Polycystin-1: a master regulator of intersecting cystic pathways

• Polycystin-1 (PC1) dosage can regulate cyst progression in autosomal dominant polycystic kidney disease (ADPKD), autosomal dominant polycystic liver disease (ADPLD), and autosomal recessive polycystic kidney disease (ARPKD).
• The rate for cyst growth can be either sped up or slowed down by alterations in functional PC1.
• Impacting PC1 levels via chemical chaperone therapy may slow down cyst progression in a subset of patients.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal monogenic disorder, with more than 12 million cases worldwide. The two causative genes for ADPKD, PKD1 and PKD2, encode protein products polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. Recent data have shed light on the role of PC1 in regulating the severity of the cystic phenotypes in ADPKD, autosomal recessive polycystic kidney disease (ARPKD), and isolated autosomal dominant polycystic liver disease (ADPLD). These studies showed that the rate for cyst growth was a regulated trait, a process that can be either sped up or slowed down by alterations in functional PC1. These findings redefine the previous understanding that cyst formation occurs as an ‘on–off’ process. Here, we review these and other related studies with an emphasis on their translational implications for polycystic diseases.