Defining the Role of DDX58 in Pediatric Glaucoma

Dr. Lev Prasov has received a Career Development Award from Research to Prevent Blindness (RPB) to continue his groundbreaking research linking a mutation in the gene DDX58 to a rare inherited syndrome typified by pediatric glaucoma.

In 2020, an international team led by Dr. Prasov was the first to document a never-before-observed misspelling in the gene DDX58, associated with a rare syndromic form of glaucoma called Singleton-Merton syndrome type II. In this syndrome, the DDX58 variant triggers an inflammatory cascade throughout the body, leading to glaucoma, skin rash, calcium deposits in blood vessels, arthritis and other conditions.

“We currently know relatively little about the role of the immune system in the mechanism of glaucoma,” says Dr. Prasov. “This obscure mutation may actually have a lot to teach us about that connection.”

As part of the study, Dr. Prasov developed a mouse model with the same DDX58 variant found in two families with the syndrome. Preliminary data indicates that the model displays many of the same eye and skin features observed in humans with the mutation. Using the model, he will conduct a number of molecular studies to identify the cells and changes in gene expression responsible for driving the eye pressure elevations that ultimately lead to glaucoma in this syndrome.

“Because we saw quite a bit of variability in the symptoms of family members with the mutation, we suspect there may be non-genetic triggers at work as well,” says Dr. Prasov. “We plan to expose the mouse model to environmental factors such as viral infections, ultraviolet light, and dietary interventions to gauge their impact on the development of glaucoma.”

Studies will also be performed using the cell lines of patients with the DDX58 mutation, and those of glaucoma patients without the mutation.

“We are curious about whether the inflammatory DDX58 pathway is activated only in the rarest forms of glaucoma, or whether it can be implicated in more common forms of the disease,” he explains. “If the latter, it could be a promising target with broader therapeutic value.”

Dr. Prasov emphasizes that interdisciplinary collaboration is vital to the success of this project. His colleagues include U-M Associate Chief of Basic and Translational Research in Rheumatology J. Michelle Kahlenberg, M.D., Ph.D.; U-M Professor of Dermatology and Skin Molecular Immunology Johann Gudjonsson, M.D., Ph.D.; U-M Assistant Professor of Dermatology and Computational Medicine and Bioinformatics Alex Tsoi, Ph.D.; Robert Hufnagel, M.D., Ph.D., of the NIH/ NEI; and a team of researchers at the University of Missouri.