Mutations in the gene BEST1 (formerly VMD2) encoding Bestrophin-1 (Best1) cause 5 clinically distinct inherited retinal degenerative diseases. Among these are Best vitelliform macular dystrophy (BVMD), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and retinitis pigmentosa (RP). The "bestrophinopathies" are characterized by accumulation of lipofuscin in the retinal pigment epithelium (RPE), and fluid and debris filled retinal detachments. BVMD, the most common bestrophinopathy, is characterized by diminished central vision resulting from an "egg-yolk" like vitelliform lesion in the fovea. These lesions eventually become disrupted leading to an atrophic form of macular degeneration. All individuals with BVMD exhibit a depressed electrooculogram (EOG) light peak (LP) with a normal clinical electroretinogram (ERG). The LP is generated by a Ca2+ dependent Cl- conductance across the basolateral plasma membrane of RPE cells, where Best1 is localized. This led to the hypothesis that Best1 is a Ca2+ activated Cl- channel (CaCC) that generates the LP, and that BVMD results from loss of Best1 CaCC activity. We found that Best1 is not required to generate the LP, and that RPE Cl- conductances are normal in Best1 knock-out and knock-in mice carrying a BVMD causing mutation. In our quest to understand how Best1 mutants cause these symptoms we found that Best1 and Best1 mutants antagonize Ca2+ signaling and Ca2+ sensitive Cl- conductances, explaining the diminished LP in BVMD. Best1 mutants also affect cellular pH homeostasis. We have found that bestrophin-2 (Best2) carries a HCO3- conductance in colon cells. Thus, we hypothesize that Best1, like Best2, physiologically carries a HCO3- conductance and regulates Ca2+ signaling in RPE cells. Dysfunction of Best1, as occurs in BVMD, alters pHi and Ca2+ homeostasis, perturbing RPE fluid transport and altering the ionic composition of the sub-retinal space, causing the symptoms of BVMD. The pathogenesis of ADVIRC and RP, on the other hand, has been suggested to involve defective Best1 mRNA splicing or defective protein folding or trafficking. We will investigate the function of Best1 in the RPE and the differential pathogenesis of the bestrophinopathies via 3 specific aims.
In aim 1 we will determine whether RPE cells use an anion channel for HCO3- transport and whether Best1 is that channel or a regulator of it.
In aim 2 we will examine the effects of Best1 on RPE Ca2+ signaling and fluid transport.
In aim 3 we will explore the novel pathogenic mechanisms potentially underlying ADVIRC and RP in cultured cells and in new knock-in mouse models. Success in these aims will result in identification of Best1 function and the pathogenic mechanisms of bestrophinopathies beyond our current, limited understanding. It will also provide information and animal models essential for the development and testing of therapeutic strategies for the treatment of these currently incurable eye diseases.

Public Health Relevance

Mutations in the gene BEST1, encoding the protein bestrophin-1 (Best1), cause 5 clinically distinct retinal degenerative eye diseases in man. Understanding the function of Best1 and determining how mutations in Best1 cause disease, is a critical public health objective. Success in this application will set the stage for identification of therapies to prevent or cure vision loss in carriers of BEST1 mutations, and potentially other blinding eye diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Shen, Grace L
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University of Arizona
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Johnson, Adiv A; Lee, Yong-Suk; Chadburn, Andrew J et al. (2014) Disease-causing mutations associated with four bestrophinopathies exhibit disparate effects on the localization, but not the oligomerization, of Bestrophin-1. Exp Eye Res 121:74-85
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McLaughlin, Precious J; Bakall, Benjamin; Choi, Jiwon et al. (2007) Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice. Hum Mol Genet 16:3059-70
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