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

被引：78

作者：

Zhang, Youwen ^{[1
]}

Stanton, J. Brett ^{[1
]}

Wu, Jiang ^{[4
]}

Yu, Kuai ^{[5
]}

Hartzell, H. Criss ^{[5
]}

Peachey, Neal S. ^{[4
,6
,7
]}

Marmorstein, Lihua Y. ^{[1
,2
]}

Marmorstein, Alan D. ^{[1
,3
]}

机构：

[1] Univ Arizona, Dept Ophthalmol & Vis Sci, Tucson, AZ 85711 USA

[2] Univ Arizona, Dept Physiol, Tucson, AZ 85711 USA

[3] Univ Arizona, Ctr Opt Sci, Tucson, AZ 85711 USA

[4] Cleveland Clin Fdn, Cole Eye Inst, Cleveland, OH 44195 USA

[5] Emory Univ, Dept Cell Biol, Atlanta, GA 30322 USA

[6] Cleveland VA Med Ctr, Res Serv, Cleveland, OH USA

[7] Case Western Reserve Univ, Dept Ophthalmol, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 06期

关键词：

VITELLIFORM MACULAR DYSTROPHY; RETINAL-PIGMENT EPITHELIUM; SENSORY NEURONS; LIGHT PEAK; GENE; VMD2; MUTATIONS; BESTROPHIN; DEGENERATION; EXPRESSION;

D O I：

10.1093/hmg/ddp583

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1108 / 1118

页数：11

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