Published August 21, 2020
Research by Steven J. Fliesler, PhD, has revealed important new information about the possible cause of a rare form of irreversible blindness in young children.
Retinitis pigmentosa (RP) is the label given to a family of disorders characterized by the degeneration and eventual death of the eye’s photoreceptor cells, which absorb and convert light into electrical signals in the retina. Symptoms often begin in childhood with night blindness and loss of peripheral vision, resulting in progressive vision loss and, ultimately, blindness.
The findings came about as part of a coordinated effort by the Jacobs School of Medicine and Biomedical Sciences and the University of Alabama at Birmingham (UAB).
Fliesler, SUNY Distinguished Professor and the Meyer H. Riwchun Endowed Chair Professor of ophthalmology, is leading the research effort for the Jacobs School. The UAB team is led by Steven J. Pittler, PhD, professor and director of the Vision Science Research Center at the UAB School of Optometry.
“RP is caused by a multitude of disparate genetic mutations,” Fliesler explains. “However, one form known as RP59 has been classified as a congenital disorder of glycosylation (CDG). The process of glycosylation involves the addition of sugars to protein molecules to make glycoproteins, which are required for cellular development, structural integrity and viability.”
But the researchers’ findings published in June in a paper in iScience — and two prior related papers published earlier this year in the journal Cells — demonstrate that this may not be the case.
Although the more common forms of RP have been known for many decades, RP59 was only first described in 2011 in patients of Ashkenazi Jewish heritage. Those patients have a genetic defect involving mutations in the gene that encodes dehydrodolichyl diphosphate synthase (DHDDS), a key enzyme required for synthesizing an essential lipid-like molecule called dolichol. These patients manifest RP-like symptoms.
Up until then, Fliesler says, it was neither known nor imagined that defects in the biochemical pathway that synthesizes dolichol could cause the disorder.
In 2018, the National Eye Institute of the National Institutes of Health awarded Fliesler and Pittler a $2.2 million grant to study RP59 with the hope of eventually developing a gene therapy to treat or cure the condition.
The aim of the grant, which supports the current work, was to study the molecular mechanism underlying RP59 pathology by deleting the DHDDS gene selectively in specific cell types in the retina and examining the consequences to retinal structure and function, Fliesler says.
“The study described in the iScience paper involved targeted deletion in mouse retinal rod photoreceptor cells of the gene that encodes a critical enzyme (DHDDS) responsible for making dolichol and its derivatives,” he says. “Those mice exhibited a profound retinal degeneration with complete loss of rod photoreceptors by 6 postnatal weeks of age, which is among the most rapid photoreceptor degenerations ever observed.“
While researchers predicted the retinal degeneration, they expected that protein glycosylation in the photoreceptor cells would be severely compromised, since that process requires dolichol; yet, it was not.
“That was a tremendous surprise,” Fliesler says.
“We have not yet discovered why this happens, or what is the actual underlying mechanism of the very rapid photoreceptor degeneration observed in our novel mouse model,” he adds. “Without knowing the underlying mechanism of RP59, it would be more difficult to develop targeted therapies to prevent, impede or cure the disease. Our results, in combination with results obtained from two other recently published studies from our group in collaboration with Dr. Pittler’s lab at UAB, challenge the prevailing notion that RP59 is a congenital disorder of glycosylation.”
The work is related to two previous papers, in which Fliesler and members of his lab are co-authors with the lead investigators at UAB. Published in Cells, the first study suggests that retinal pigment epithelium pathology may be a significant contributor to the retinal degeneration observed in humans with RP59 mutations.
Subsequently, the Jacobs School and UAB teams collaborated on a companion study, also reported in Cells, that showed that a “knock-in” mouse model (where an endogenous gene or parts of a gene have been replaced with exogenous genetic material) harboring the same mutation as found in human RP59 patients not only showed no defect in glycosylation, but failed to undergo retinal degeneration, and exhibited only very subtle physiological defects. These findings again point to a more complex mechanism for RP59 than originally thought, Fliesler notes.
Sriganesh Ramachandra Rao, PhD, formerly a graduate student in Fliesler’s lab at UB and now a postdoctoral research fellow there, is first author on the iScience paper, as well as on the second Cells paper.
Other authors on the iScience paper from the Department of Ophthalmology are:
Mark C. Butler, PhD, formerly a research technician in the Department of Ophthalmology, is also a co-author on the iScience paper.
Pittler and colleagues at UAB are co-authors, along with researchers from the Polish Academy of Sciences.
The research was supported primarily by the above cited NIH grant, with additional support from a Knights Templar Eye Foundation Career-Starter Award and a Fight for Sight Summer Student Award and Postdoctoral, as well as support from a Clinical and Translational Science Award granted to UB by the National Center for Advancing Translational Sciences of the NIH.
Fliesler conducted the research at the VA Western New York Healthcare System, where he holds a Research VA MERIT Review Award, as well as a Research Career Scientist Award, both from the U.S. Department of Veterans Affairs.