Molecular genetics of nephronophthisis and medullary cystic kidney disease

Nephronophthisis (NPH) and medullary cystic kidney disease (MCKD) constitut e a group of renal cystic diseases that share the macroscopic feature of cy st development at the corticomedullary border of the kidneys. The disease v ariants also have in common a characteristic renal histologic triad of tubu lar basement membrane disintegration, tubular atrophy with cyst development , and interstitial cell infiltration with fibrosis. NPH and, in most instan ces, MCKD lead to chronic renal failure with an onset in the first two deca des of life for recessive NPH and onset in adult life for autosomal dominan t MCKD. There is extensive genetic heterogeneity with at least three differ ent loci for NPH (NPHP1, NPHP2, and NPNP3) and two different loci for MCKD (MCKD1 and MCKD2). Juvenile nephronophthisis, in addition, can be associate d with extrarenal organ involvement. As a first step toward understanding t he pathogenesis of this disease group, the gene (NPH1) for juvenile nephron ophthisis (NPH1) has been identified by positional cloning. Its gene produc t, nephrocystin, is a novel protein of unknown function that contains a src -homology 3 domain. It is hypothesized that the pathogenesis of NPH might b e related to signaling processes at focal adhesions (the contact points bet ween cells and extracellular matrix) and/or adherens junctions (the contact points between cells). This hypothesis is based on the fact that most src- homology 3-containing proteins are part of focal adhesion signaling complex es, on animal models that exhibit an NPH-like phenotype, and on the recent finding that nephrocystin binds to the protein p130(cas), a major mediator of focal adhesion signaling.