Guziewicz Karina E, Sinha Divya, Gómez Néstor M, Zorych Kathryn, Dutrow Emily V, Dhingra Anuradha, Mullins Robert F, Stone Edwin M, Gamm David M, Boesze-Battaglia Kathleen, Aguirre Gustavo D
Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA 19104, USA.
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA.
Prog Retin Eye Res. 2017 May;58:70-88. doi: 10.1016/j.preteyeres.2017.01.005. Epub 2017 Jan 19.
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.
最佳rophin病是最常见的遗传性黄斑变性形式之一，由视网膜色素上皮（RPE）中表达的BEST1基因突变引起。人类和犬类与BEST1相关的黄斑病变均以RPE细胞内自发荧光物质异常积聚和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。我们现在概述了关于最佳rophin病分子病理学的当前知识状态，并利用首个BEST1相关视网膜病变的自发动物模型——犬类Best（cBest），探索促进RPE-神经视网膜分离形成的因素。在这里，我们描述了自发荧光RPE细胞内含物的性质，并报告了人类和犬类视网膜之间RPE相关荧光团的匹配光谱特征，表明Best卵黄样黄斑营养不良（BVMD）患者及其犬类疾病模型中内源性RPE沉积物的组成类似。这项研究还揭示了RPE-光感受器界面处一系列与锥体细胞相关的微绒毛包裹受损和不溶性光感受器间基质（IPM）受损相关的生化和结构异常情况，这些是导致RPE-神经视网膜相互作用减弱以及因此形成卵黄样病变的主要病理因素。在cBest以及BVMD和ARB-hiPSC-RPE模型系统的RPE顶端区域检测到的这些显著改变，为BEST1相关疾病的病理机制提供了新的见解，这将有助于制定指导最佳rophin病治疗策略的关键结果指标。
