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

doi:10.1038/nature08971

Cited by 1,265Amyotrophic Lateral Sclerosis ResearchHereditary Neurological DisordersGenetic Neurodegenerative Diseases

Mutations of optineurin in amyotrophic lateral sclerosis

Maruyama, Hirofumi, Morino, Hiroyuki, Ito, Hidefumi, Izumi, Yuishin, Kato, Hidemasa, Watanabe, Yasuhito, Kinoshita, Yoshimi, Kamada, Masaki +19 more·2010·Nature

DOI 10.1038/nature08971

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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 cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). 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), 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-kappaB), 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-kappaB 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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Genetic analyses have uncovered more than 20 OPTN mutations in ALS patient cohorts, accounting for approximately 3% of familial disease and approximately 1% of sporadic disease.
“Genetic analyses have uncovered >20 OPTN mutations in ALS patient cohorts, accounting for ~3% of familial disease and ~1% of sporadic disease [258].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [258]
A recent genetic association of ALS with optineurin, together with other evidence, implies an interaction with NF-κB leading to downstream apoptotic neuronal cell death.
“include one with optineurin (Maruyama et al. 2010) that together with other evidence implies an interaction with NF-κB (see later) leading to the downstream effects of apoptotic neuronal cell death”
From Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples (2010) · cites this paper as Maruyama et al. 2010

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“~3% of familial disease and ~1% of sporadic disease [258].”
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Authors: 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.
Affiliations: Hiroshima University (JP)
Kansai Medical University (JP)
Tokushima University (JP)
Saitama Medical University (JP)
Hiroshima Bunkyo University (JP)
South Osaka Neurosurgical Hospital (JP)
Kobatake Hospital (JP)
Okayama University (JP)
Tohoku University (JP)
Tokyo Metropolitan Neurological Hospital (JP)
Yamagata University (JP)
Shiga University of Medical Science (JP)
Montefiore Medical Center (US)
Corresponding author: Kawakami, Hideshi
ORCID: Maruyama, Hirofumi
Morino, Hiroyuki
Ito, Hidefumi
Izumi, Yuishin
Nodera, Hiroyuki
Suzuki, Hidenori
Matsuura, Shinya
Abe, Koji
Suzuki, Naoki
Aoki, Masashi
Kato, Takeo
Takumi, Toru
Kusaka, Hirofumi
Hagiwara, Koichi
Kaji, Ryuji
Kawakami, Hideshi
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2010-04-28
Volume: 465
Issue: 7295
Pages: 223-226
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature08971
OpenAlex: W2048813950
Cited by: 1,265
References: 22
Citations by year: 2026: 28 · 2025: 54 · 2024: 46 · 2023: 55 · 2022: 67 · 2021: 85 · 2020: 112 · 2019: 79 · 2018: 92 · 2017: 84 · 2016: 99 · 2015: 93 · 2014: 64 · 2013: 74 · 2012: 96
FWCI: 57.46
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Smoking Research Foundation
Japan Society for the Promotion of Science (21500336)
Core Research for Evolutional Science and Technology
Topics: Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords: amyotrophic lateral sclerosis, optineurin, familial ALS, NF-κB inhibition, ubiquitin-binding domain, nonsense mutation, missense mutations, exon 5 deletion, primary open-angle glaucoma, ubiquitin ligase, motor neuron disease, susceptibility genes, SOD1, TDP-43, FUS
MeSH terms: Superoxide Dismutase-1, Adolescent, Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Amyotrophic Lateral Sclerosis, Base Sequence, Child, Consanguinity, Cytoplasm, DNA-Binding Proteins, Exons, Female, Humans, Japan, Male, Middle Aged, Mutation, Pedigree, Superoxide Dismutase, NF-kappa B, Sequence Deletion, Codon, Nonsense, Cell Cycle Proteins, Mutation, Missense, Polymorphism, Single Nucleotide, Protein Transport, Membrane Transport Proteins, Transcription Factor TFIIIA, Asian People, Mutant Proteins, Young Adult

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Mutations of optineurin in amyotrophic lateral sclerosis

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