Investigators from Northwestern University Feinberg School of Medicine and Vanderbilt University School of Medicine have discovered new molecular mechanisms that cause type 1 congenital long QT syndrome (LQT1), a genetic heart disorder that causes irregular heartbeats and can increase the risk of sudden death in children and young adults, according to a recent study published in the Proceedings of the National Academy of Sciences.
The findings may inform new personalized medicine treatment approaches for patients with LQT1, according to Al George, Jr., MD, chair and the Alfred Newton Richards Professor of Pharmacology, who was a co-corresponding author of the study.
In children and young adults, genetic heart rhythm disorders such as type 1 congenital long QT syndrome (LQT1) — when electrical instability in the heart leads to irregular heartbeats — can increase the risk of sudden cardiac death.
On a molecular scale, LQT1 is caused by a genetic mutation in the KCNQ1 gene, which encodes potassium channels that support the proper functioning of cardiomyocytes, specialized muscle cells that form the heart muscle and help the heart properly contract and pump blood throughout the body. In patients with LQT1, this process is prolonged and causes life-threatening irregular heartbeats.
To better understand the range of molecular mechanisms that give rise to LQT1 and which might inform new treatment strategies for patients, George and his colleagues used a combination of biochemical techniques, including flow cytometry and electrophysiology experiments, to characterize 61 KCNQ1 genetic variants.
The scientists aimed to measure protein stability and trafficking, or how well a protein moves within a cell.
“This is the first study of its kind at this scale to demonstrate how KCNQ1 mutations affect protein stability, how stability relates to channel function, and lastly how this relates to the ability of the protein to get to the location in the cell where it needs to be to function normally,” said George, who is also the director of the Center for Pharmacogenomics.
From their analyses, the scientists discovered that impaired trafficking of variant channel proteins to the plasma membrane was the most common cause of KCNQ1 dysfunction. This is caused by a destabilized ability of the protein to fold normally, leading to abnormal function.
“This combination of methods helped us understand that the root cause of KCNQ1 dysfunction is this destabilizing effect caused by many of the mutations,” George said. “That explained the impairment of these mutant proteins to get to the cell surface where they needed to be for function.”
The scientists are now working to identify drugs that can target and ultimately restore protein function, according to George.
“We imagine for KCNQ1 that it is possible to identify molecules that correct impaired trafficking or correct the misfolded nature of those mutant proteins,” George said. “This paper provides a foundation for having an integrative approach to finding drugs that could treat long QT syndrome caused by this gene.”
Charles Sanders, PhD, the Aileen M. Lange & Annie Mary Lyle Chair, Cardiovascular Research and vice dean of basic sciences at the Vanderbilt University School of Medicine, was a co-corresponding author of the study.
Kathryn Brewer, a graduate student in the Sanders laboratory, was first author of the study. Carlos Vanoye, PhD, adjunct lecturer and former research professor in the Department of Pharmacology, was a co-author of the study.
This work was supported by National Institute of Health grants RO1 HL122010 and R35 GM125028.
