TY - JOUR
T1 - Mutations of optineurin in amyotrophic lateral sclerosis
AU - Maruyama, Hirofumi
AU - Morino, Hiroyuki
AU - Ito, Hidefumi
AU - Izumi, Yuishin
AU - Kato, Hidemasa
AU - Watanabe, Yasuhito
AU - Kinoshita, Yoshimi
AU - Kamada, Masaki
AU - Nodera, Hiroyuki
AU - Suzuki, Hidenori
AU - Komure, Osamu
AU - Matsuura, Shinya
AU - Kobatake, Keitaro
AU - Morimoto, Nobutoshi
AU - Abe, Koji
AU - Suzuki, Naoki
AU - Aoki, Masashi
AU - Kawata, Akihiro
AU - Hirai, Takeshi
AU - Kato, Takeo
AU - Ogasawara, Kazumasa
AU - Hirano, Asao
AU - Takumi, Toru
AU - Kusaka, Hirofumi
AU - Hagiwara, Koichi
AU - Kaji, Ryuji
AU - Kawakami, Hideshi
N1 - Funding Information:
Acknowledgements This work was supported in part by grants-in-aid from the Ministry of Education, Science, and Culture of Japan, by a grant from the Smoking Research Foundation to H. Kawakami, and by the Japan Science and Technology Agency, Core Research for Evolutional Science & Technology to T.T. We thank E. Nakajima for technical support, K. Nakayama, H. W. Shin, M. Omi and H. Nakamura for conducting some of the experiments, and T. Miki and K. Noda for providing some DNA samples and clinical information. This paper is dedicated to the patients and families who contributed to this project.
PY - 2010/5/13
Y1 - 2010/5/13
N2 - 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-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-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.
AB - 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-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-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.
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U2 - 10.1038/nature08971
DO - 10.1038/nature08971
M3 - Article
C2 - 20428114
AN - SCOPUS:77952419246
SN - 0028-0836
VL - 465
SP - 223
EP - 226
JO - Nature
JF - Nature
IS - 7295
ER -