Analyzing thousands of genes has helped a team of researchers connect a dozen gene variants that are potentially linked and the cause of a rare eye disease known as MacTel.

The new findings are published in the journal Nature Metabolism in a paper titled, “Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease.”

MacTel, or macular telangiectasia type 2, is a disease of the retina, which leads to a gradual deterioration of central vision. The disease affects two million people worldwide, and becomes noticeable around 50–60 years of age. The new discovery was made by a team of researchers from Scripps Research and the Lowy Medical Research Institute, in collaboration with Columbia University and the University of California, San Diego.

“MacTel is a progressive, late-onset retinal degenerative disease linked to decreased serum levels of serine that elevate circulating levels of a toxic ceramide species, deoxysphingolipids (deoxySLs); however, causal genetic variants that reduce serine levels in patients have not been identified,” wrote the researchers. “Here we identify rare, functional variants in the gene encoding the rate-limiting serine biosynthetic enzyme, phosphoglycerate dehydrogenase (PHGDH), as the single locus accounting for a significant fraction of MacTel.”

“It’s exciting to uncover new answers to the many questions surrounding this rare and complex eye disease,” said Martin Friedlander, MD, PhD, professor at Scripps Research and president of the Lowy Medical Research Institute. “Although we’ve known that MacTel has a genetic component, the precise variants had remained elusive. These findings will serve as a springboard for further scientific investigation and as a guide to potential therapeutic targets.”

Friedlander and colleagues previously found that low serine levels were responsible for a buildup of toxic lipids that caused photoreceptor cells to die, yet further studies were needed to uncover what caused the decline in serine.

In the current study, Rando Allikmets, PhD, the William and Donna Acquavella professor of ophthalmic sciences, Columbia University, used a new strategy to discover genetic drivers of disease. The researchers analyzed groups of mutations instead of assessing individual mutations in genes, which gave them the upper hand in identifying genes that caused diseases in a small population of people with MacTel.

The researchers observed that the gene, PHGDH, had more variants in MacTel patients than those without the disease. The team identified 22 rare variants in PHGDH which, together, account for approximately 3 to 4% of MacTel cases.

Several of the gene variants identified in the study are known to cause rare, severe neuropathies when both of the alleles, or copies of the gene, are affected.

“The PHGDH gene is essential for the production of serine, which plays a central role in cellular metabolism,” said Kevin Eade, PhD, a former Scripps Research postdoctoral associate and who is now a senior scientist at the Lowy Medical Research Institute. “Through genetic analyses and experiments in human-derived retinal tissue, we were able to confirm that even a partial loss of PHGDH function can have a damaging effect on the retina.”

The scientists then used human induced pluripotent stem cells to generate specialized retinal cells that contained one of the MacTel-associated PHGDH mutations. They found that a PHGDH mutation in these cells leads to the production of a toxic lipid previously shown to cause MacTel.

The researchers still need to investigate and learn further about the changes related to serine metabolism and retinal degeneration, but it is a step that is paving the way for new insights and potential therapeutic treatments to come.

“We still have much to learn about this rare disease, including why systemic changes in serine metabolism lead to retinal degeneration,” said Marin Gantner, PhD, senior staff scientist at the Lowy Medical Research Institute and doctoral graduate of Scripps Research. “We have come such a long way in identifying links to the disease, and every step provides new insights that can be leveraged in creating a therapy.”

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