Mutations in human bestrophin-1 (hBest1) are associated with Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC), but the precise function of hBest1 remains in doubt and the mechanisms linking hBest1 dysfunction with disease are unknown. There is strong evidence that hBest1 is an anion (Cl) channel. There is also evidence that hBest1 regulates voltage-gated Ca channels. This application will test the hypothesis that hBest1 is a multifunctional protein that is both a Cl channel, possibly with both plasma membrane and intracellular functions, and a regulator of other ion channels, including Ca channels. Mutations in hBest1 are hypothesized to produce retinal disease by disrupting ion transport in the retina at the level of the retinal pigment epithelium (RPE). We suggest that disruption of ion transport across the RPE results in abnormal fluid content and composition in the space between photoreceptors and RPE. This compromises the interaction between RPE and photoreceptors and favors accumulation of retinoid-derived pigments and development of vitelliform lesions. In this application, we will investigate the functions and pathophysiological mechanisms of hBest1 using a combination of molecular, genetic, and electrophysiological approaches with cultured cells transfected with hBest1 and hBest1 mutants, transgenic mice with disrupted or mutant hBest1 genes, and freshly-isolated and cultured retinal pigment epithelial cells. These studies will not only provide important insights into the mechanisms of vitelliform macular dystrophies, but will also shed light on the role of ion transport across the retinal pigment epithelium on normal retinal homeostasis.

Public Health Relevance

This research addresses the mechanisms of macular degeneration, one of the major causes of blindness. Specifically, we will investigate how dysfunction of a protein called bestrophin causes an inherited juvenile-onset form of macular degeneration. We expect that these studies will provide insights into the mechanisms of macular degeneration and the mechanisms that maintain normal retinal function.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Mariani, Andrew P
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Emory University
Anatomy/Cell Biology
Schools of Medicine
United States
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Cruz-Rangel, Silvia; De Jesús-Pérez, José J; Aréchiga-Figueroa, Iván A et al. (2017) Extracellular protons enable activation of the calcium-dependent chloride channel TMEM16A. J Physiol 595:1515-1531
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