ITEM METADATA RECORD
Title: Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration
Authors: Simpson, Claire L *
Lemmens, Robin *
Miskiewicz, Katarzyna
Broom, Wendy J
Hansen, Valerie K
van Vught, Paul W. J
Landers, John E
Sapp, Peter
Van Den Bosch, Ludo
Knight, Joanne
Neale, Benjamin M
Turner, Martin R
Veldink, Jan H
Ophoff, Roel A
Tripathi, Vineeta B
Beleza, Ana
Shah, Meera N
Proitsi, Petroula
Van Hoecke, Annelies
Carmeliet, Peter
Horvitz, H. Robert
Leigh, P. Nigel
Shaw, Christopher E
van den Berg, Leonard H
Sham, Pak C
Powell, John F
Verstreken, Patrik
Brown, Robert H
Robberecht, Wim
Al-Chalabi, Ammar # ×
Issue Date: Feb-2009
Publisher: IRL Press
Series Title: Human Molecular Genetics vol:18 issue:3 pages:472-481
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.
URI: 
ISSN: 0964-6906
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vesalius Research Centre (-)
Molecular Genetics Section (-)
Clinical Residents Medicine
Research Group Experimental Neurology
Laboratory for Neurobiology (Vesalius Research Center)
Department of Human Genetics - miscellaneous
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
* (joint) first author
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Claire L. Simpson Variants of the RNA 2009.pdfmain article Published 517KbAdobe PDFView/Open Request a copy
472.full.pdfOA Article Published 590KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members

 




All items in Lirias are protected by copyright, with all rights reserved.

© Web of science