The National Eye Institute has awarded Jackson Laboratory (JAX) Professor Juergen Naggert, Ph.D., a five-year grant totaling $2,187,500 to study genetically controlled breaks in an eye structure known as the external limiting membrane (ELM), which could hold the key to understanding and treating enhanced S-cone syndrome (ESCS) and other diseases of the retina.
The adult human retina has about 120 million rods and 6 million cones. Cones come in three subtypes according to the wavelength of light they process: short (S), medium (M) and long (L). In a normal retina the S cones make up just 10 percent of cones, but in ESCS they are the most populous subtype. This causes dysplasia (deformation) of the retina and progressive degeneration of photoreceptors, leading to early night blindness and loss of visual acuity.
“ESCS is a rare disease caused by mutations in a gene, NR2E3,” says Naggert. “There is quite a bit of variability in the severity of the disease in humans. And in mouse models, the amount of degeneration varies depending on the genetic background of the mouse carrying the mutation. So it’s clear there are ‘modifier’ genes involved.”
Studies in mice have shown a connection between the retinal dysplasia seen in ESCS and breaks in the external limiting membrane (ELM), made up of cell-cell junctions between two cell types in the neuroretina, the Muller glia and photoreceptor cells.
The Naggert lab has identified a genetic modifier that prevents the fragmentation of the ELM in two different mouse models models of ESCS. “This discovery strongly suggests a causative role for the ELM fragmentation in the development of photoreceptor dysplasia,” Naggert says, “and provides a tool with which to establish the mechanisms by which ELM breaks occur, how they lead to retinal dysplasia, and how this affects disease progression.”
The new grant will fund studies in Naggert’s lab to explore the modifier gene’s mechanisms, with the goal of finding new prevention and treatment strategies for ESCS and other retinal diseases associated with dysplasia, such as Leber’s Congenital Amaurosis, and diabetic retinopathy.
The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a National Cancer Institute-designated Cancer Center, a facility in Sacramento, Calif., and a genomic medicine institute in Farmington, Conn. It employs more than 2,000 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.