Genetic information from healthy UK Biobank participants provides insight into an understudied disorder – and reveals a puzzle piece that could help to find treatments.
Summary
Data from healthy UK Biobank participants have revealed how one enzyme being in the wrong place in the body can cause RVCL-S, an extremely rare hereditary condition. RVCL-S has been difficult to study because so few people have it. The results could point towards treatments for the deadly disease.
Researchers have revealed how an ultra-rare, deadly disease is caused by one biological component being in the wrong place at the wrong time. Key to the discovery were genetic information and brain scans from UK Biobank participants, none of whom actually have the disease. The results could help to find treatments for the condition, for which no cure exists.
An understudied condition
It’s something we already thought was happening, but this study provides proof for this hypothesis in an elegant manner. I really hope it [leads to new treatments].
Irene de Boer, Leiden University Medical Centre, Netherlands
RVCL-S – retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations – is a hereditary disease caused by a genetic mutation, a variation in the DNA passed on from parents to children at conception. The condition slowly damages the small blood vessels of the brain, eyes, kidneys, liver and other organs, and ultimately leads to premature death.
People who have the disease often remain healthy until they reach their 40s or 50s. Early signs include vision loss and small strokes, although symptoms are different for everyone.
Because RVCL-S runs within families, “often people already know that they might get it,” explains Irene de Boer from Leiden University Medical Centre in the Netherlands, who researches RVCL-S independently of the study team. “They live with the uncertainty that they won’t know how the disease will affect them and how it will progress.”
Only a few hundred people worldwide have RVCL-S, although the real number might be higher because it’s often misdiagnosed or remains undiagnosed. The disease affects so few people that it’s not widely researched and there are no treatments available.
Enzyme on the loose
Even though no UK Biobank participants have the condition, genetic data have provided a piece of the puzzle.
Genetic data from UK Biobank participants have now illuminated an important part of the puzzle of how RVCL-S develops – even though none of the half-a-million UK Biobank participants have the condition.
RVCL-S happens if a genetic mutation affects a cellular component called TREX1. It’s an enzyme that gets rid of waste inside the cell. TREX1 is usually ‘tethered’, meaning it’s confined to the areas within the cell where it’s needed.
But certain genetic mutations untether TREX1. When the enzyme wanders off to where it isn’t supposed to be, its cleaning action wreaks havoc on essential parts of the cell.
Genetic information and brain imaging data from UK Biobank participants revealed that severe TREX1 mutations that both untether the enzyme and completely stop it from working are, in fact, mostly harmless. This suggests that it’s the untethered yet functioning TREX1 that leads to RVCL-S.
“It’s something we already thought was happening, but this study provides proof for this hypothesis in an elegant manner,” de Boer says.
Path to new treatments
We didn’t understand the disorder well enough. As physicians, we are itching to help our patients.
Irene de Boer, Leiden University Medical Centre, Netherlands
“I really hope it [leads to new treatments],” de Boer adds. “If you were able to remove the faulty copy of the protein or silence the mutated gene, you would potentially resolve RVCL-S. The idea isn’t new, but how to get there, that’s the difficult part.”
Early tests of other potential RVCL-S drugs were abandoned, likely because “we didn’t understand the disorder well enough”, de Boer says. “As physicians, we are itching to help our patients,” she says, yet finding treatments that actually work requires a lot of patience – and studies such as this one that unravel the complex biological mechanisms behind the condition.
