Gene mutations explain why MacTel patients are not able to make enough of the amino acids needed for eye health
La Jolla, California – Analysis of thousands of genomes from people with and without the rare eye disease known as MacTel has shown more than a dozen genetic variants that are likely to cause the condition to develop and worsen in a large proportion of patients.
This discovery, by a team of scientists from Scripps Research and the Lowy Medical Research Institute, in collaboration with Columbia University in New York and University of California, San Diego, provides a new way to pursue diagnosis and treatment. It also highlights essential aspects of the metabolism of the retina, which is a tissue that has one of the highest energy requirements in the human body. The results appear today in the journal Nature’s metabolism.
“It is exciting to uncover new answers to the many questions related to this rare and complex eye disease,” says Martin Friedlander, MD, PhD, professor of Scripps research and president of the Lowe Institute for Medical Research in La Jolla. “Although we knew that MacTel contained a genetic component, subtle variants remained elusive. These results would serve as a starting point for further scientific research and a guide to potential therapeutic targets.”
MacTel, short for “macular telangiectasia type 2”, is a progressive, debilitating, progressive eye disease that affects roughly 1 in 5,000 people, or about 2 million people worldwide. A disease of the retina, which is the light-sensing tissue in the back of the eye, MacTel causes a progressive deterioration of central vision, which interferes with critical tasks such as reading and driving.
Solve the mystery together
For more than 15 years, scientists have collaborated on an international effort, the MacTel Project, to find the cause of MacTel and develop therapies. Previous studies found that patients had low levels of an amino acid called serine in their bloodstream. However, while serine is essential for many biological processes, it was not known at the time to affect eye health.
In 2019, Friedlander and his colleagues found the connection. They made the startling discovery that low levels of serine were responsible for the accumulation of toxic fats, which cause the photoreceptor cells to die. But many questions remain. For example, what caused the serine level to be low? The investigation continued.
In the new study, Rando Alekemetes, Ph.D. from Columbia University, used an alternative approach to find genetic drivers for diseases. Instead of evaluating individual mutations in genes, he and his team analyzed groups of mutations, giving them greater ability to identify disease-causing genes in a small group of people with MacTel.
One gene, PHGDH, contains much more variants in MacTel patients than in those without the disease. The team identified 22 rare variants of PHGDH that together account for roughly 3 to 4 percent of MacTel cases. It is possible that many other variants are present but not yet found – which is a challenge given the number of young patients with diverse genetic causes.
The implications for other diseases
PHGDH is a key enzyme that enables the body to produce serine, and these studies have provided the long-awaited association with the reduced serine level observed in MacTel patients. Its function is essential for the health of nerve cells in the eyes and elsewhere in the body.
Several of the genetic variants identified in the study are known to cause severe and rare neuropathies when both alleles, or copies of a gene, are affected. In MacTel’s case, only one allele is affected, resulting in partial loss of enzyme function, leading to retinal degeneration.
Many of these variants were first identified in PHGDH and were expected to cause defects in the gene, and Friedlander’s group has worked to confirm this. They directly tested whether each of the multiple variants identified in MacTel patients was actually detrimental to PHGDH function, and found that they were.
“The PHGDH gene is necessary for the production of serine, which plays a major role in cellular metabolism,” says Kevin Ed, PhD, a former Scripps research and postdoctoral research fellow and a senior scientist at Lowy Medical Research Institute. “Through genetic analyzes and experiments in human-derived retinal tissues, we were able to confirm that even a partial loss of PHGDH function can have a deleterious effect on the retina.”
The scientists then used human-induced pluripotent stem cells to generate specialized retinal cells containing one of the PHGDH mutations associated with MacTel. They found that the PHGDH mutation in these cells leads to the production of a fatty substance previously proven to cause MacTel.
A vision for a cure
With a full understanding of PHGDH’s role in MacTel, scientists hope to be able to begin identifying potential treatment approaches.
“We still have a lot to learn about this rare disease, including why systemic changes in serine metabolism lead to retinal degeneration,” says Marin Gantner, PhD, chief scientist at Lowe Institute for Medical Research and a PhD in Scripps Research. “We have come a long way in identifying links with disease, and each step provides new insights that can be leveraged in creating a cure.”
The study, “Serene Defect in Biosynthesis Due to Insufficient Individual PHGDH Causing Retinal Diseases,” was written by Kevin Ed, Marin Gantner, Joseph Hustick, Takayuki Nagasaki, Sarah Giles, Regis Fallon, Sarah Harkins Berry, Michelle Baldini, Esther Lim, Leah Shipk , Michael Dorrell, Caroline Kay, Evan Poe, Charles Woolock, Martina Wallace, Rebecca B. Pirlo, David Goldstein, Christian Metalou, Martin Friedlander and Rando Alykhmitz.
The work was supported by the Lowe family, Lowe Institute for Medical Research, and the National Institutes of Health and Research to Prevent Blindness for the Department of Ophthalmology at Columbia University.