More Proof That Specific Genetic Error Causes Thoracic Aortic Aneurysm, Dissection

Patients who have an error in the gene known as LOX—shorthand for lysyl oxidase, the enzyme it encodes—are particularly prone to thoracic aortic aneurysm and dissection, a new study has found. The relationship, which researchers confirmed by inserting faulty copies of the gene into mice, appears to be causative.

“Most aneurysm is due to secondary risk factors, like if you’re older, smoking, and have had cholesterol and blood pressure problems. Aneurysm at a young age is fairly rare,” senior author Nathan O. Stitziel, MD (Washington University of St. Louis, MO), told TCTMD. Most young individuals who present with signs of enlarged aorta, he said, “end up having genetic testing, because it’s often thought to be an inherited condition.”

The study, published online July 18, 2016, ahead of print in the Proceedings of the National Academy of Sciences, further builds the case for a connection between aortic disease and rare genetic variants of LOX. It comes on the heels of another study, published earlier this year in Circulation Research by a different set of investigators, which found other LOX errors. “Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections,” that paper points out. “However, the causative gene remains unknown in 75% of families.” Both conclude LOX mutations should be added the mix of possible causes.

According to Stitziel, it would not be too difficult to get LOX added to the standard slate of genetic tests. “I think the evidence implicating this gene in human disease is pretty strong at this point,” he said. “People that are doing gene sequencing for aortic disease should probably consider adding it to their panel.”

The information can be used to identify individuals at risk of disease and lead to regular monitoring. Some may need to undergo aneurysm surgery, he said. “There is the possibility that, in the future, we could have targeted therapies that are specific for this genetic form.”

Although conditions such as this one are rare, they aren’t unheard of in an academic medical center setting, Stitziel commented. Hopefully, he said, these findings will inspire clinicians to refer people to research centers. “These are the kinds of families that can provide pretty profound insights into human biology,” he observed.

A Weakened Aorta

For the current study, which involved collaboration between the Washington University School of Medicine in St. Louis, MO, and Brigham and Women’s Hospital in Boston, MA, researchers first performed whole-genome sequencing of a 35-year-old man and his mother, both of whom had histories of thoracic aortic disease. That testing identified a loss-of-function mutation in LOX.

When Stitzel and colleagues edited that genetic error into mice, there were ill effects: heterozygotes had longer ascending aortas with fragmented elastic fibers and homozygotes died shortly after birth due to ruptured aortic aneurysms.

The mouse model showed that the LOX mutation did its damage by decreasing the activity of lysyl oxidase rather than by decreasing mRNA expression or protein synthesis. That enzyme is normally responsible for properly crosslinking the collagen and elastin molecules that maintain the mechanical integrity of the arterial wall, the paper explains.

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