MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma
MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma
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DOI：
10.1073/pnas.1401464112
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发表时间：
2015-06-23
影响因子：
11.1
通讯作者：
Black, Graeme C. M.
中科院分区：
文献类型：
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作者：
Conte, Ivan;Hadfield, Kristen D.;Black, Graeme C. M.
眼部发育障碍，包括小眼症、无眼症和缺损 (MAC) 以及遗传性视网膜营养不良，共同代表了遗传性失明的主要原因。以极端的遗传和临床异质性为特征，不同的群体有许多共同的遗传原因，特别是与控制视网膜和视网膜色素上皮维持的途径有关。为了了解这些共享途径并描述这些群体之间的重叠，我们研究了常染色体显性遗传的视网膜营养不良和双侧缺损的遗传原因，这些疾病在一个大的五代家庭中不同程度地存在。通过连锁分析和外显子组测序，我们在 microRNA-204 (miR-204) 的种子区域中发现了一个先前未描述的杂合突变 n.37C > T，该突变与所有受影响个体中的疾病分离。我们通过体外测定（包括转录组分析）证明，这种突变决定了 miR-204 靶向能力的显着改变。在青鳉鱼（Oryzias latipes）体内注射突变的 miR-204 引起与在该家族中观察到的表型一致的表型，包括由于细胞凋亡增加而导致视锥细胞和视杆细胞数量减少的光感受器改变，从而证实了 n.37C > T 突变的致病作用。最后，青鳉鱼的敲低实验证明 miR-204 对于正常的光感受器功能是必需的。总体而言，这些数据强调了 miR-204 在调节眼部发育和维持中的重要性，并提供了据我们所知，其可能通过功能获得机制对眼部疾病做出贡献的第一个证据。
Ocular developmental disorders, including the group classified as microphthalmia, anophthalmia, and coloboma (MAC) and inherited retinal dystrophies, collectively represent leading causes of hereditary blindness. Characterized by extreme genetic and clinical heterogeneity, the separate groups share many common genetic causes, in particular relating to pathways controlling retinal and retinal pigment epithelial maintenance. To understand these shared pathways and delineate the overlap between these groups, we investigated the genetic cause of an autosomal dominantly inherited condition of retinal dystrophy and bilateral coloboma, present in varying degrees in a large, five-generation family. By linkage analysis and exome sequencing, we identified a previously undescribed heterozygous mutation, n.37C > T, in the seed region of microRNA-204 (miR-204), which segregates with the disease in all affected individuals. We demonstrated that this mutation determines significant alterations of miR-204 targeting capabilities via in vitro assays, including transcriptome analysis. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family, including photoreceptor alterations with reduced numbers of both cones and rods as a result of increased apoptosis, thereby confirming the pathogenic effect of the n.37C > T mutation. Finally, knockdown assays in medaka fish demonstrated that miR-204 is necessary for normal photoreceptor function. Overall, these data highlight the importance of miR-204 in the regulation of ocular development and maintenance and provide the first evidence, to our knowledge, of its contribution to eye disease, likely through a gain-of-function mechanism.