MTOR is out of control in polycystic kidney disease

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disease caused by mutations in the PKD1 gene. This adult-onset disease results in the accumulation of destructive kidney cysts, leading to progressive loss of renal function and eventually to renal failure. A need for kidney transplantation and dialysis are common outcomes. There are currently no treatment options to prevent or delay the disease onset. Although the PKD1 gene was identified more than a decade ago, the development of treatment strategies has been hampered by a lack of understanding of the function of polycystin-1 (PC1), the protein encoded by the PKD1 gene (1, 2). Work by Shillingford et al. (3) in this issue of PNAS now identifies a new function of PC1, which immediately suggests a possibility for future treatment options. PC1 is a very large integral membrane protein with a much smaller C-terminal cytoplasmic tail. Previous work had implicated this tail in numerous signaling events, but their relevance to ADPKD had remained largely unclear. Shillingford et al. (3) now report that the PC1 tail interacts with a very interesting player by the name of tuberin, the product of the TSC2 gene. Tuberin mutations lead to the complex disease tuberous sclerosis (TSC), which is ≈10 times less common than ADPKD. Three earlier observations had already suggested that tuberin and PC1 could be functionally linked. First, in addition to benign tumors in multiple organs, TSC patients also exhibit kidney cysts. Second, the TSC2 gene is located only a handful of base pairs away from the PKD1 gene. A subset of patients has larger chromosomal deletions that affect both the TSC2 and the PKD1 genes at the same time. These patients suffer from very severe, early onset polycystic kidney disease. Third, previous results using tuberin null cells had suggested that tuberin may play … *Correspondence should be addressed: Department of Anatomy, University of California School of Medicine, Genentech Hall, Room N212B, Box 2140, 600 16th Street, San Francisco, CA 94107. E-mail: mostov{at}itsa.ucsf.edu