A Frameshift mutation in RPGR Exon ORF15 causes photoreceptor degeneration and inner retina remodeling in a model of X-linked retinitis pigmentosa
A Frameshift mutation in RPGR Exon ORF15 causes photoreceptor degeneration and inner retina remodeling in a model of X-linked retinitis pigmentosa
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DOI：
10.1167/iovs.05-0845
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Aguirre, GD
中科院分区：
文献类型：
--
作者：
Beltran, WA;Hammond, P;Aguirre, GD
目的。为了解X连锁进行性视网膜萎缩症(XLPRA2)的视网膜病变过程，建立了一种由RPGR ORF15基因微缺失引起的早发性X连锁视网膜色素变性(XLRP)犬模型。方法收集25只患XLPRA2的狗(年龄2~40.6周)和年龄匹配的对照组的视网膜，将其固定在环氧树脂中进行形态学评价，或在最佳切割温度(OCT)中进行TUNEL分析和免疫组织化学染色。使用细胞特异性抗体检测视杆细胞和视锥细胞的变化，并评价初级感光细胞变性对视网膜内细胞的影响。结果：早在3.9周龄就可以识别出光感受器的异常发育。外节段(OS)错位之后是它们的解体和碎裂。随后观察到视杆和视锥内段(IS)的长度缩短和增宽，随后视杆和视锥的焦点消失。死亡光感受器的比例在大约6到7周龄时达到顶峰，12周龄后显著降低。除视杆视锥细胞定位错误外，视杆细胞突起早期萌发，视杆双极细胞树突回缩，Muller细胞反应性增强。在病程后期，水平细胞和无长突细胞也发生了改变。结论：XLPRA2是一种早期发病的XLRP模型，其形态特征是光感受器异常成熟，随后是进行性视杆细胞锥体变性和早期视网膜内侧重塑。结果表明，这种视网膜变性的治疗策略不仅应该针对光感受器细胞，还应该针对视网膜内神经元。
PURPOSE. To characterize the Course of retinal disease in X-linked progressive retinal atrophy 2 (XLPRA2), a canine model of early onset X-linked retinitis pigmentosa (XLRP) caused by a two-nucleotide microdeletion in RPGR ORF15.METHODS. The retinas of 25 XLPRA2-affected dogs (age range, 2-40.6 weeks) and age-matched control subjects were collected, fixed, and embedded in epoxy resin for morphologic evaluation or in optimal Cutting temperature (OCT) medium for TUNEL assay and immunohistochemistry. Cell-specific antibodies were used to examine changes in rods and cones and to evaluate the effects of the primary photoreceptor degeneration on inner retinal cells.RESULTS. Abnormal development of photoreceptors was recognizable as early as 3.9 weeks of age. Outer segment (OS) misalignment was followed by their disorganization and fragmentation. Reduction in length and broadening of rod and cone inner segments (IS) was next observed, followed by the focal loss of rod and cone IS at later time points. The proportion of dying photoreceptors peaked at approximately 6 to 7 weeks of age and was significantly reduced after 12 weeks. In addition to rod and cone opsin mislocalization, there was early rod neurite sprouting, retraction of rod bipolar cell dendrites, and increased Muller cell reactivity. Later in the course of the disease, changes were also noted in horizontal cells and amacrine cells.CONCLUSIONS. XLPRA2 is an early-onset model of XLRP that is morphologically characterized by abnormal photoreceptor maturation followed by progressive rod-cone degeneration and early inner retina remodeling. The results suggest that therapeutic strategies for this retinal degeneration should target not solely photoreceptor cells but also inner retinal neurons.