title: Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration.
abstract: Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P=1.96 x 10(-9)). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: -0.49, P=1.83 x 10(-12) (start codon morpholino) and -0.46, P=4.05 x 10(-9) (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P=0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.
authors.affiliation: Department of Neurology, King's College London, London SE5 8AF, UK.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Simpson
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Miskiewicz
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Broom
authors.forename: Valerie K
authors.initials: VK
authors.lastname: Hansen
authors.forename: Paul W J
authors.initials: PW
authors.lastname: van Vught
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.forename: Peter
authors.initials: P
authors.lastname: Sapp
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Joanne
authors.initials: J
authors.lastname: Knight
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Martin R
authors.initials: MR
authors.lastname: Turner
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Vineeta B
authors.initials: VB
authors.lastname: Tripathi
authors.forename: Ana
authors.initials: A
authors.lastname: Beleza
authors.forename: Meera N
authors.initials: MN
authors.lastname: Shah
authors.forename: Petroula
authors.initials: P
authors.lastname: Proitsi
authors.forename: Annelies
authors.initials: A
authors.lastname: Van Hoecke
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D044465:White People / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; C538730:ELP3 protein, Drosophila; C538729:ELP3 protein, human; C538731:ELP3 protein, zebrafish; D051548:Histone Acetyltransferases