Journal
HUMAN MOLECULAR GENETICS
Volume 19, Issue 6, Pages 1108-1118Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddp583
Keywords
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Funding
- NIH [EY13160, EY13847, EY14465, EY014852, GM60448]
- Veterans Administration
- Macular Vision Research Foundation
- Hope for Vision
- American Health Assistance Foundation
- Career Development Award
- Research to Prevent Blindness
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Mutations in BEST1, encoding bestrophin-1 (Best1), cause Best vitelliform macular dystrophy (BVMD), a dominantly inherited macular degeneration characterized by a diminished electrooculogram light peak (LP), lipofuscin in retinal pigment epithelial cells (RPE), and fluid- and debris-filled retinal detachments. To understand the pathogenesis of BVMD we generated knock-in mice carrying the BVMD-causing mutation W93C in Best1. Both Best1(+/W93C)and Best1(W93C/W93C) mice had normal ERG a- and b-waves, but exhibited an altered LP luminance response reminiscent of that observed in BVMD patients. Morphological analysis identified fluid- and debris-filled retinal detachments in mice as young as 6 months of age. By 18-24 months of age Best1(+/W93C)and Best1(W93C/W93C) mice exhibited enhanced accumulation of lipofuscin in the RPE, and a significant deposition of debris composed of unphagocytosed photoreceptor outer segments and lipofuscin granules in the subretinal space. Although Best1 is thought to function as a Ca2+-activated Cl- channel, RPE cells from Best1(W93C) mice exhibited normal Cl- conductances. We have previously shown that Best1(-/-) mice exhibit increased [Ca2+](i) in response to ATP stimulation. However, ATP-stimulated changes in [Ca2+](i) in RPE cells from Best1(+/W93C) and Best1(W93C/W93C) mice were suppressed relative to Best1(+/+) littermates. Based on these data we conclude that mice carrying the Best1(W93C) mutation are a valid model for BVMD. Furthermore, these data suggest that BVMD is not because of Best1 deficiency, as the phenotypes of Best1(+/W93C) and Best1(W93C/W93C) mice are distinct from that of Best1(-/-) mice with regard to lipofuscin accumulation, and changes in the LP and ATP Ca2+ responses.
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