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 KatoKazumasa Ogasawara, Asao Hirano, Toru Takumi, Hirofumi Kusaka, Koichi Hagiwara, Ryuji Kaji, Hideshi Kawakami

Research output: Contribution to journalArticle

699 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)223-226
Number of pages4
JournalNature
Volume465
Issue number7295
DOIs
StatePublished - May 13 2010

Fingerprint

Amyotrophic Lateral Sclerosis
Mutation
NF-kappa B
Nonsense Codon
Missense Mutation
Genes
Liposarcoma
Inclusion Bodies
Motor Cortex
DNA-Binding Proteins
Motor Neurons
Ubiquitin
Sarcoma
Transgenic Mice
Brain Stem
Transfection
Anti-Idiotypic Antibodies
Exons
Pharmaceutical Preparations
Superoxide Dismutase-1

ASJC Scopus subject areas

  • General

Cite this

Maruyama, H., Morino, H., Ito, H., Izumi, Y., Kato, H., Watanabe, Y., ... Kawakami, H. (2010). Mutations of optineurin in amyotrophic lateral sclerosis. Nature, 465(7295), 223-226. https://doi.org/10.1038/nature08971

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

In: Nature, Vol. 465, No. 7295, 13.05.2010, p. 223-226.

Research output: Contribution to journalArticle

Maruyama, H, Morino, H, Ito, H, Izumi, Y, Kato, H, Watanabe, Y, Kinoshita, Y, Kamada, M, Nodera, H, Suzuki, H, Komure, O, Matsuura, S, Kobatake, K, Morimoto, N, Abe, K, Suzuki, N, Aoki, M, Kawata, A, Hirai, T, Kato, T, Ogasawara, K, Hirano, A, Takumi, T, Kusaka, H, Hagiwara, K, Kaji, R & Kawakami, H 2010, 'Mutations of optineurin in amyotrophic lateral sclerosis', Nature, vol. 465, no. 7295, pp. 223-226. https://doi.org/10.1038/nature08971
Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010 May 13;465(7295):223-226. https://doi.org/10.1038/nature08971
Maruyama, Hirofumi ; Morino, Hiroyuki ; Ito, Hidefumi ; Izumi, Yuishin ; Kato, Hidemasa ; Watanabe, Yasuhito ; Kinoshita, Yoshimi ; Kamada, Masaki ; Nodera, Hiroyuki ; Suzuki, Hidenori ; Komure, Osamu ; Matsuura, Shinya ; Kobatake, Keitaro ; Morimoto, Nobutoshi ; Abe, Koji ; Suzuki, Naoki ; Aoki, Masashi ; Kawata, Akihiro ; Hirai, Takeshi ; Kato, Takeo ; Ogasawara, Kazumasa ; Hirano, Asao ; Takumi, Toru ; Kusaka, Hirofumi ; Hagiwara, Koichi ; Kaji, Ryuji ; Kawakami, Hideshi. / Mutations of optineurin in amyotrophic lateral sclerosis. In: Nature. 2010 ; Vol. 465, No. 7295. pp. 223-226.
@article{d8fd072671c34843800765e474d766a7,
title = "Mutations of optineurin in amyotrophic lateral sclerosis",
abstract = "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.",
author = "Hirofumi Maruyama and Hiroyuki Morino and Hidefumi Ito and Yuishin Izumi and Hidemasa Kato and Yasuhito Watanabe and Yoshimi Kinoshita and Masaki Kamada and Hiroyuki Nodera and Hidenori Suzuki and Osamu Komure and Shinya Matsuura and Keitaro Kobatake and Nobutoshi Morimoto and Koji Abe and Naoki Suzuki and Masashi Aoki and Akihiro Kawata and Takeshi Hirai and Takeo Kato and Kazumasa Ogasawara and Asao Hirano and Toru Takumi and Hirofumi Kusaka and Koichi Hagiwara and Ryuji Kaji and Hideshi Kawakami",
year = "2010",
month = "5",
day = "13",
doi = "10.1038/nature08971",
language = "English (US)",
volume = "465",
pages = "223--226",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7295",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=77952419246&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952419246&partnerID=8YFLogxK

U2 - 10.1038/nature08971

DO - 10.1038/nature08971

M3 - Article

C2 - 20428114

AN - SCOPUS:77952419246

VL - 465

SP - 223

EP - 226

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7295

ER -