Suppression of Ca²⁺ signaling in a mouse model of Best disease

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^+/W93Cand 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^+/W93Cand 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. Published by Oxford University Press 2010.