The ABCA4 gene encodes a retina specific ATP binding cassette (ABC) transporter, ABCR, which is localized to the rod and cone photoreceptor outer segments. ABCR is thought to function in the transport of retinal derivatives across photoreceptor disk membranes. Mutations in the ABCA4 gene lead to several inherited forms of retinal degeneration (RD); including Stargardt disease, cone-rod dystrophy (arCRD), fundus flavimaculatus (FFM) and age related macular degeneration (ARMD). These degenerations represent a broad spectrum of clinical phenotypes, all associated with accumulations of lipofuscin, which is thought to be in part due to defects in transport by ABCR. Our overall aim is to investigate the mechanism of action of ABCR protein and how genetic mutations observed in Stargardt disease and other RDs influence ABCR structure and function so that new and more precise therapies could be developed in the near future. Our proposed studies will focus on two areas, first the function of specific domains of ABCR and second the function of the protein as a whole. We plan to test the hypothesis that RD associated mutations, in the extracellular (ECD) or nucleotide binding (NBD) domains lead to conformational changes, which in turn influence protein-protein or protein-ligand interactions. This will help us to develop a predictive model for the likely effect of a given mutation on structural and functional changes in these domains. Second, we shall test the hypothesis that retinal or retinal derivatives interact directly with the domains of ABCR in a membrane bound environment. We shall express full-length ABCR directly in membrane vesicles in order to test this hypothesis. These studies will provide us an avenue to investigate the effects of RD associated mutations on the ABCR molecule as a whole. Macular degenerations are the leading cause of blindness in the United States, and visual impairment is an increasing public health issue, particularly with our aging population. Several types of degeneration, affecting both the young and the old, have been associated with mutations in the ABCR gene. These studies will lead to a more accurate understanding of the involvement ABCR in the development of macular degenerations, such as Cone Rod Dystrophy, Stargardt disease, and Age Related Macular Degeneration. This will enable us to develop a more accurate prognosis of those individuals identified with mutations in the ABCR gene, and ultimately, the development of better therapies. Overall, our studies seek to bridge the knowledge obtained through clinical genetics, and the consequences of these mutations at the molecular level -- thereby enabling us to develop a clinical genotype-biochemical phenotype correlation. ? ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-CB-G (90))
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Mariani, Andrew P
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Thomas Jefferson University
Biostatistics & Other Math Sci
Schools of Allied Health Profes
United States
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Wangtiraumnuay, Nutsuchar; Capasso, Jenina; Tsukikawa, Mai et al. (2018) Novel ABCA4 mutation leads to loss of a conserved C-terminal motif: implications for predicting pathogenicity based on genetic testing. Eur J Ophthalmol 28:123-126
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Biswas-Fiss, Esther E; Affet, Stephanie; Ha, Malissa et al. (2012) Retinoid binding properties of nucleotide binding domain 1 of the Stargardt disease-associated ATP binding cassette (ABC) transporter, ABCA4. J Biol Chem 287:44097-107
Biswas-Fiss, Esther E; Kurpad, Deepa S; Joshi, Kinjalben et al. (2010) Interaction of extracellular domain 2 of the human retina-specific ATP-binding cassette transporter (ABCA4) with all-trans-retinal. J Biol Chem 285:19372-83
Biswas-Fiss, Esther E (2006) Interaction of the nucleotide binding domains and regulation of the ATPase activity of the human retina specific ABC transporter, ABCR. Biochemistry 45:3813-23
Biswas-Fiss, Esther E (2003) Functional analysis of genetic mutations in nucleotide binding domain 2 of the human retina specific ABC transporter. Biochemistry 42:10683-96
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