論文 - 詳細
| RRC ID | 5630 |
|---|---|
| 著者 | Simpson CL, Lemmens R, Miskiewicz K, Broom WJ, Hansen VK, van Vught PW, Landers JE, Sapp P, Van Den Bosch L, Knight J, Neale BM, Turner MR, Veldink JH, Ophoff RA, Tripathi VB, Beleza A, Shah MN, Proitsi P, Van Hoecke A, Carmeliet P, Horvitz HR, Leigh PN, Shaw CE, van den Berg LH, Sham PC, Powell JF, Verstreken P, Brown RH Jr, Robberecht W, Al-Chalabi A. |
| タイトル | Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. |
| ジャーナル | Hum Mol Genet |
| 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. |
| 巻・号 | 18(3) |
| ページ | 472-81 |
| 公開日 | 2009-2-1 |
| DOI | 10.1093/hmg/ddn375 |
| PII | ddn375 |
| PMID | 18996918 |
| PMC | PMC2638803 |
| MeSH | 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* Whites / genetics Zebrafish / genetics Zebrafish / metabolism |
| IF | 5.101 |
| 引用数 | 179 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY GENETICS & HEREDITY |
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
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