Gross Alecia K, Decker Glenn, Chan Fung, Sandoval Ivette M, Wilson John H, Wensel Theodore G
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Vision Res. 2006 Dec;46(27):4510-8. doi: 10.1016/j.visres.2006.07.012. Epub 2006 Sep 18.
Retinal neurodegeneration occurs in several inherited diseases. Some of the most severe disease alleles involve mutations at the C-terminus of rhodopsin, but in no case is the pathogenic mechanism leading to cell death well understood. We have examined a mouse model of recessive retinal degeneration caused by a knock-in of a human rhodopsin-EGFP fusion gene (hrhoG/hrhoG) at the rhodopsin locus. Whereas heterozygous mutant mice were indistinguishable from control mice, homozygous mutant mice had retinal degeneration. We hypothesized that degeneration might be due to aberrant rhodopsin signaling; however, inhibiting signaling by rearing mice in total darkness had no effect on the rate of degeneration. Using confocal and electron microscopy, we identified the fundamental defect as failed biogenesis of disk membranes, which is observed at the earliest stages of outer segment development. These results reveal that in addition to its role in transport and sorting of rhodopsin to disk membranes, rhodopsin is also essential for formation of disks.
视网膜神经变性发生在多种遗传性疾病中。一些最严重的致病等位基因涉及视紫红质C末端的突变，但导致细胞死亡的致病机制在任何情况下都尚未完全清楚。我们研究了一种隐性视网膜变性的小鼠模型，该模型是通过在视紫红质基因座敲入人视紫红质-增强绿色荧光蛋白融合基因（hrhoG/hrhoG）而产生的。杂合突变小鼠与对照小鼠没有区别，而纯合突变小鼠则出现视网膜变性。我们推测变性可能是由于视紫红质信号异常所致；然而，在完全黑暗中饲养小鼠以抑制信号传导对变性速率没有影响。利用共聚焦显微镜和电子显微镜，我们确定根本缺陷是盘膜生物发生失败，这在外部段发育的最早阶段就已观察到。这些结果表明，视紫红质除了在将视紫红质运输和分选到盘膜中起作用外，对于盘的形成也是必不可少的。
