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Mutations of optineurin in amyotrophic lateral sclerosis.

Nature | May 13, 2010

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.

Pubmed ID: 20428114 RIS Download

Mesh terms: Adolescent | Adult | Aged | Aged, 80 and over | Amino Acid Sequence | Amyotrophic Lateral Sclerosis | Asian Continental Ancestry Group | Base Sequence | Child | Codon, Nonsense | Consanguinity | Cytoplasm | DNA-Binding Proteins | Exons | Female | Humans | Japan | Male | Middle Aged | Mutant Proteins | Mutation | Mutation, Missense | NF-kappa B | Pedigree | Polymorphism, Single Nucleotide | Protein Transport | Sequence Deletion | Superoxide Dismutase | Superoxide Dismutase-1 | Transcription Factor TFIIIA | Young Adult

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