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Mutations of optineurin in amyotrophic lateral sclerosis


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.

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Figure 1: Exon 5 deletion, nonsense and missense mutations of the OPTN gene.
Figure 2: Influence of OPTN mutations.
Figure 3: Identification of OPTN in distinctive intracytoplasmic inclusions of subjects with ALS.


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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.

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Author Contributions H. Kawakami designed and supervised the study. H.Mo. and K.H. extracted candidate genes. H.Ma. and M.K. performed sequencing analysis. H.Ma., H.Mo., Y.W., T.T., S.M., H. Kawakami and H.S. conducted molecular biological analysis. H.I., Y.K., H. Ku., H. Kato, K.O. and A.H. performed pathological analysis and provided pathological samples. Y.I., H.N., R.K., O.K., N.M., K.A., A.K., T.H, T.K., M.A., N.S. and K.K. collected clinical information and samples. H. Kawakami, H.Ma., H.I. and K.H. wrote the paper.

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Correspondence to Hideshi Kawakami.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 2 and 4, Supplementary Figures 1-9 with legends, Supplementary Patient Information and Supplementary Notes and References. (PDF 7299 kb)

Supplementary Table 1

This file contains the SNP typing of subjects 1, 2, 3 and 4. (PDF 253 kb)

Supplementary Table 3

This file contains the SNP typing of subjects 5, 6, 7 and 8. (PDF 641 kb)

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Maruyama, H., Morino, H., Ito, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223–226 (2010).

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