Non-syndromic retinal ciliopathies: translating gene discovery into therapy
Non-syndromic retinal ciliopathies: translating gene discovery into therapy
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DOI：
10.1093/hmg/dds298
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发表时间：
2012-10-15
影响因子：
3.5
通讯作者：
Mans, Dorus A.
中科院分区：
文献类型：
--
作者：
Estrada-Cuzcano, Alejandro;Roepman, Ronald;Mans, Dorus A.
纯合性作图和外显子组测序加速了与人类遗传性视网膜变性有关的基因突变和修饰等位基因的发现。到目前为止，已经发现158个基因在视网膜营养不良患者中发生突变。大约三分之一的视网膜变性基因缺陷会影响光感受器中连接纤毛的结构和/或功能。这种结构对应于典型纤毛的过渡区，这一区域与纤毛内稳态的相关性越来越大。连接纤毛连接光感受器的内外节段，调节视觉所需的光传导蛋白的双向运输。事实上，外节连接纤毛和相关的基底体，形成高度专门化的感觉纤毛，完全致力于光接收和随后的信号转导到大脑。至少有21个编码纤毛蛋白的基因与非综合征性视网膜营养不良有关，如视锥细胞营养不良、圆锥细胞营养不良、Leber先天性黑色素、黄斑变性或视网膜色素变性(RP)。脊椎动物视网膜纤毛病变动物模型的产生和特征揭示了对分子疾病机制的深入了解，这对于开发和评估治疗策略是必不可少的。基因增强疗法已被证明在恢复患有LCA或RP的小鼠、狗和人类的长期视力方面是安全和成功的。在这里，我们对非综合征性视网膜纤毛病变涉及的基因、突变和修饰等位基因进行了全面的综述，回顾了相关视网膜疾病机制的研究进展，并评价了在这些纤毛疾病中对抗视网膜变性的基因增强方法。
Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defects underlying retinal degeneration affect the structure and/or function of the oconnecting cilium' in photoreceptors. This structure corresponds to the transition zone of a prototypic cilium, a region with increasing relevance for ciliary homeostasis. The connecting cilium connects the inner and outer segments of the photoreceptor, mediating bi-directional transport of phototransducing proteins required for vision. In fact, the outer segment, connecting cilium and associated basal body, forms a highly specialized sensory cilium, fully dedicated to photoreception and subsequent signal transduction to the brain. At least 21 genes that encode ciliary proteins are implicated in non-syndromic retinal dystrophies such as cone dystrophy, conerod dystrophy, Leber congenital amaurosis (LCA), macular degeneration or retinitis pigmentosa (RP). The generation and characterization of vertebrate retinal ciliopathy animal models have revealed insights into the molecular disease mechanism which are indispensable for the development and evaluation of therapeutic strategies. Gene augmentation therapy has proven to be safe and successful in restoring long-term sight in mice, dogs and humans suffering from LCA or RP. Here, we present a comprehensive overview of the genes, mutations and modifier alleles involved in non-syndromic retinal ciliopathies, review the progress in dissecting the associated retinal disease mechanisms and evaluate gene augmentation approaches to antagonize retinal degeneration in these ciliopathies.