Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Hum Mol Genet. 2012 Oct 15;21(R1):R111-24. doi: 10.1093/hmg/dds298. Epub 2012 Jul 26.
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 'connecting 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, cone-rod 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.
纯合子定位和外显子组测序加速了基因突变和修饰等位基因在人类遗传性视网膜变性中的发现。迄今为止，已经发现 158 个基因在视网膜营养不良患者中发生突变。大约三分之一的导致视网膜变性的基因缺陷影响光感受器中的“连接纤毛”的结构和/或功能。该结构对应于典型纤毛的过渡区，该区域对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节和外节，介导视觉所需的光转导蛋白的双向运输。事实上，外节、连接纤毛和相关的基体形成了高度特化的感觉纤毛，完全致力于光感受器和随后向大脑的信号转导。至少有 21 个编码纤毛蛋白的基因与非综合征性视网膜变性有关，如 cones 营养不良、cone-rod 营养不良、Leber 先天性黑矇（LCA）、黄斑变性或色素性视网膜炎（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，这对于治疗策略的开发和评估是必不可少的。基因增强疗法已被证明在恢复因 LCA 或 RP 而失明的小鼠、狗和人类的长期视力方面是安全且成功的。在这里，我们全面介绍了非综合征性视网膜纤毛病变相关的基因、突变和修饰等位基因，回顾了相关视网膜疾病机制的研究进展，并评估了基因增强方法在这些纤毛病变中的拮抗视网膜变性的效果。
