Polycystic kidney disease (PKD), comprising
autosomal dominant polycystic kidney disease (
ADPKD) and
autosomal recessive polycystic kidney disease (
ARPKD), is characterized by incessant
cyst formation in the kidney and liver.
ADPKD and
ARPKD represent the leading genetic causes of renal disease in adults and children, respectively.
ADPKD is caused by mutations in PKD1 encoding polycystin1 (PC1) and PKD2 encoding
polycystin 2 (PC2). PC1/2 are multi-pass transmembrane
proteins that form a complex localized in the primary cilium. Predominant
ARPKD cases are caused by mutations in
polycystic kidney and hepatic disease 1 (PKHD1) gene that encodes the Fibrocystin/Polyductin (FPC)
protein, whereas a small subset of cases are caused by mutations in DAZ interacting zinc finger
protein 1 like (DZIP1L) gene. FPC is a type I transmembrane
protein, localizing to the cilium and basal body, in addition to other compartments, and DZIP1L encodes a transition zone/basal body
protein. Apparently, PC1/2 and FPC are signaling molecules, while the mechanism that cilia employ to govern renal tubule morphology and prevent
cyst formation is unclear. Nonetheless, recent genetic and biochemical studies offer a glimpse of putative physiological malfunctions and the pathomechanisms underlying both disease entities. In this review, I summarize the results of genetic studies that deduced the function of PC1/2 on cilia and of cilia themselves in
cyst formation in
ADPKD, and I discuss studies regarding regulation of
polycystin biogenesis and cilia trafficking. I also summarize the synergistic genetic interactions between Pkd1 and Pkhd1, and the unique tissue patterning event controlled by FPC, but not PC1. Interestingly, while DZIP1L mutations generate compromised PC1/2 cilia expression, FPC deficiency does not affect PC1/2 biogenesis and ciliary localization, indicating that divergent mechanisms could lead to
cyst formation in
ARPKD. I conclude by outlining promising areas for future PKD research and highlight rationales for potential therapeutic interventions for PKD treatment.