The polycystins: a novel class of membrane-associated proteins involved inrenal cystic disease

Polycystin-1, polycystin-2 and polycystin-L are the predicted protein produ cts of the PKD1, PKD2 and PKDL genes, respectively. Mutations in PKD1 and P KD2 are responsible for almost all cases of autosomal dominant polycystic k idney disease (ADPKD). This condition is one of the commonest mendelian dis orders of man with a prevalence of 1:800 and is responsible for nearly 10% of cases of end-stage renal failure in adults. The cloning of PKD1 and PKD2 in recent years has provided the initial steps in defining the mechanisms underlying renal cyst formation in this condition, with the aim of defining pharmacological and genetic interventions that may ameliorate the diverse and often serious clinical manifestations of this disease. The PKD genes sh are regions of sequence similarity, and all predictintegral membrane protei ns. Whilst the predicted protein domain structure of polycystin-1 suggests it is involved in cell-cell or cell-matrix interactions, the similarity of polycystin-2 and polycystin-L to the pore-forming domains of some cation ch annels suggests that they all form subunits of a large plasma membrane ion channel. In the few years since the cloning of the PKD genes, a consensus t hat defines the range of mutations, expression pattern, interactions and fu nctional domains of these genes and their protein products is emerging. Thi s review will therefore attempt to summarise these data and provide an insi ght in to the key areas in which polycystin research is unravelling the mec hanisms involved in renal cyst formation.