A study led by Washington University School of Medicine in St. Louis, in collaboration with Brigham and Women’s Hospital in Boston, has identified a genetic error that weakens the aorta, placing patients with this and similar errors at high risk of aortic aneurysms and ruptures. The findings will help diagnose, monitor and treat patients with aortic disease not caused by well-known conditions, such as Marfan syndrome and other genetic mutations known to disrupt connective tissues.
The study appears July 18 in the Proceedings of the National Academy of Sciences.
Working with the Brigham Genomic Medicine Program, the researchers identified the mutation in a family with a history of aortic disease but no known genetic reason for the condition. The error is in a gene called lysyl oxidase (LOX), which Washington University researchers have shown is responsible for connecting networks of tissue fibers that make up blood vessels.
A number of genetic mutations, including those that cause Marfan syndrome and Loeys-Dietz syndrome, are known to interfere with the integrity of connective tissues. Such weakening puts patients at high risk of death from a ruptured aorta. Standard genetic tests often pinpoint the reason for inherited aortic disease, but such tests can’t explain all cases.
“When a patient comes to the clinic with an enlarged aorta, clinicians can evaluate a standard list of genes to look for a cause of the condition,” said senior author Nathan O. Stitziel, MD, PhD, a Washington University cardiologist and assistant professor of medicine. “Lysyl oxidase should now be added to the standard test panel. This type of information can provide clarity for families with histories of unexplained aortic aneurysms.”
The findings also may allow affected individuals to be identified early, before the aorta begins to enlarge, so that doctors can help these patients take steps to lower pressure on the aorta, and decide when surgery may be required to prevent a sudden rupture.
To confirm that this mutation was the cause of the weakened aorta rather than an association, Stitziel and his colleagues recreated the genetic mistake in mice using the gene editing technology CRISPR. Washington University’s Robert P. Mecham, PhD, the Alumni Endowed Professor of Cell Biology and Physiology, and graduate student Vivian Lee showed that mice with two copies of the mutated gene died of aortic rupture at birth. Mice with only one copy — like members of the family the researchers identified with the mutation — had disrupted collagen and elastin fibers in the aorta.
The aorta is the body’s largest artery that carries blood from the heart to the rest of the body. A lifetime of smoking and poor cardiovascular health can lead to aortic aneurysms in older adults. But bulging and tearing of the aorta in a young person is most often due to an inherited condition.
The featured article was originally published by Washington University’s Source: Genetic error that increases risk of aortic rupture identified