Missense Mutations in a Retinal Pigment Epithelium Protein, Bestrophin-1, Cause Retinitis Pigmentosa
Missense Mutations in a Retinal Pigment Epithelium Protein, Bestrophin-1, Cause Retinitis Pigmentosa
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DOI：
10.1016/j.ajhg.2009.09.015
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发表时间：
2009-11-13
影响因子：
9.8
通讯作者：
Manson, Forbes D. C.
中科院分区：
文献类型：
--
作者：
Davidson, Alice E.;Millar, Ian D.;Manson, Forbes D. C.
Bestrophin-1优先表达于视网膜色素上皮(RPE)的基底膜。BEST]基因突变导致视网膜营养不良、卵黄状黄斑营养不良、常染色体显性玻璃体脉络膜病和常染色体隐性遗传性黄斑变性。在这里，我们描述了在诊断为常染色体显性和隐性视网膜色素变性(RP)的患者中，Bestrophin-1的四个错义突变，其中三个我们认为是以前未报道的。尽管Bestrophin-1的异源表达诱导了一种氯离子特异性电流，但其生理功能仍然知之甚少。我们测试了引起RP的突变体对Bestrophin-1的氯通道活性和细胞定位的影响。与野生型蛋白相比，两种蛋白(p.L140V和p.1205T)产生的氯离子选择性全细胞电流显著降低。在极化上皮的模型系统中，三个突变中的两个(p.L140V和p.D228N)导致Bestrophin-1从基底膜到细胞质的错误定位。Bestrophin-1的突变越来越被认为是遗传性视网膜营养不良的重要原因。
Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST] gene cause the retinal dystrophies vitelliform macular dystrophy, autosomal-dominant vitreochoroidopathy, and autosomal-recessive bestrophinopathy. Here, we describe four missense mutations in bestrophin-1, three that we believe are previously unreported, in patients diagnosed with autosomal-dominant and -recessive forms of retinitis pigmentosa (RP). The physiological function of bestrophin-1 remains poorly understood although its heterologous expression induces a Cl--specific current. We tested the effect of RP-causing variants on Cl- channel activity and cellular localization of bestrophin-1. Two (p.L140V and p.1205T) produced significantly decreased chloride-selective whole-cell currents in comparison to those of wild-type protein. In a model system of a polarized epithelium, two of three mutations (p.L140V and p.D228N) caused mislocalization of bestrophin-1 from the basolateral membrane to the cytoplasm. Mutations in bestrophin-1 are increasingly recognized as an important cause of inherited retinal dystrophy.