A Northwestern Medicine study has uncovered the molecular mechanisms behind the development of autosomal dominant polycystic kidney disease (ADPKD), a common genetic disorder characterized by the growth of numerous cysts in the kidneys.
The investigators discovered that specific mutations in a gene called PKD2 dysregulate ion channels in the cilia of kidney cells. PKD2’s dysfunction not only contributes to the pathogenesis of the disease, but may also be a target for future drug development, according to findings published in the Proceedings of the National Academy of Sciences.
Paul DeCaen, PhD, assistant professor of Pharmacology, was the senior author of the study.
ADPKD is a progressive disease with symptoms usually developing between the ages of 30 and 50. When symptoms do eventually emerge, severity varies for each patient. Those with mild symptoms are able to live with the disease and are generally prescribed drugs for hypertension, a result of the disease. On the other hand, those with more severe cases commonly suffer from kidney failure and, as a result, are required to go on dialysis and will eventually need a kidney transplant.
On a molecular level, PKD2 forms ion channels, which allow ions to move into the cell. PKD2 is found in an organelle called the primary cilia, which are antennae-like structures on the surface of cells that receive chemical signals from the rest of the body.
But despite wide understanding of the genetic basis of the disease, the impact of genetic mutations on PKD2 channel function has remained in question for more than 20 years, according to Thuy Vien, PhD, a research associate in the DeCaen lab and the first author of the study.
“This is arguably one of the most common genetic diseases, yet a molecular understanding for what underlies the disease required the development of innovative tools to study it,” Vien said. “Dr. DeCaen was a pioneer in establishing state-of-the-art methodologies which allowed us, for the first time, to directly test the function of the PKD2 channel in primary cilia and characterize how pathogenic gene variants contributed to the disease.”
In the current study, the authors focused on the structural and mechanistic regulation of PKD2 by its TOP domain — a site commonly altered by genetic mutations. By utilizing cilia electrophysiology and high-resolution microscopic imaging techniques, the authors determined that PKD2 mutations in the TOP domain destabilized channel structure and impaired proper channel opening.
Surprisingly, they also found that the genetic mutation is potentially druggable. Using a personalized medicine approach which involves targeting a patient’s specific gene variant with drugs to modulate the channel and restore its proper function is the team’s next goal, according to Vien, who also noted that the approach is currently being patented by Northwestern University.
“This study is allowing us for the first time to understand at the molecular level what is happening when patients inherit ADPKD disease-causing genes. This knowledge will advance our ability to develop new therapeutic interventions that directly address the underlying cause of their disease,” Vien said.
Now, Vien is using the same imaging techniques from the current study to understand the childhood form of the same disease, called autosomal recessive polycystic kidney disease (ARPKD). Children who are born with ARPKD have numerous cysts in their kidneys; half of these children will not live for more than one year. Infants who do survive are required to go on dialysis and may suffer from additional organ failure later in life.
“For the kids that have this devastating genetic disease, I think we can make a meaningful impact in understanding what causes it and perhaps how to significantly improve their chances at survival and increase their quality of life. That’s what really drives me,” Vien said.
This work was funded by NIH National Institute of Diabetes and Digestive and Kidney Diseases grants 1R56DK119709-01, R00 DK106655 and 1R01DK123463-01; the Northwestern University GoKidney George M. O’Brien Kidney Research Core Center grant P30DK11485; the PKD Foundation Research Grant; the Mayo Clinic’s PKD Center Pilot and Feasibility Program grant; and the Carl W. Gottschalk Research Scholar Grant from the American Nephrology Society.