title: Suppression of Ca2+ signaling in a mouse model of Best disease.
abstract: 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 Ca(2+)-activated Cl(-) channel, RPE cells from Best1(W93C) mice exhibited normal Cl(-) conductances. We have previously shown that Best1(-/-) mice exhibit increased [Ca(2+)](i) in response to ATP stimulation. However, ATP-stimulated changes in [Ca(2+)](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 Ca(2+) responses.
authors.affiliation: Department of Ophthalmology and Vision Science, University of Arizona, 655 N. Alvernon Way, Suite 108, Tucson, AZ 85711, USA.
authors.forename: Youwen
authors.initials: Y
authors.lastname: Zhang
authors.forename: J Brett
authors.initials: JB
authors.lastname: Stanton
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.forename: Kuai
authors.initials: K
authors.lastname: Yu
authors.forename: H Criss
authors.initials: HC
authors.lastname: Hartzell
authors.forename: Neal S
authors.initials: NS
authors.lastname: Peachey
authors.forename: Lihua Y
authors.initials: LY
authors.lastname: Marmorstein
authors.forename: Alan D
authors.initials: AD
authors.lastname: Marmorstein
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000075002:Bestrophins; D020013:Calcium Signaling / Q000187:drug effects / Q000528:radiation effects; D002712:Chlorides / Q000378:metabolism; D004195:Disease Models, Animal; D004585:Electrooculography; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D055879:Gene Knock-In Techniques; D005838:Genotype; D015640:Ion Channel Gating / Q000187:drug effects / Q000528:radiation effects; D007473:Ion Channels; D008027:Light; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects / Q000648:ultrastructure
chemical_list: C491856:Best1 protein, mouse; D000075002:Bestrophins; D002712:Chlorides; D005136:Eye Proteins; D007473:Ion Channels; D050505:Mutant Proteins; D000255:Adenosine Triphosphate