Tuberin-dependent membrane localization of polycystin-1: A functional linkbetween polycystic kidney disease and the TSC2 tumor suppressor gene

The PKD1 gene accounts for 85% of autosomal dominant polycystic kidney dise ase (ADPKD), the most common human genetic disorder. Rats with a germline i nactivation of one allele of the Tsc2 tumor suppressor gene developed early onset severe bilateral polycystic kidney disease, with similarities to the human contiguous gene syndrome caused by germline codeletion of PKD1 and T SC2 genes. Polycystic rat renal cells retained two normal Pkd1 alleles but were null for Tsc2 and exhibited loss of lateral membrane-localized polycys tin-1. In tuberin-deficient cells, intracellular trafficking of polycystin- 1 was disrupted, resulting in sequestration of polycystin-1 within the Golg i and reexpression of Tsc2 restored correct polycystin-1 membrane localizat ion. These data identify tuberin as a determinant of polycystin-1 functiona l localization and, potentially, ADPKD severity.