Genetic Defects Of Ciliary Genes Causing The Loss Of Primary Cilium In ADPKD


The study evaluates the genetic defects of ciliary genes causing the loss of primary cilium in autosomal dominant polycystic (ADPKD). Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder characterized by the formation of cysts in the kidneys and other organs. ADPKD affects more than 12.5 million people worldwide.

Approximately 50% of patients with ADPKD have the end-stage renal disease (ESRD) by 60 years of age. Dialysis and kidney transplantation are the only treatment options for patients with ESRD. The reason for the absence of targeted treatment is insufficient understanding of the molecular mechanism of cystogenesis. The primary cilium is a signaling organelle that extends from the surface of the plasma membrane of most mammalian cells.

Assembly of cilia depends on cell cycle progression because the centrioles regulating the cell cycle are essential components in the formation of the basal body of the cilia. The maintenance and elongation of cilia are ensured by a process called intraflagellar transport (IFT).

In this process, protein complexes known as IFT trains carry cargo along tracks that run along the length of the cilia. Many studies have shown that the loss of primary cilia promotes renal cyst formation in vivo. However, the epithelial cells of renal cysts are characterized not only by an absence of cilia but also by excessively long cilia.

Recent studies have confirmed that kidney cysts occurred following inactivation of polycystins in otherwise intact cilia or following complete removal of cilia by inactivation of IFT proteins. In the present study, they identified genetic changes in the structural ciliary genes in human ADPKD tissues.

The most frequently affected genes encoded the centriolar and centrosomal proteins PCM1, ODF2, HTT, and CEP89, which are essential for ciliogenesis. Recent studies have confirmed that the loss of these proteins specifically blocks ciliogenesis at the step of centriole-to-membrane docking.

Undocked centrioles lose the signs of cilia assembly, even when they were previously under the influence of signals that support ciliogenesis. Thus, disruption of the function of these genes may be the cause of cilia loss in the epithelial cells of renal cysts. The most commonly affected gene in this group was PCM1, which is also essential for the correct localization of several centrosomal proteins and for anchoring microtubules to the centrosome.

In conclusion, the study revealed genetic defects of ciliary genes that can lead to loss of the primary cilium in human ADPKD tissues. In addition, we identified unique genetic findings associated with the disease, which may play a significant role in the pathogenesis of the disease.

However, other functional analyses are necessary to confirm this hypothesis. The results of our work thus provided valuable indications for the direction of further research in the molecular pathogenesis of ADPKD.