Department of Cell and Neurobiology and Department of Ophthalmology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
PLoS One. 2010 Jun 2;5(6):e10904. doi: 10.1371/journal.pone.0010904.
Q344ter is a naturally occurring rhodopsin mutation in humans that causes autosomal dominant retinal degeneration through mechanisms that are not fully understood, but are thought to involve an early termination that removed the trafficking signal, QVAPA, leading to its mislocalization in the rod photoreceptor cell. To better understand the disease mechanism(s), transgenic mice that express Q344ter were generated and crossed with rhodopsin knockout mice. Dark-reared Q344ter(rho+/-) mice exhibited retinal degeneration, demonstrating that rhodopsin mislocalization caused photoreceptor cell death. This degeneration is exacerbated by light-exposure and is correlated with the activation of transducin as well as other G-protein signaling pathways. We observed numerous sub-micrometer sized vesicles in the inter-photoreceptor space of Q344ter(rho+/-) and Q344ter(rho-/-) retinas, similar to that seen in another rhodopsin mutant, P347S. Whereas light microscopy failed to reveal outer segment structures in Q344ter(rho-/-) rods, shortened and disorganized rod outer segment structures were visible using electron microscopy. Thus, some Q344ter molecules trafficked to the outer segment and formed disc structures, albeit inefficiently, in the absence of full length wildtype rhodopsin. These findings helped to establish the in vivo role of the QVAPA domain as well as the pathways leading to Q344ter-induced retinal degeneration.
Q344ter 是人类中一种自然发生的视蛋白突变，通过尚未完全阐明的机制导致常染色体显性视网膜变性，但据认为该机制涉及早期终止，从而去除了转运信号 QVAPA，导致其在杆状光感受器细胞中的错误定位。为了更好地理解疾病机制，生成了表达 Q344ter 的转基因小鼠，并将其与视蛋白敲除小鼠杂交。暗饲养的 Q344ter(rho+/-) 小鼠表现出视网膜变性，表明视蛋白错误定位导致光感受器细胞死亡。这种变性在暴露于光线下会加剧，并与转导蛋白以及其他 G 蛋白信号通路的激活相关。我们在 Q344ter(rho+/-) 和 Q344ter(rho-/-) 视网膜的光感受器间空间中观察到许多亚微米大小的囊泡，类似于另一种视蛋白突变体 P347S 中观察到的囊泡。虽然在 Q344ter(rho-/-) 杆状细胞中，光镜未能揭示外节结构，但使用电子显微镜可以观察到缩短和紊乱的杆状细胞外节结构。因此，一些 Q344ter 分子能够转运到外节，并在外节中形成盘状结构，尽管在没有全长野生型视蛋白的情况下效率较低。这些发现有助于确定 QVAPA 结构域以及导致 Q344ter 诱导的视网膜变性的途径在体内的作用。
