Woodruff Michael L, Wang Zhongyan, Chung Hae Yun, Redmond T Michael, Fain Gordon L, Lem Janis
Department of Physiological Science, University of California Los Angeles, Los Angeles, California 90095, USA.
Nat Genet. 2003 Oct;35(2):158-64. doi: 10.1038/ng1246. Epub 2003 Sep 21.
Mutations in Rpe65 disrupt synthesis of the opsin chromophore ligand 11-cis-retinal and cause Leber congenital amaurosis (LCA), a severe, early-onset retinal dystrophy. To test whether light-independent signaling by unliganded opsin causes the degeneration, we used Rpe65-null mice, a model of LCA. Dark-adapted Rpe65-/- mice behaved as if light adapted, exhibiting reduced circulating current, accelerated response turn-off, and diminished intracellular calcium. A genetic block of transducin signaling completely rescued degeneration irrespective of an elevated level of retinyl ester. These studies clearly show that activation of sensory transduction by unliganded opsin, and not the accumulation of retinyl esters, causes light-independent retinal degeneration in LCA. A similar mechanism may also be responsible for degeneration induced by vitamin A deprivation.
Rpe65基因突变会破坏视蛋白发色团配体11-顺式视黄醛的合成，并导致莱伯先天性黑蒙（LCA），这是一种严重的早发性视网膜营养不良。为了测试未结合配体的视蛋白的非光信号传导是否会导致视网膜退化，我们使用了Rpe65基因敲除小鼠，这是一种LCA模型。暗适应的Rpe65-/-小鼠表现得如同光适应一样，表现为循环电流降低、反应关闭加速和细胞内钙减少。转导素信号传导的基因阻断完全挽救了视网膜退化，而与视黄酯水平升高无关。这些研究清楚地表明，未结合配体的视蛋白激活感觉转导，而非视黄酯的积累，导致了LCA中与光无关的视网膜退化。类似的机制也可能是维生素A缺乏引起退化的原因。
