Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, represents the most frequent genetic cause of end-stage kidney disease in the first three decades of life. Contrary to polycystic kidney disease, NPHP shows normal or diminished kidney size, cysts are concentrated at the corticomedullary junction, and tubulointerstitial fibrosis is dominant. NPHP can be associated with retinitis pigmentosa (Senior-Løken syndrome), liver fibrosis, and cerebellar vermis aplasia (Joubert syndrome) in approximately 10% of patients. Positional cloning of six novel genes (NPHP1 through 6) as mutated in NPHP and functional characterization of their encoded proteins have contributed to the concept of "ciliopathies." It has helped advance a new unifying theory of cystic kidney diseases. This theory states that the products of all genes that are mutated in cystic kidney diseases in humans, mice, or zebrafish are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, osmotic, and other stimuli to mechanisms of cell-cycle control and epithelial cell polarity. The ciliary theory explains the multiple organ involvement in NPHP regarding retinitis pigmentosa, liver fibrosis, ataxia, situs inversus, and mental retardation. Mutations in NPHP genes cause defects in signaling mechanisms, including the noncanonical Wnt signaling pathway. The "ciliopathy" NPHP thereby is caused by defects in tissue differentiation and maintenance as a result of impaired processing of extracellular cues. Nephrocystins, the proteins that are encoded by NPHP genes, are highly conserved in evolution. Positional cloning of additional causative genes of NPHP will elucidate further signaling mechanisms that are involved, thereby establishing therapeutic approaches using animal models in mouse, zebrafish, and Caenorhabditis elegans.
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