title: C9ORF72 and UBQLN2 mutations are causes of amyotrophic lateral sclerosis in New Zealand: a genetic and pathologic study using banked human brain tissue.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which causes progressive and eventually fatal loss of motor function. Here, we describe genetic and pathologic characterization of brain tissue banked from 19 ALS patients over nearly 20 years at the Department of Anatomy and the Centre for Brain Research, University of Auckland, New Zealand. We screened for mutations in SOD1, TARDBP, FUS, and C9ORF72 genes and for neuropathology caused by phosphorylated TDP-43, dipeptide repeats (DPRs), and ubiquilin. We identified 2 cases with C9ORF72 repeat expansions. Both harbored phosphorylated TDP-43 and DPR inclusions. We show that DPR inclusions can incorporate or occur independently of ubiquilin. We also identified 1 case with a UBQLN2 mutation, which showed phosphorylated TDP-43 and characteristic ubiquilin protein inclusions. This is the first study of ALS genetics in New Zealand, adding New Zealand to the growing list of countries in which C9ORF72 repeat expansion and UBQLN2 mutations are detected in ALS cases.
authors.affiliation: Centre for Brain Research, University of Auckland, Auckland, New Zealand; Department of Pharmacology, University of Auckland, Auckland, New Zealand. Electronic address: emma.scotter@auckland.ac.nz.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Scotter
authors.affiliation: Centre for Brain Research, University of Auckland, Auckland, New Zealand; Department of Pharmacology, University of Auckland, Auckland, New Zealand.
authors.forename: Leon
authors.initials: L
authors.lastname: Smyth
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: J Ames W T
authors.initials: JAWT
authors.lastname: Bailey
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Wong
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: de Majo
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Vance
authors.affiliation: Department of Anatomical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Beth J
authors.initials: BJ
authors.lastname: Synek
authors.affiliation: Department of Anatomical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Clinton
authors.initials: C
authors.lastname: Turner
authors.affiliation: Centre for Brain Research, University of Auckland, Auckland, New Zealand; Department of Neurology, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pereira
authors.affiliation: Department of Neurology, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Alison
authors.initials: A
authors.lastname: Charleston
authors.affiliation: Centre for Brain Research, University of Auckland, Auckland, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Waldvogel
authors.affiliation: Centre for Brain Research, University of Auckland, Auckland, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand.
authors.forename: Maurice A
authors.initials: MA
authors.lastname: Curtis
authors.affiliation: Centre for Brain Research, University of Auckland, Auckland, New Zealand; Department of Pharmacology, University of Auckland, Auckland, New Zealand.
authors.forename: Mike
authors.initials: M
authors.lastname: Dragunow
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.affiliation: Centre for Brain Research, University of Auckland, Auckland, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand.
authors.forename: Richard L M
authors.initials: RLM
authors.lastname: Faull
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000071183:Autophagy-Related Proteins; D001921:Brain / Q000473:pathology*; D000073885:C9orf72 Protein / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009520:New Zealand; D014452:Ubiquitins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D018797:Cell Cycle Proteins; C405662:UBQLN2 protein, human; D014452:Ubiquitins
keywords: Amyotrophic lateral sclerosis; Brain bank; C9ORF72; Motor neurone disease; TARDBP; Ubiquilin