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 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.
Maruyama
Hirofumi
H
Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
Morino
Hiroyuki
H
Ito
Hidefumi
H
Izumi
Yuishin
Y
Kato
Hidemasa
H
Watanabe
Yasuhito
Y
Kinoshita
Yoshimi
Y
Kamada
Masaki
M
Nodera
Hiroyuki
H
Suzuki
Hidenori
H
Komure
Osamu
O
Matsuura
Shinya
S
Kobatake
Keitaro
K
Morimoto
Nobutoshi
N
Abe
Koji
K
Suzuki
Naoki
N
Aoki
Masashi
M
Kawata
Akihiro
A
Hirai
Takeshi
T
Kato
Takeo
T
Ogasawara
Kazumasa
K
Hirano
Asao
A
Takumi
Toru
T
Kusaka
Hirofumi
H
Hagiwara
Koichi
K
Kaji
Ryuji
R
Kawakami
Hideshi
H
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
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