PUBLICATION
Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration
- Authors
- Simpson, C.L., Lemmens, R., Miskiewicz, K., Broom, W.J., Hansen, V.K., van Vught, P.W., Landers, J.E., Sapp, P., Van Den Bosch, L., Knight, J., Neale, B.M., Turner, M.R., Veldink, J.H., Ophoff, R.A., Tripathi, V.B., Beleza, A., Shah, M.N., Proitsi, P., Van Hoecke, A., Carmeliet, P., Horvitz, H.R., Leigh, P.N., Shaw, C.E., van den Berg, L.H., Sham, P.C., Powell, J.F., Verstreken, P., Brown, R.H. Jr, Robberecht, W., and Al-Chalabi, A.
- ID
- ZDB-PUB-081114-8
- Date
- 2009
- Source
- Human molecular genetics 18(3): 472-481 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Adult
- Aged
- Aged, 80 and over
- Amyotrophic Lateral Sclerosis/genetics*
- Amyotrophic Lateral Sclerosis/metabolism
- Animals
- Drosophila/genetics
- Drosophila/metabolism
- Female
- Genetic Predisposition to Disease
- Genetic Variation*
- Histone Acetyltransferases/genetics*
- Histone Acetyltransferases/metabolism*
- Humans
- Male
- Mice
- Mice, Transgenic
- Middle Aged
- Motor Neurons/metabolism*
- Mutation
- Nerve Tissue Proteins/genetics*
- Nerve Tissue Proteins/metabolism*
- White People/genetics
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 18996918 Full text @ Hum. Mol. Genet.
Citation
Simpson, C.L., Lemmens, R., Miskiewicz, K., Broom, W.J., Hansen, V.K., van Vught, P.W., Landers, J.E., Sapp, P., Van Den Bosch, L., Knight, J., Neale, B.M., Turner, M.R., Veldink, J.H., Ophoff, R.A., Tripathi, V.B., Beleza, A., Shah, M.N., Proitsi, P., Van Hoecke, A., Carmeliet, P., Horvitz, H.R., Leigh, P.N., Shaw, C.E., van den Berg, L.H., Sham, P.C., Powell, J.F., Verstreken, P., Brown, R.H. Jr, Robberecht, W., and Al-Chalabi, A. (2009) Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Human molecular genetics. 18(3):472-481.
Abstract
Amyotrophic lateral sclerosis is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within three 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 1,884 microsatellite markers, allelic variants of ELP3 were associated with amyotrophic lateral sclerosis in three human populations comprising 1,483 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 amyotrophic lateral sclerosis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping