Biomolecular Analysis of Proteins in Visual Diseases

项目总结/文摘

PROJECT SUMMARY/ABSTRACT The ABCA4 gene is associated with a broad range of autosomal recessive retinal degenerations including Stargardt disease (STGD1), cone rod dystrophy (arCRD), retinitis pigmentosa (arRP) and fundus flavimaculatus (FFM). Disease-associated ABCA4 alleles show an extraordinary genetic heterogeneity, numbering over 700 mutations, and are found throughout the entire open reading frame. The wide spectrum of phenotypes and the corresponding dysfunctions of ABCA4 protein due to disease associated mutation(s) remains poorly understood. ABCA4 encodes a retina specific ATP binding cassette (ABC) transporter which is localized to the rod and cone photoreceptor outer segments discs. Defective ABCA4 transport of retinoids appears to contribute to the accumulation of cytotoxic lipofuscin ultimately leading to photoreceptor cell death and loss of central vision. Recent studies have suggested that ABCA4 may play a role in the translocation of 11-cis-, as well as, all-trans- retinal, adding to the complexity of this protein's mechanism of action. Currently, there are no therapeutics (small molecules or biologics) that target ABCA4, although gene and perhaps stem cell therapy hold great promise for some individuals. Molecular testing of ABCA4 is increasingly common in clinical diagnosis, yet biochemical and physiological correlations have not been made between the consequences of a given mutation in ABCA4 and the clinical development, progression and spectrum of retinal degenerations - limiting our ability to inform patients early in their diagnosis. The studies in this proposal seek to bridge the knowledge obtained from clinical genetics with the biochemical consequences of mutations in ABCA4 gene which influence macular degeneration so that more accurate prognoses and more targeted therapies may be developed in the near future.