Mutations of optineurin in amyotrophic lateral sclerosis

Nature. 2010 May 13;465(7295):223-6. doi: 10.1038/nature08971. Epub 2010 Apr 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Asian People
  • Base Sequence
  • Cell Cycle Proteins
  • Child
  • Codon, Nonsense / genetics
  • Consanguinity
  • Cytoplasm / metabolism
  • Cytoplasm / pathology
  • DNA-Binding Proteins / metabolism
  • Exons / genetics
  • Female
  • Humans
  • Japan
  • Male
  • Membrane Transport Proteins
  • Middle Aged
  • Mutant Proteins / analysis
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • NF-kappa B / agonists
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics
  • Protein Transport
  • Sequence Deletion / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Transcription Factor TFIIIA / analysis
  • Transcription Factor TFIIIA / chemistry
  • Transcription Factor TFIIIA / genetics*
  • Transcription Factor TFIIIA / metabolism
  • Young Adult

Substances

  • Cell Cycle Proteins
  • Codon, Nonsense
  • DNA-Binding Proteins
  • Membrane Transport Proteins
  • Mutant Proteins
  • NF-kappa B
  • OPTN protein, human
  • SOD1 protein, human
  • Transcription Factor TFIIIA
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1