Mutations of optineurin in amyotrophic lateral sclerosis
Mutations of optineurin in amyotrophic lateral sclerosis
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DOI：
10.1038/nature08971
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发表时间：
2010-05-13
期刊：
影响因子：
64.8
通讯作者：
Kawakami, Hideshi
中科院分区：
文献类型：
--
作者：
Maruyama, Hirofumi;Morino, Hiroyuki;Kawakami, Hideshi
肌萎缩侧索硬化症（ALS）在中年发病，是一种进行性疾病，其特征是初级运动皮层、脑干和脊髓的运动神经元变性（1）。大多数ALS病例是散发性的，但约10%是家族性的。已知引起典型家族性ALS（FALS）的基因是超氧化物歧化酶1（SOD 1）（2）、编码血管生成素的ANG（3）、编码反式反应（TAR）DNA结合蛋白TDP-43的TARDP（参考文献4），并在肉瘤中融合/在脂肪肉瘤中翻译（FUS，也称为TLS）（5，6）。然而，这些遗传缺陷仅发生在约20-30%的FALS病例中，并且大多数导致FALS的基因是未知的。在这里，我们发现ALS患者编码视神经磷酸酶（OPTN）的基因存在突变，该基因先前被报道为原发性开角型青光眼（POAG）的致病基因（7）。我们发现OPTN有三种类型的突变：外显子5的纯合性缺失、Q398 X的纯合性无义突变和泛素结合域E478 G的杂合性错义突变。细胞转染分析表明，OPTN的无义和错义突变消除了对核因子κ B（NF-κ B）激活的抑制，E478 G突变显示了与野生型或POAG突变不同的胞质分布。1例E478 G突变的病例显示OPTN免疫反应性胞浆包涵体。此外，散发性ALS和SOD 1病例的TDP-43或SOD 1阳性包涵体也明显被抗OPTN抗体免疫标记。我们的研究结果强烈表明，OPTN参与ALS的发病机制。他们还表明，NF-kB抑制剂可用于治疗ALS，携带各种OPTN突变的转基因小鼠将与开发这种疾病的新药有关。
Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord(1). Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1)(2), ANG encoding angiogenin(3), TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS)(5,6). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG)(7), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappa B), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.