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.

多囊肾病( PKD) 包括一种常染色体显性多囊肾病( ADPKD ) 和一种常染色体隐性多囊肾病( ARPKD )，其特征是在肾脏和肝脏中不断形成囊肿. ADPKD 和 ARPKD 分别代表成人和儿童肾病的主要遗传原因。ADPKD 是由编码多囊蛋白 1 (PC1) 和PKD2的PKD1突变引起的编码多囊蛋白 2 (PC2)。PC1/2 是多通道跨膜蛋白，在初级纤毛中形成复合物。主要的 ARPKD 病例是由多囊肾和肝病 1 ( PKHD1)基因突变引起的，该基因编码纤维囊蛋白/多导管素 (FPC) 蛋白，而一小部分病例是由 DAZ 相互作用的锌指蛋白 1 样(DZIP1L)突变引起的基因。FPC 是一种 I 型跨膜蛋白，定位于纤毛和基体，除其他隔室外，还有DZIP1L编码过渡区/基底体蛋白。显然，PC1/2 和 FPC 是信号分子，而纤毛用于控制肾小管形态和防止囊肿形成的机制尚不清楚。尽管如此，最近的遗传和生化研究提供了推定的生理功能障碍和这两种疾病实体的病理机制的一瞥。在这篇综述中，我总结了推断 PC1/2 对纤毛和纤毛本身在 ADPKD 囊肿形成中的作用的基因研究结果，并讨论了关于多囊蛋白生物发生和纤毛运输调节的研究。我还总结了Pkd1和Pkhd1之间的协同遗传相互作用，以及由 FPC 控制的独特组织模式事件，但不是 PC1。有趣的是，虽然DZIP1L突变导致 PC1/2 纤毛表达受损，FPC 缺乏不影响 PC1/2 生物发生和纤毛定位，表明不同的机制可能导致 ARPKD 中的囊肿形成。最后，我概述了未来 PKD 研究的有希望的领域，并强调了 PKD 治疗的潜在治疗干预的基本原理。