Publication Date:
2010-04-30
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- England -- Nature. 2010 May 13;465(7295):223-6. doi: 10.1038/nature08971. Epub 2010 Apr 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20428114" target="_blank"〉PubMed〈/a〉
Keywords:
Adolescent
;
Adult
;
Aged
;
Aged, 80 and over
;
Amino Acid Sequence
;
Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology/physiopathology
;
Asian Continental Ancestry Group
;
Base Sequence
;
Child
;
Codon, Nonsense/genetics
;
Consanguinity
;
Cytoplasm/metabolism/pathology
;
DNA-Binding Proteins/metabolism
;
Exons/genetics
;
Female
;
Humans
;
Japan
;
Male
;
Middle Aged
;
Mutant Proteins/analysis/chemistry/genetics/metabolism
;
Mutation/*genetics
;
Mutation, Missense/genetics
;
NF-kappa B/agonists/antagonists & inhibitors/metabolism
;
Pedigree
;
Polymorphism, Single Nucleotide/genetics
;
Protein Transport
;
Sequence Deletion/genetics
;
Superoxide Dismutase/metabolism
;
Transcription Factor TFIIIA/analysis/chemistry/*genetics/metabolism
;
Young Adult
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
