A research team at Western Michigan University Homer Stryker M.D. School of Medicine (WMed) led by Erik Larson, PhD, has recently published results in Nature Communications explaining how Autosomal Dominant Polycystic Kidney Disease (ADPKD) emerges, a discovery that opens the potential for preventing what is currently considered an incurable ailment.
ADPKD is lethal, affecting one in every 400 to 1,000 people, according to the National Institutes of Health (NIH). It is one of the most common inherited diseases, and an affected individual will accumulate kidney cysts that eventually cause kidney failure.
ADPKD is caused by inheriting a non-functional PKD1 gene, but a cyst does not happen until the second working copy is turned off, a process called “second hit” inactivation.
Despite decades of research on how PKD1 functions, the root cause of these second hit mutations in PKD1 has remained a mystery -- until now. Dr. Larson’s group has discovered that the formation of an alternative four-stranded DNA structure in PKD1, known as guanine quadruplex, results in damage that can inactivate the gene.
“The reason this paper is so significant is that it demonstrates a mechanism for second hit inactivation,” said Dr. Larson, who serves as professor and vice chair in the Department of Biomedical Sciences. “It reveals a pathway to prevent disease occurrence in the first place. Previously, there was no strategy for preventing cyst formation. Now, we have the information needed to stop ADPKD.”
“The medical school is incredibly proud of Dr. Larson and his team for making a meaningful discovery in the realm of ADPKD,” WMed Dean Robert G. Sawyer, MD, said. “This research will have a lasting impact and marks a key step forward in hopefully one day curing this disease.”
The article published in Nature Communications, “G-quadruplex stabilization provokes DNA breaks in human PKD1, revealing a second hit mechanism for ADPKD,” is the culmination of conversations that began in 2017 between Dr. Larson, then new to WMed, and Gregory Vanden Heuvel, PhD, associate dean for foundational research and professor in the Department of Biomedical Sciences, and a co-author on the paper. Dr. Vanden Heuvel, who has worked in the PKD field for over 25 years, said, “advances often occur when people from different research backgrounds join forces.”
Questioning why people who inherit one pathogenic PKD1 gene lose the other copy, Dr. Larson delved into the gene sequence. Receiving support in the form of a WMed Pilot Research Project Support Program grant and an R15 grant from the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Larson assembled a team to examine the PKD1 gene in humans and in mice.
The research was conducted at WMed by lead author Agata Parsons, DVM, MS; Dr. Vanden Heuvel; Gerrit Bouma, PhD, professor in the Department of Biomedical Sciences; M3 Jesse Kooistra; WMU student Seth Byrne, WMed alumni Jack Dewey (Class of 2022) and Aaron Zebolsky (Class of 2021), and PhD student Gloria Alvorado.
Through this work, the team discovered that the guanine quadruplex DNA structures are abundant throughout human, but not mouse, PKD1 where they activate the DNA damage response. This was a big clue, according to Dr. Larson, because mice do not naturally inherit ADPKD.
“We drew upon the expertise of faculty in WMed biomedical sciences, which made this project a success,” Dr. Larson said. “Teaming with faculty and students was rewarding, it provided perspectives important for advancing the research.”
The implications of this research are incredibly meaningful, according to Dr. Vanden Heuvel. Since retention of at least one functional copy of PKD1 is sufficient to prevent cyst formation, treatment strategies can now aim to unfold guanine quadruplexes within PKD1, which would then prevent gene inactivation and ADPKD.
“Now we know what to target,” Dr. Vanden Heuvel said. “We know what is causing these second hit mutations. And so, if there is a way to prevent those second hit mutations from happening, that is the key. And I think that can be done.”
Second hit inactivation also affects cancer-related genes, so this discovery may have broader implications for tumor prevention.
“It's much broader than ADPKD,” Dr. Larson said. “It's uncovering a mechanism that may apply to other diseases, like cancer, so I am excited to continue the research.”
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