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Bestrophinopathy: An RPE-photoreceptor interface disease
Progress in Retinal and Eye Research ( IF 17.8 ) Pub Date : 2017-01-19 , DOI: 10.1016/j.preteyeres.2017.01.005
Karina E. Guziewicz , Divya Sinha , Néstor M. Gómez , Kathryn Zorych , Emily V. Dutrow , Anuradha Dhingra , Robert F. Mullins , Edwin M. Stone , David M. Gamm , Kathleen Boesze-Battaglia , Gustavo D. Aguirre

Bestrophinopathies, one of the most common forms of inherited macular degenerations, are caused by mutations in the BEST1 gene expressed in the retinal pigment epithelium (RPE). Both human and canine BEST1-linked maculopathies are characterized by abnormal accumulation of autofluorescent material within RPE cells and bilateral macular or multifocal lesions; however, the specific mechanism leading to the formation of these lesions remains unclear. We now provide an overview of the current state of knowledge on the molecular pathology of bestrophinopathies, and explore factors promoting formation of RPE-neuroretinal separations, using the first spontaneous animal model of BEST1-associated retinopathies, canine Best (cBest). Here, we characterize the nature of the autofluorescent RPE cell inclusions and report matching spectral signatures of RPE-associated fluorophores between human and canine retinae, indicating an analogous composition of endogenous RPE deposits in Best Vitelliform Macular Dystrophy (BVMD) patients and its canine disease model. This study also exposes a range of biochemical and structural abnormalities at the RPE-photoreceptor interface related to the impaired cone-associated microvillar ensheathment and compromised insoluble interphotoreceptor matrix (IPM), the major pathological culprits responsible for weakening of the RPE-neuroretina interactions, and consequently, formation of vitelliform lesions. These salient alterations detected at the RPE apical domain in cBest as well as in BVMD- and ARB-hiPSC-RPE model systems provide novel insights into the pathological mechanism of BEST1-linked disorders that will allow for development of critical outcome measures guiding therapeutic strategies for bestrophinopathies.



中文翻译:

最佳脊椎病:RPE-感光体界面疾病

Bestrophinopathies是遗传性黄斑变性的最常见形式之一,是由视网膜色素上皮(RPE)中表达的BEST1基因突变引起的。人和犬类与BEST1连锁的黄斑病变均以RPE细胞内自体荧光物质异常蓄积以及双侧黄斑或多灶性病变为特征。然而,导致这些病变形成的具体机制仍不清楚。我们现在提供知识的当前状态的概述对bestrophinopathies的分子病理学,探索促进形成RPE-视神经视网膜分离的因素,使用的第一次自发性动物模型将Best1相关的视网膜病变,犬类最佳(cBest)。在这里,我们表征了自体荧光RPE细胞包裹体的性质,并报告了人与犬视网膜之间RPE相关荧光团的匹配光谱特征,表明最佳线形黄斑营养不良(BVMD)患者及其犬病模型中内源性RPE沉积物的相似组成。这项研究还揭示了RPE-光感受器界面处的一系列生化和结构异常,这些异常与视锥相关的微绒毛包膜受损和不溶性不溶性光感受器间基质(IPM)受损有关,后者是导致RPE-神经视网膜相互作用减弱的主要病理原因,并且因此,形成玻璃状病变。与BEST1连锁的疾病,将允许开发关键的结局指标,指导对石蛋白病的治疗策略。

更新日期:2017-01-19
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