystic kidney disease and the most common inherited cause of chronic renal failure in children. Four genetically and clinically distinct forms of this autosomal recessive disorder have been identified (NPHP1 - 4); the associated genetic loci have been mapped and the genes mutated in NPHP1 and NPHP4 identified. It has long been assumed that the different genetic defects associated with the disease must contribute to a single pathogenic mechanism, resulting in the common outcome of cystic renal failure. Two reports in the August edition of Nature Genetics each identify one of the genes underlying the remaining two forms of the disease, NPHP2 [Otto, E.A. et al. (2003) Nat. Genet. 34, 413-420 (Abstract)] and NPHP3 [Olbrich, H. et al. (2003) Nat. Genet. 34, 455-459 (Abstract)].Together these studies provide compelling evidence for a single underlying pathogenic mechanism for cystic kidney disease: defects in the cilia. Cilia are fine, hair-like cellular projections that beat constantly in a single direction. The products of the genes mutated in NPHP2 and NPHP3 are shown to interact with the product of the gene mutated in NPHP1, nephrocystin, which in turn interacts with -tubulin, the major component of renal cilia. The product of the gene mutated in NPHP4, nephroretinin, also interacts with nephrocystin.

Comment: These studies contribute substantially to the evidence that genetic forms of cystic kidney disease have a universal underlying pathology related to dysfunction of the renal cilia. Understanding of the pathological basis of disease is essential for the development of treatments to cure or alleviate the disorder. However, a review of the two reports by Watnick and Germino notes that, although the model of cilial dysfunction as a cause of cyst formation and renal failure is attractive, a definitive causal connection has yet to be established. The model must also explain the clinical heterogeneity of the different forms of genetic kidney disease.

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