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Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration

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Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. / Simpson, Claire L.; Lemmens, Robin; Miskiewicz, Katarzyna et al.
In: Human Molecular Genetics, Vol. 18, No. 3, 01.02.2009, p. 472-481.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Simpson, CL, Lemmens, R, Miskiewicz, K, Broom, WJ, Hansen, VK, van Vught, PWJ, 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, Robberecht, W & Al-Chalabi, A 2009, 'Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration', Human Molecular Genetics, vol. 18, no. 3, pp. 472-481. https://doi.org/10.1093/hmg/ddn375

APA

Simpson, C. L., Lemmens, R., Miskiewicz, K., Broom, W. J., Hansen, V. K., van Vught, P. W. J., 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., ... 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. https://doi.org/10.1093/hmg/ddn375

Vancouver

Simpson CL, Lemmens R, Miskiewicz K, Broom WJ, Hansen VK, van Vught PWJ et al. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Human Molecular Genetics. 2009 Feb 1;18(3):472-481. Epub 2008 Nov 7. doi: 10.1093/hmg/ddn375

Author

Simpson, Claire L. ; Lemmens, Robin ; Miskiewicz, Katarzyna et al. / Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 3. pp. 472-481.

Bibtex

@article{4610ca6912fb4f4db77207c3a8e75020,
title = "Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration",
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.",
keywords = "Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Animals, Drosophila, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genetic Variation, Histone Acetyltransferases, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Motor Neurons, Mutation, Nerve Tissue Proteins, Zebrafish",
author = "Simpson, {Claire L.} and Robin Lemmens and Katarzyna Miskiewicz and Broom, {Wendy J.} and Hansen, {Valerie K.} and {van Vught}, {Paul W. J.} and Landers, {John E.} and Peter Sapp and {Van Den Bosch}, Ludo and Joanne Knight and Neale, {Benjamin M.} and Turner, {Martin R.} and Veldink, {Jan H.} and Ophoff, {Roel A.} and Tripathi, {Vineeta B.} and Ana Beleza and Shah, {Meera N.} and Petroula Proitsi and {Van Hoecke}, Annelies and Peter Carmeliet and Horvitz, {H. Robert} and Leigh, {P. Nigel} and Shaw, {Christopher E.} and {van den Berg}, {Leonard H.} and Sham, {Pak C.} and Powell, {John F.} and Patrik Verstreken and Brown, {Robert H.} and Wim Robberecht and Ammar Al-Chalabi",
year = "2009",
month = feb,
day = "1",
doi = "10.1093/hmg/ddn375",
language = "English",
volume = "18",
pages = "472--481",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "3",

}

RIS

TY - JOUR

T1 - Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration

AU - Simpson, Claire L.

AU - Lemmens, Robin

AU - Miskiewicz, Katarzyna

AU - Broom, Wendy J.

AU - Hansen, Valerie K.

AU - van Vught, Paul W. J.

AU - Landers, John E.

AU - Sapp, Peter

AU - Van Den Bosch, Ludo

AU - Knight, Joanne

AU - Neale, Benjamin M.

AU - Turner, Martin R.

AU - Veldink, Jan H.

AU - Ophoff, Roel A.

AU - Tripathi, Vineeta B.

AU - Beleza, Ana

AU - Shah, Meera N.

AU - Proitsi, Petroula

AU - Van Hoecke, Annelies

AU - Carmeliet, Peter

AU - Horvitz, H. Robert

AU - Leigh, P. Nigel

AU - Shaw, Christopher E.

AU - van den Berg, Leonard H.

AU - Sham, Pak C.

AU - Powell, John F.

AU - Verstreken, Patrik

AU - Brown, Robert H.

AU - Robberecht, Wim

AU - Al-Chalabi, Ammar

PY - 2009/2/1

Y1 - 2009/2/1

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Amyotrophic Lateral Sclerosis

KW - Animals

KW - Drosophila

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Histone Acetyltransferases

KW - Humans

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Middle Aged

KW - Motor Neurons

KW - Mutation

KW - Nerve Tissue Proteins

KW - Zebrafish

U2 - 10.1093/hmg/ddn375

DO - 10.1093/hmg/ddn375

M3 - Journal article

C2 - 18996918

VL - 18

SP - 472

EP - 481

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 3

ER -