Dominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l^+/− mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival.

中文翻译：

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尽管对OPA1一样，DNM1L的突变仍导致显着的视神经萎缩，尽管对线粒体融合和裂变有相反的影响

显性视神经萎缩是由于视网膜神经节细胞变性引起的致盲疾病，视网膜神经节细胞的轴突形成了视神经。在大多数情况下，该疾病是由OPA1突变引起的，OPA1是一种编码线粒体大GTP酶的基因，参与cr结构和线粒体网络融合。使用外显子组测序，我们鉴定了三个独立的视神经萎缩大家族（包括定义OPA5的两个家族）中染色体12p11.21上DNM1L的显性突变染色体19q12.1-13.1上的基因座，本研究拒绝了该基因座的存在。对患者成纤维细胞的分析显示DNM1L的生理丰度和均聚性，在细胞质中和高度成管的线粒体网络上形成聚集体，而过氧化物酶体网络的结构差异和呼吸机械均未发现。野生型小鼠视网膜的荧光显微镜检查显示，神经节细胞层和轴突中DNM1L的表达很强，而3个月大的野生型小鼠和Dnm1l ^+/-小鼠之间的比较表明，视网膜神经节细胞的体细胞和轴突中线粒体长度增加，但没有退化。因此，我们的结果表明，除了OPA1，OPA3之外，MFN2，AFG3L2和SPG7，在显性突变DNM1L危及视神经的完整性，这表明执政线粒体融合，分裂对立势力的改变，同样会影响视网膜神经节细胞的存活。