Grant: Project Grant

Inherited retinal degenerative diseases are a heterogeneous group of disorders that are a major cause of blindness in the world population. They typically result in progressive loss in vision due to mutations in genes encoding proteins essential for the function and survival of rod and cone photoreceptor cells. Mutations in the gene encoding the membrane transporter ABCA4 are known to cause Stargardt disease and related retinal degenerative diseases with a prevalence of about 1 in 8000 individuals worldwide. Affected individuals typically experience loss in central vision in their first or second decade of life followed by progressive loss in peripheral vision in later stages of the disease. Currently, there are no treatments for ABCA4-related diseases. We have previously shown that ABCA4 is present in rod and cone photoreceptors where it functions as an ATP-dependent membrane transporter - facilitating the removal of a retinoid compound that is produced as part of the visual process. The loss in ABCA4 retinoid transport activity leads to the accumulation of toxic retinoids that cause rod and cone photoreceptor cell death and a loss in vision. Although the role of ABCA4 in vision and retinal degeneration is generally understood, currently we know little about the molecular structure of ABCA4, the mechanism by which ABCA4 transports its substrate across membranes, and how disease-causing mutations affect the structure of ABCA4. The goal of this project is to determine the high resolution structure of ABCA4 in the presence and absence of its substrates using 'state-of-the art' cryoelectron microscopy, define how ABCA4 transports it substrate across membranes using biochemical and biophysical techniques, identify and characterize regions that are important in function of ABCA4. This information will serve as a basis for developing novel drug and gene based therapeutic strategies to prevent or slow vision loss in affected individuals.