title: A novel amyotrophic lateral sclerosis mutation in OPTN induces ER stress and Golgi fragmentation in vitro.
abstract: Mutations in the optineurin gene (OPTN) have been identified in a small proportion (<1%) of sporadic and familial ALS cases, and the exact role of optineurin in the pathogenesis of ALS remains unclear. To further examine the role of OPTN in ALS, we sought to identify novel ALS variants in OPTN and examine their potential for pathogenicity in vitro. Whole exome sequence data from 74 familial ALS cases were analysed for the presence of novel OPTN mutations. Pathogenicity was assessed by analysing effects on Golgi fragmentation, endoplasmic reticulum (ER) stress-linked CHOP activation, and cellular localization of optineurin in motor neuron-like NSC-34 cells expressing mutant optineurin. We identified a novel heterozygous missense mutation in OPTN (c.883G > T, p.Val295Phe) in a single familial ALS case. This mutation induced recognized cellular features of ALS pathogenesis including Golgi fragmentation and ER stress in NSC-34 cells. In conclusion, the identification of a novel OPTN mutation in an Australian ALS family, and its capacity to induce ALS-like pathological features in vitro, further strengthens evidence for the role of optineurin in the pathogenesis of ALS.
authors.affiliation: a Faculty of Medicine and Health Sciences , Macquarie University , Sydney , New South Wales , Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Fifita
authors.affiliation: a Faculty of Medicine and Health Sciences , Macquarie University , Sydney , New South Wales , Australia.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Williams
authors.affiliation: a Faculty of Medicine and Health Sciences , Macquarie University , Sydney , New South Wales , Australia.
authors.forename: Vinod
authors.initials: V
authors.lastname: Sundaramoorthy
authors.affiliation: a Faculty of Medicine and Health Sciences , Macquarie University , Sydney , New South Wales , Australia.
authors.forename: Emily P
authors.initials: EP
authors.lastname: Mccann
authors.affiliation: a Faculty of Medicine and Health Sciences , Macquarie University , Sydney , New South Wales , Australia.|b Northcott Neuroscience Laboratory , ANZAC Research Institute , Sydney , New South Wales , Australia.|c Sydney Medical School, University of Sydney , Sydney , New South Wales , Australia.|d Molecular Medicine Laboratory , Concord Hospital , Concord , New South Wales , Australia , and.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: a Faculty of Medicine and Health Sciences , Macquarie University , Sydney , New South Wales , Australia.|e Department of Biochemistry and Genetics , La Trobe Institute for Molecular Science, La Trobe University , Victoria , Australia.
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
authors.affiliation: a Faculty of Medicine and Health Sciences , Macquarie University , Sydney , New South Wales , Australia.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Blair
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001315:Australia; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005192:Family Health; D005260:Female; D006056:Golgi Apparatus / Q000235:genetics / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D009154:Mutation / Q000235:genetics*; D051742:Transcription Factor CHOP / Q000235:genetics; D035582:Transcription Factor TFIIIA / Q000235:genetics*; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; C497249:DDIT3 protein, human; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA; C485184:enhanced green fluorescent protein; D051742:Transcription Factor CHOP; D049452:Green Fluorescent Proteins
keywords: Golgi fragmentation; Optineurin; exome sequencing; mutation