Impact of Rare Disease Mutation Could Extend to More Prevalent Conditions

REX1 is a gene that directs the maintenance of the entire body’s DNA, but new research shows that when people are born with mutated TREX1, the DNA suffers catastrophic damage over time, resulting in a deadly rare disease known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL).

The study, published in Nature Communications, was led by researchers from the University of Pennsylvania’s Perelman School of Medicine and Niigata University’s Brain Research Institute in Japan.

While it was recognized that a TREX1 mutation was responsible with RVCL, the mechanism by which it caused damage remained unknown. In identifying that TREX1 accelerates the normal process of DNA damage—which some feel is linked to every animal’s aging process—, the researchers may have not only found the weapon TREX1 employs against RVCL patients but also provided information 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, 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.”

Jonathan Miner, MD, PhD, Study Lead Author and Associate Professor, Department of Rheumatology, Perelman School of Medicine

RVCL affects around 200 individuals globally and is commonly misdiagnosed as lupus, multiple sclerosis, or cancer. The condition causes the body's tiny blood vessels to break down, affecting a variety of organs such as the brain, eyes, kidneys, liver, and bones.

Patients with the condition often do not experience symptoms such as memory loss, partial vision loss, and minor strokes until their 40s or 50s.

Eventually, the breakdowns can cause organ damage and failure, such as brain atrophy and vision loss. There is no cure or therapy, and many patients die within five to 10 years after symptom onset.

We are hopeful that our work will put us on the path toward improving the lives of patients with RVCL, with our discoveries, we feel we will be much better equipped to address what is happening within their bodies.”

Taisuke Kato, PhD, Study Lead Author and Associate Professor, Department of Molecular Neuroscience, Niigata University

Miner and his colleagues studied RVCL models in animal and human cells to test their hypothesis that the TREX1 mutation, which shortens the gene, caused cell instability and damage comparable to that found in radiation injuries.

They discovered that the mutation interfered with a DNA repair mechanism that happens when both strands of DNA are broken. This interruption caused DNA to be erased, and cells prematurely aged and ceased proliferating, resulting in overall premature aging and organ damage.

In addition to determining RVCL’s major mechanism of damage, the researchers discovered that the TREX1 mutation caused a cell-level susceptibility similar to that seen in persons with BRCA1 and BRCA2 gene mutations, both of which cause breast cancer.

The scientists discovered that individuals with TREX1 mutations had similar heightened rates of breast cancer risk as those with mutations in the BRCA1 and BRCA2 genes.

Furthermore, the scientists discovered that the TREX1 mutation's influence on DNA damage renders persons with it more susceptible to chemotherapy harm.

Miner added, “I do worry that certain treatments may have accelerated the progression of disease in some patients, in many cases, chemotherapy was prescribed as a way of treating suspected ‘autoimmunity’ since certain chemotherapeutic agents can also be used to treat patients with systemic lupus. This was frequently employed in the treatment of RVCL in the past, and even recently by some, and we are concerned that this would actually make the disease worse.”

The study's findings shed light on the types of treatments and drugs that might be considered for people with RVCL. They might include reducing TREX1 levels in the body, repairing the mutation, or simply inhibiting the gene’s DNA-damaging actions.

Miner added, “Until those therapies are developed, we are working to figure out whether certain mediations already FDA-approved for the treatment of other diseases might be repurposed for RVCL or potentially impact TREX1 levels in the body overall, TREX1 levels increase with age in multiple tissues in all humans even in healthy individuals without RVCL and we need to understand the processes linked to this.”

The study’s results have far-reaching implications beyond the RVCL patient community since they could lead to the DNA damage theory of aging.

Miner concluded, “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.”