The human body is an intricate network of cells, tissues, and organs, all guided by the instructions encoded in our genes. These genes, segments of DNA, dictate our physical characteristics and the complex biological processes that keep us alive. Among the thousands of genes contributing to human health, the EYS gene plays a notable role in maintaining vision. Its proper functioning supports the intricate machinery of the eye.
What is the EYS Gene?
The EYS gene, formally known as Eyes Shut Homolog, is a large gene located on human chromosome 6 at position 6q12. It spans approximately 2 megabases (Mb) of genomic DNA. This gene provides the blueprint for a protein comprising 3,145 amino acids, which includes multiple N-terminal epidermal growth factor (EGF)-like domains and C-terminal Laminin G domains.
The EYS protein is an extracellular matrix protein, meaning it exists outside of cells and contributes to the structural support and organization of tissues. It is predominantly found in the retina, the light-sensitive tissue at the back of the eye. While its precise function is still under investigation, it is believed to contribute to the structure and maintenance of photoreceptor cells, which detect light.
How the EYS Gene Affects Vision
Within the retina, the EYS protein is localized to a specific structure within photoreceptor cells called the connecting cilium. This cilium acts as a bridge, linking the outer segment of the photoreceptor, which contains light-sensing molecules, to the inner segment, which houses the cell’s metabolic machinery. The connecting cilium’s integrity is important for the efficient transport of molecules necessary for photoreceptor function.
The EYS protein is thought to stabilize the ciliary axonemes, the core structural components of these cilia, in both rod and cone photoreceptor cells. Rods are responsible for vision in dim light and peripheral vision, while cones mediate color vision and high-acuity central vision. By contributing to the stability and maintenance of these connecting cilia, the EYS protein indirectly supports the conversion of light signals into electrical impulses that the brain interprets as vision.
Eye Conditions Caused by EYS Gene Mutations
When mutations occur in the EYS gene, the protein it produces may be absent or dysfunctional, leading to a range of eye conditions. The most recognized condition associated with EYS gene mutations is autosomal recessive retinitis pigmentosa (RP), specifically referred to as RP25. This form of RP is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the mutated EYS gene, one from each parent, to develop the condition.
RP25 is characterized by progressive degeneration of photoreceptor cells in the retina, primarily affecting rods before cones. Individuals experience early symptoms such as night blindness, often beginning in the second or third decade of life. As the disease progresses, there is a gradual loss of peripheral vision, leading to a constricted visual field, sometimes described as “tunnel vision.” Other signs include attenuated retinal vessels, optic disc pallor, and bone-spicule-like pigmentations in the mid-periphery of the retina. Central vision can remain relatively preserved until later stages, though subcapsular cataracts may develop at a relatively young age.
Research and Potential Therapies
Current research is actively exploring ways to address EYS gene mutations and their resulting vision loss. Gene therapy is a promising avenue, aiming to introduce healthy copies of the EYS gene into retinal cells. However, the large size of the EYS gene presents a challenge for delivery using common viral vectors like adeno-associated viruses (AAVs), which have limited carrying capacity. Researchers are investigating strategies such as using dual AAV vectors to deliver the gene in parts, which could then reassemble inside the cells.
Stem cell research offers another approach for EYS-related retinal degenerations. While no FDA-approved stem cell treatments for eye diseases currently exist, clinical trials are underway globally for various retinal conditions. Scientists are developing induced pluripotent stem cells (iPSCs) from patient blood samples to grow “miniature retinas” or retinal organoids in laboratories. These models allow for studying disease progression and testing potential drug therapies without risk to patients, especially since there is no mammalian animal model for human EYS disease. Some studies are also exploring the transplantation of stem cell-derived photoreceptor or retinal pigment epithelium cells to replace degenerated cells or provide support to remaining ones, though clinical efficacy for these cell-based therapies is still being evaluated.