Human CRB1-Associated Retinal Degeneration: Comparison with the rd8 Crb1-Mutant Mouse Model
Human CRB1-Associated Retinal Degeneration: Comparison with the rd8 Crb1-Mutant Mouse Model
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DOI：
10.1167/iovs.11-7701
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发表时间：
2011-08-01
影响因子：
4.4
通讯作者：
Jacobson, Samuel G.
中科院分区：
文献类型：
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作者：
Aleman, Tomas S.;Cideciyan, Artur V.;Jacobson, Samuel G.
目的.目的研究CRB 1基因突变引起的人类疾病，并与rd 8小鼠进行比较。研究了22例CRB 1突变患者。用视野检查和视网膜电图（ERG）评估功能，用光学相干断层扫描（OCT）评估视网膜结构。皮质结构和功能的量化与磁共振成像（MRI）。Rd 8小鼠接受ERG、OCT和视网膜组织病理学检查。视力范围为20/25至光感。杆ERG检测不到;小锥信号可记录。通过视野检查，小的中央视觉岛被中周边暗点与远颞周边岛分开。中央岛屿锥介导的，而周边岛屿保留了一些杆的功能。OCT检查可见外核层变薄的小中央凹岛，周围有厚分层的视网膜，视网膜内有高反射病变。MRI显示结构正常的视神经，仅枕叶白色和灰质轻微改变。功能性磁共振成像显示，与正常对照组相比，患者的全脑反应幅度和空间范围减少。Rd 8小鼠的ERG基本正常; OCT和组织病理学显示斑片状视网膜紊乱，腹侧比背侧视网膜更明显的假视网膜。感光细胞变性与发育不良区域相关。CRB 1突变导致早发性严重视力丧失，视网膜增厚、紊乱、无视。周边视力受损可持续到疾病晚期。Rd 8小鼠也具有紊乱的视网膜，但有足够的感光体完整性来产生基本上正常的视网膜功能。人类和小鼠疾病之间的差异将使旨在推进治疗计划的概念验证研究复杂化。（Invest Ophthalmol维斯科学。2011;52：6898-6910）DOI：10.1167/iovs.11-7701
PURPOSE. To investigate the human disease due to CRB1 mutations and compare results with the Crb1-mutant rd8 mouse.METHODS. Twenty-two patients with CRB1 mutations were studied. Function was assessed with perimetry and electroretinography (ERG) and retinal structure with optical coherence tomography (OCT). Cortical structure and function were quantified with magnetic resonance imaging (MRI). Rd8 mice underwent ERG, OCT, and retinal histopathology.RESULTS. Visual acuities ranged from 20/25 to light perception. Rod ERGs were not detectable; small cone signals were recordable. By perimetry, small central visual islands were separated by midperipheral scotomas from far temporal peripheral islands. The central islands were cone mediated, whereas the peripheral islands retained some rod function. With OCT, there were small foveal islands of thinned outer nuclear layer (ONL) surrounded by thick delaminated retina with intraretinal hyperreflective lesions. MRI showed structurally normal optic nerves and only subtle changes to occipital lobe white and gray matter. Functional MRI indicated that whole-brain responses from patients were of reduced amplitude and spatial extent compared with those of normal controls. Rd8 mice had essentially normal ERGs; OCT and histopathology showed patchy retinal disorganization with pseudorosettes more pronounced in ventral than in dorsal retina. Photoreceptor degeneration was associated with dysplastic regions.CONCLUSIONS. CRB1 mutations lead to early-onset severe loss of vision with thickened, disorganized, nonseeing retina. Impaired peripheral vision can persist in late disease stages. Rd8 mice also have a disorganized retina, but there is sufficient photoreceptor integrity to produce largely normal retinal function. Differences between human and mouse diseases will complicate proof-of-concept studies intended to advance treatment initiatives. (Invest Ophthalmol Vis Sci. 2011;52:6898-6910) DOI:10.1167/iovs.11-7701