title: [Identification of a new causative gene of amyotrophic lateral sclerosis; optineurin].
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. ALS patients die within 3 to 5 years without respiratory support. Detecting the causing gene is necessary to elucidate ALS. We identified mutations of optineurin (OPTN) in 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. Cell transfection experiments showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B. The missense mutation revealed a cytoplasmic distribution different from that of the wild type. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic retention, and Golgi fragmentation was identified in 70% of the anterior horn cells. TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also immunolabelled with anti-OPTN antibodies. Furthermore, optineurin is co-localized with fused in sarcoma (FUS) in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. Our findings suggest that OPTN is involved in the great part of pathogenesis of ALS.
authors.affiliation: Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maruyama
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D003241:Consanguinity; D005091:Exons / Q000235:genetics; D006801:Humans; D026901:Membrane Transport Proteins; D020125:Mutation, Missense; D016328:NF-kappa B; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D035582:Transcription Factor TFIIIA / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000502:physiology
chemical_list: D001323:Autoantibodies; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D026901:Membrane Transport Proteins; D016328:NF-kappa B; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA