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 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.
authors.affiliation: Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maruyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morino
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Yuishin
authors.initials: Y
authors.lastname: Izumi
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Kato
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Masaki
authors.initials: M
authors.lastname: Kamada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nodera
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Osamu
authors.initials: O
authors.lastname: Komure
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsuura
authors.forename: Keitaro
authors.initials: K
authors.lastname: Kobatake
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Morimoto
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.forename: Naoki
authors.initials: N
authors.lastname: Suzuki
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kawata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirai
authors.forename: Takeo
authors.initials: T
authors.lastname: Kato
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ogasawara
authors.forename: Asao
authors.initials: A
authors.lastname: Hirano
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kusaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Hagiwara
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
authors.forename: Hideshi
authors.initials: H
authors.lastname: Kawakami
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D044466:Asian People; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics; D003241:Consanguinity; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D050505:Mutant Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D021381:Protein Transport; D017384:Sequence Deletion / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D035582:Transcription Factor TFIIIA / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D050505:Mutant Proteins; D016328:NF-kappa B; C409460:OPTN protein, human; C000606290:SOD1 protein, human; D035582:Transcription Factor TFIIIA; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1