Small vessel disease (SVD) causes damage to small arteries and capillaries that reduces blood flow to sensitive organs like the eye, brain, and kidney and can be triggered by aging, high blood pressure, and genetic abnormalities. Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is an SVD caused by an inherited mutation in the TREX1 gene. It’s rare, with fewer than 200 known cases worldwide. Symptoms develop between 35 and 55 and affect the liver, kidneys, eyes, and brain, leading to organ damage and failure and early death.
Scientists were aware of the link between the TREX1 gene and RVCL but not how the mutated gene caused small vessel damage. Now, a new study led by researchers from the Perelman School of Medicine at the University of Pennsylvania (Penn Medicine) and the Brain Research Institute at Niigata University, Japan, has shed light on the mutated gene’s mechanism of action. And the findings may have repercussions beyond RVCL.
“It seems that accelerated DNA damage in RVCL causes the premature aging of certain cells, including the cells in the blood vessel wall,” said Jonathan Miner, an associate professor of rheumatology at the Perelman School of Medicine and the study’s corresponding author. “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 disease, autoimmune disorders, and cancer.
Many factors contribute to aging, one being DNA damage. DNA integrity is essential to the health of cells, tissues, and the entire organism. We can detect and repair DNA damage; this so-called ‘DNA damage response’ is commonly seen when our body attempts to fight off cancer. But if the damage response is prolonged and DNA damage goes unrepaired, it’s thought to stop cells from growing and dividing and cause them to age prematurely. This is known as the ‘DNA damage theory of aging.’
Examining RCVL models in animal and human cells, the researchers found that when both DNA strands were broken, mutation of the TREX1 gene interfered with the repair process, allowing DNA to be deleted and causing cells to stop dividing and prematurely age, which led to overall aging and organ damage.
Surprisingly, they also made a preliminary finding that RVCL patients had an increased odds ratio of breast cancer. The BRCA1 and BRCA2 genes play a critical role in DNA repair. Mutations of these genes are associated with an increased risk of breast cancer because they compromise this repair and cause the accumulation of DNA damage, increasing genome instability and cancer susceptibility. The finding that RVCL patients had high odds of developing breast cancer supports the hypothesis, the researchers say, that TREX1-caused DNA damage increases the risk of breast cancer.
The study’s findings have provided insight into how RCVL might be treated, including lowering the levels of the TREX1 protein produced by the gene, correcting the mutation, or blocking the gene’s DNA-damaging effects. However, the findings extend beyond RVCL because they contribute to the DNA damage theory of aging.
“One hope is that understanding the role of TREX1 in RVCL might help us uncover mechanisms that could link the TREX1 gene to a wide variety of human conditions that could also include normal aging,” Miner said.
The study was published in the journal Nature Communications.
Source: Penn Medicine