Rare disease’s DNA-damaging mutation could have consequences for more common conditions

In their pursuit to discover the mechanism behind how the deadly rare disease RVCL does its damage, Penn Medicine researchers found some clues to the DNA damage theory of aging.

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) impacts about 200 people worldwide and is often misdiagnosed as lupus, multiple sclerosis, or cancer. The disease causes the breakdown of small blood vessels in the body, which can affect many organs, including the brain, eyes, kidneys, liver, and bones.

Strands of DNA.
Image: iStock/piyaset

TREX1 is a gene that is supposed to direct the maintenance of the entire body’s DNA, but new research shows that when people are born with mutated TREX1, it causes catastrophic damage to the DNA over time, resulting in RVCL. Published in Nature Communications, the research is led by teams at the Perelman School of Medicine and the Brain Research Institute at Niigata University in Japan.

While it was already known that a mutation in TREX1 was behind RVCL, the mechanism by which it did its damage was not known. In discovering that TREX1 speeds up the typical process of DNA damage—a process some theorize is tied to every animal’s aging process—the researchers may not have only discovered the weapon TREX1 uses on RVCL patients, but also offered insight beyond this rare disease population.

“It seems that accelerated DNA damage in RVCL causes the premature aging of certain cells, including the cells in the blood vessel wall,” says the study’s lead author Jonathan Miner, an associate professor of rheumatology at the Perelman School of Medicine. “If this is the case, then targeting TREX1 could have very broad implications for the treatment of many human diseases linked to aging, including cardiovascular diseases, autoimmune disorders, and cancer.”

They researchers found that the mutation was interfering with a DNA repair process, which occurs when there is a break in both strands of DNA. This interruption of the process allowed DNA to be deleted, and cells prematurely aged and stopped dividing, which leads to overall premature aging and organ damage.

Read more at Penn Medicine News.