Human Molecular Genetics Advance Access originally published online on November 7, 2008
Human Molecular Genetics 2009 18(3):472-481; doi:10.1093/hmg/ddn375
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Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration
1 Department of Neurology 2 Department of Neuroscience, MRC Centre for Neurodegeneration Research 3 MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London SE5 8AF, UK 4 Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium 5 Vesalius Research Center, Flanders Institute for Biotechnology (VIB) 6 Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium 7 Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium 8 Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA 9 Department of Neurology 10 Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands 11 Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA 12 Neuropsychiatric Institute, University of California, Los Angeles, CA, USA 13 Department of Psychiatry and Genome Centre, University of Hong Kong, Hong Kong
* To whom correspondence should be addressed at: MRC Centre for Neurodegeneration Research, King’s College London, Institute of Psychiatry P 043, London SE5 8AF, UK. Tel: +44 2078485172; Fax: +44 2078485190; Email: ammar{at}iop.kcl.ac.uk
Received September 7, 2008; Revised October 14, 2008; Accepted November 4, 2008
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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