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.
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 macular degeneration, affecting both the young and the old, are associated with mutations in the ABCA4 gene. The studies in this proposal seek to bridge the knowledge obtained from clinical genetics with the biochemical consequences of mutations in the ABCA4 gene that lead to macular degeneration so that more accurate prognoses and targeted therapies may be developed in the near future.
|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|
|Suarez, Tatiana; Biswas, Subhasis B; Biswas, Esther E (2002) Biochemical defects in retina-specific human ATP binding cassette transporter nucleotide binding domain 1 mutants associated with macular degeneration. J Biol Chem 277:21759-67|
|Biswas, E E (2001) Nucleotide binding domain 1 of the human retinal ABC transporter functions as a general ribonucleotidase. Biochemistry 40:8181-7|
|Biswas, E E; Biswas, S B (2000) The C-terminal nucleotide binding domain of the human retinal ABCR protein is an adenosine triphosphatase. Biochemistry 39:15879-86|