We identified the causative role of either compound heterozygous or homozygous mutations of ABCR in classic autosomal recessive Stargardt's macular dystrophy. The ABCR gene (also known as ABCA4) encodes a photoreceptor-specific ATP-binding cassette transporter, which has been shown recently to transport retinal or a derivative thereof. ABCR mutations also have a role in some forms of retinitis pigmentosa and a large fraction of cone-rod dystrophy. Thus, ABCR is likely to be responsible for a substantial portion of diverse retinal pathologies. That some heterozygous ABCR mutations are associated with the multifactorial disorder Age-Related Macular Degeneration suggests an even more prominent role for ABCR in visual impairment. We and others have proposed a model, the """"""""ABCR activity vs. retinal disease phenotype hypothesis,"""""""" in which the severity of retinal dystrophic phenotype is inversely proportional to the residual fraction of ABCR wild-type activity. That is, an RP phenotype results from essentially zero ABCR activity associated with two null mutations, while a late-onset Stargardt's macular dystrophy results from a selected combination of mutations that retain substantial ABCR activity. In this model, heterozygous ABCR mutations represent a dominant susceptibility locus for AMD. The common final pathophysiological pathway is influenced by how much A2E (a conjugate of retinaldehyde and phosphatidylethanolamine that appears to be transported by the """"""""ABCR flippase"""""""" and is the major toxic constituent of lipofuscin that accumulates in the flecks of STGD patients and drusen of those with AMD) accumulates in the retinal pigment epithelium. Using an assay to assess protein expression and ATP-binding activity we will perform functional analyses of disease-associated ABCR mutations. Further, we will systematically investigate and classify synergistic effects and the functional consequences of complex alleles. We will also develop a novel transporter assay to directly evaluate ABCR transporter/flippase function and the effects of disease-causing mutation. Functional analyses of ABCR and mutations in retinopathy patients will expand greatly our knowledge of normal ABCR function and the dysfunction resulting in retinal pathology. Understanding the molecular pathway involving ABCR opens new avenues for the predictive diagnosis of selected retinal diseases and may lead to novel prophylactic and interventional therapies for these devastating disorders.
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