OPTN基因在ALS疾病中的突变

运动神经元疾病“肌萎缩性脊髓侧索硬化”（ALS）大约10%的病例是家族型的，但迄今所识别出的少量突变只占这些病例的20-30%左右。现在，对来自携带ALS的家族的个体所做的一项新的研究，识别出了OPTN基因（编码视神经蛋白的基因）三种不同的、以前未知的突变。

OPTN早先被报道是罕见家族型青光眼的致病基因。视神经蛋白抑制调控蛋白NF-κB的激发的能力在这些突变体中丢失了，说明NF-κB抑制因子在ALS治疗中也许有用。

Mutations of optineurin in amyotrophic lateral sclerosis
Hirofumi Maruyama,Hiroyuki Morino,Hidefumi Ito,Yuishin Izumi,Hidemasa Kato,Yasuhito Watanabe,Yoshimi Kinoshita,Masaki Kamada,Hiroyuki Nodera,Hidenori Suzuki,Osamu Komure,Shinya Matsuura,Keitaro Kobatake,Nobutoshi Morimoto,Koji Abe,Naoki Suzuki,Masashi Aoki,Akihiro Kawata,Takeshi Hirai,Takeo Kato,Kazumasa Ogasawara,Asao Hirano,Toru Takumi,Hirofumi Kusaka,Koichi Hagiwara,
Ryuji Kaji & Hideshi Kawakami et al.

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 cord1. 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 angiogenin3, 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-κB）, 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-κB 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.