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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7295
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pubmed:dateCreated |
2010-5-13
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pubmed:abstractText |
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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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Codon, Nonsense,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mutant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/OPTN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Superoxide Dismutase,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor TFIIIA,
http://linkedlifedata.com/resource/pubmed/chemical/protein TDP-43,
http://linkedlifedata.com/resource/pubmed/chemical/superoxide dismutase 1
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1476-4687
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pubmed:author |
pubmed-author:AokiMasashiM,
pubmed-author:HagiwaraKoichiK,
pubmed-author:HiraiTakeshiT,
pubmed-author:HiranoAsaoA,
pubmed-author:ItoHidefumiH,
pubmed-author:IzumiYuishinY,
pubmed-author:KajiRyujiR,
pubmed-author:KamadaMasakiM,
pubmed-author:KatoHidemasaH,
pubmed-author:KatoTakeoT,
pubmed-author:KawakamiHideshiH,
pubmed-author:KawataAkihiroA,
pubmed-author:KinoshitaYoshimiY,
pubmed-author:KnowE GEG,
pubmed-author:KobatakeKeitaroK,
pubmed-author:KomureOsamuO,
pubmed-author:KusakaHirofumiH,
pubmed-author:MaruyamaHirofumiH,
pubmed-author:MatsuuraShinyaS,
pubmed-author:MorimotoNobutoshiN,
pubmed-author:MorinoHiroyukiH,
pubmed-author:NoderaHiroyukiH,
pubmed-author:OgasawaraKazumasaK,
pubmed-author:SuzukiHidenoriH,
pubmed-author:SuzukiNaokiN,
pubmed-author:TakumiToruT,
pubmed-author:WatanabeYasuhitoY
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pubmed:issnType |
Electronic
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pubmed:day |
13
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pubmed:volume |
465
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
223-6
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pubmed:meshHeading |
pubmed-meshheading:20428114-Adolescent,
pubmed-meshheading:20428114-Adult,
pubmed-meshheading:20428114-Aged,
pubmed-meshheading:20428114-Aged, 80 and over,
pubmed-meshheading:20428114-Amino Acid Sequence,
pubmed-meshheading:20428114-Amyotrophic Lateral Sclerosis,
pubmed-meshheading:20428114-Asian Continental Ancestry Group,
pubmed-meshheading:20428114-Base Sequence,
pubmed-meshheading:20428114-Child,
pubmed-meshheading:20428114-Codon, Nonsense,
pubmed-meshheading:20428114-Consanguinity,
pubmed-meshheading:20428114-Cytoplasm,
pubmed-meshheading:20428114-DNA-Binding Proteins,
pubmed-meshheading:20428114-Exons,
pubmed-meshheading:20428114-Female,
pubmed-meshheading:20428114-Humans,
pubmed-meshheading:20428114-Japan,
pubmed-meshheading:20428114-Male,
pubmed-meshheading:20428114-Middle Aged,
pubmed-meshheading:20428114-Mutant Proteins,
pubmed-meshheading:20428114-Mutation,
pubmed-meshheading:20428114-Mutation, Missense,
pubmed-meshheading:20428114-NF-kappa B,
pubmed-meshheading:20428114-Pedigree,
pubmed-meshheading:20428114-Polymorphism, Single Nucleotide,
pubmed-meshheading:20428114-Protein Transport,
pubmed-meshheading:20428114-Sequence Deletion,
pubmed-meshheading:20428114-Superoxide Dismutase,
pubmed-meshheading:20428114-Transcription Factor TFIIIA,
pubmed-meshheading:20428114-Young Adult
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pubmed:year |
2010
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pubmed:articleTitle |
Mutations of optineurin in amyotrophic lateral sclerosis.
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pubmed:affiliation |
Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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