1. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration
- Author
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Peter C. Sapp, Annelies Van Hoecke, John Powell, Meera N. Shah, Claire L. Simpson, Valerie K. Hansen, Ludo Van Den Bosch, Pak C. Sham, John Landers, Petroula Proitsi, Vineeta B. Tripathi, Christopher Shaw, Patrik Verstreken, Robert H. Brown, Jan H. Veldink, Ammar Al-Chalabi, Paul W.J. van Vught, Roel A. Ophoff, Joanne Knight, Peter Carmeliet, Wim Robberecht, Wendy J. Broom, Ana Beleza, Leonard H. van den Berg, Robin Lemmens, P. Nigel Leigh, Martin R Turner, H. Robert Horvitz, Benjamin M. Neale, Katarzyna Miskiewicz, Massachusetts Institute of Technology. Department of Biology, Horvitz, H. Robert, and University of Groningen
- Subjects
Male ,Candidate gene ,ELONGATOR ,Morpholino ,Genome-wide association study ,SUSCEPTIBILITY ,Medical and Health Sciences ,AMYOTROPHIC-LATERAL-SCLEROSIS ,DISEASE ,Transgenic ,Mice ,MITOCHONDRIA ,80 and over ,WIDE ASSOCIATION ,Amyotrophic lateral sclerosis ,Genetics (clinical) ,Zebrafish ,Histone Acetyltransferases ,Genetics ,Aged, 80 and over ,Motor Neurons ,Genetics & Heredity ,Neurodegeneration ,General Medicine ,Articles ,Middle Aged ,Biological Sciences ,GENOME ,POOLED DNA ,Drosophila ,Female ,Adult ,European Continental Ancestry Group ,Mice, Transgenic ,Nerve Tissue Proteins ,and over ,Biology ,TARDBP ,ELP3 ,White People ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Aged ,MUTATIONS ,Amyotrophic Lateral Sclerosis ,Genetic Variation ,medicine.disease ,POLYMORPHISM ,Mutation - 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.
- Published
- 2008