Genetic cause of debilitating eye disease discovered

11 September 2019
Key Researchers
Microscopic image of retina cells coloured red, pink and blue
Cell death (green) is observed in a cross-section of a retinal
organoid exposed to deoxysphingolipids. Photoreceptors
are red, cell nuclei are blue. Photo credit: Kevin Eade.
A global collaboration has led to the discovery of a genetic defect that causes MacTel (macular telangiectasia type 2), a debilitating eye disease that can lead to loss of vision and blindness.

In a world first, researchers have pinpointed low levels of serine, an amino acid used in many pathways of the body, as being critical in the development of MacTel. They showed that low serine levels in MacTel patients led to an accumulation of toxic lipids called deoxysphingolipids, which cause retinal cell death.

It is the first time that a specific gene has been linked to the condition, raising hopes that a therapy could be developed for this currently untreatable disease. The discovery was published today in the New England Journal of Medicine. The research was led by scientists from the Lowy Medical Research Institute, and included collaborators from the US, UK and Australia. Professor Melanie Bahlo and Mr Roberto Bonelli from the Walter and Eliza Hall Institute collaborated on the project.

At a glance

  • Scientists have discovered a genetic cause of MacTel, a debilitating eye disease that can lead to blindness.
  • Patients with the genetic defect have low levels of serine and high levels of toxic chemicals called deoxysphingolipids, which kill cells in the retina.
  • Institute researchers first identified a possible link between dysregulation of serine production and MacTel in 2017. In this paper, Professor Bahlo and her team led the statistical and metabolomics analysis that helped to confirm the link between decreased serine and MacTel.

Rare hereditary clue

A critical clue to the discovery came from a family in which two people were affected by both MacTel and a rare peripheral neuropathy called hereditary sensory and autonomic neuropathy 1 (HSAN1). HSAN1 is known to be caused by a genetic error that causes an accumulation of toxic deoxysphingolipids, which cause nerve damage. The team subsequently examined 13 people with HSAN1 for signs of MacTel, and discovered the majority had the condition. Following this revelation, the research team tested the blood of 200 additional MacTel patients who did not have HSAN1, and found that they too had low serine levels and associated increase in deoxysphingolipids.

Dr Marin Gantner, Lowy Medical Research Institute scientist, said deoxysphingolipids were toxic to neurons in other parts of the body, but no one knew if they also played a role in eye disease.

“Thanks to clues provided by patients with both MacTel and HSAN1, we hypothesised the low serine we’ve seen in MacTel patients could be causing the body to make toxic lipids that damage the eye,” Dr Gantner said.

Woman and man standing and talking, drawing on whiteboard


Professor Melanie Bahlo (left) and Mr Roberto
Bonelli led the statistical analysis in the study.

An Australian connection

Professor Bahlo, Healthy Development and Ageing theme leader, and PhD student Mr Bonelli led the biostatistical analysis as part of the international collaboration. In 2017, research led by Professor Melanie Bahlo’s laboratory identified five genetic loci associated with MacTel, in a paper published in Nature Genetics. It hinted that MacTel may be linked to dysregulation in the production of serine.

Professor Bahlo said this was the first time that researchers had identified a gene that connected peripheral nerve and eye diseases. “What is so exciting about these studies of small cohorts of patients is how quickly they can uncover critical insights into a disease,” Professor Bahlo said. “As a result, research that would usually take many decades to identify a specific gene and biological mechanism for the disease has occurred much more rapidly.

“We have known that there are some links between neuropathy and eye disease, but until now we haven’t been able to understand the biological or ‘mechanistic’ connection. This discovery gives us a druggable target that could potentially lead to a therapy that could prevent or treat MacTel.”

Toxic build-up

To confirm their findings, the research team undertook further experiments to examine the link between serine production, deoxysphingolipids and MacTel. In mouse models, they demonstrated that a decrease in serine led to the accumulation of deoxysphingolipids and, in turn, damage to retinal and nerve cells.

Bringing the research back to humans, the scientists used retinal organoids made from human induced pluripotent stem cells (iPSC) to confirm that deoxysphingolipids are toxic to human retinal tissue. They found that adding the prescription lipid-lowering medication fenofibrate to retinal organoids exposed to deoxysphingolipids protected against photoreceptor cell death. Fenofibrate has been shown to stimulate the breakdown of deoxysphingolipids.

Professor Martin Friedlander, president of the Lowy Medical Research Institute and professor at Scripps Research Institute said this was a breakthrough. “In this case, a single biochemical mechanism causes disease in both the eye and the peripheral nervous system,” said Professor Friedlander.

“This is a breakthrough not just for MacTel research, but for eye, neurological, and metabolic research more broadly. This discovery was only made possible through a global network of talented collaborating physicians, scientists and patients; generously supported by enlightened philanthropists, the Lowys.”

The research was funded by the Lowy Medical Research Institute, Australian National Health and Medical Research Council, National Eye Institute (US), National Institutes of Health (US), National Science Foundation (US).

Written with the Lowy Medical Research Institute.

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