University of Oklahoma Health Sciences Center, Department of Cell Biology, Oklahoma City, Oklahoma, United States.
University of Oklahoma Health Sciences Center, Department of Ophthalmology, Oklahoma City, Oklahoma, United States.
Invest Ophthalmol Vis Sci. 2022 Jul 8;63(8):19. doi: 10.1167/iovs.63.8.19.
More than 200 different mutations in peripherin-2 (PRPH2) are associated with multiple subtypes of inherited retinal diseases (IRDs), including retinitis pigmentosa and cone or macular diseases. Our goal was to understand how the poorly characterized PRPH2 mutation p.Pro210Arg (P210R) affects visual function and retinal structure as well as gain insight into the mechanism driving the clinical pathology.
Eleven patients had clinical assessments including best-corrected visual acuity (BCVA), full field and multifocal electroretinography (ERG), static (spot size V) and kinetic perimetry (Octopus 900), and dark-adapted chromatic (DAC; Medmont; spot size V) perimetry. Images were acquired with the Optos ultra-wide field camera and spectral-domain optical coherence tomography (SD-OCT). Molecular characteristics of the P210R mutant protein were evaluated in vitro.
Patients with the P210R mutation had BCVA (Snellen) ranging from 20/15 to 20/80. Perimetry showed a reduction in sensitivity, while ERG findings suggested that cone function was more impaired than rod function. Scotomas were identified corresponding to atrophic retinal lesions. Imaging revealed heterogeneous outer retinal changes such as hyperfluorescent flecks, hypo-autofluorescence (AF) regions of atrophy, and thinning of the photoreceptor layer on SD-OCT. In vitro findings suggested that P210R-Prph2 retains the ability to interact with binding partner Rom1 but abnormally accumulates in the endoplasmic reticulum (ER), suggesting the protein does not fold properly.
Rod and cone sensitivities were decreased in subjects with the P210R mutation in PRPH2. There was scotomatous vision loss that occurred within the macula, likely due to atrophy that occurs after drusen have formed and have begun to resolve. This suggests that although rod and cone photoreceptors are dependent on PRPH2, preventing blindness in this specific subgroup of patients could involve therapeutics that impede the formation or lifecycle of drusen.
外周蛋白-2（PRPH2）的 200 多种不同突变与多种遗传性视网膜疾病（IRDs）相关，包括色素性视网膜炎和视锥或黄斑疾病。我们的目标是了解描述不佳的 PRPH2 突变 p.Pro210Arg（P210R）如何影响视觉功能和视网膜结构，并深入了解驱动临床病理学的机制。
11 名患者接受了临床评估，包括最佳矫正视力（BCVA）、全视野和多焦视网膜电图（ERG）、静态（光斑大小 V）和动态视野计（Octopus 900）以及暗适应色觉（DAC；Medmont；光斑大小 V）视野计。使用 Optos 超广角相机和光谱域光学相干断层扫描（SD-OCT）采集图像。体外评估了 P210R 突变蛋白的分子特征。
患有 P210R 突变的患者的 BCVA（Snellen）范围为 20/15 至 20/80。视野检查显示敏感性降低，而 ERG 结果表明视锥功能受损比视杆功能更严重。在萎缩性视网膜病变处发现了黄斑病变。成像显示外视网膜存在异质性变化，如高荧光斑、萎缩的自发荧光（AF）区域和 SD-OCT 上的光感受器层变薄。体外研究结果表明，P210R-Prph2 仍然能够与结合伴侣 Rom1 相互作用，但异常地在内质网（ER）中积累，表明该蛋白不能正确折叠。
PRPH2 中 P210R 突变的受试者的视杆和视锥敏感性降低。黄斑内出现了黄斑病变的视力丧失，这可能是由于在 drusen 形成并开始消退后发生的萎缩所致。这表明，尽管视杆和视锥感光细胞依赖于 PRPH2，但在该特定亚组患者中预防失明可能需要使用阻止 drusen 形成或生命周期的治疗方法。
