Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration.
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.
Simpson
Claire L
CL
Department of Neurology, King's College London, London SE5 8AF, UK.
Lemmens
Robin
R
Miskiewicz
Katarzyna
K
Broom
Wendy J
WJ
Hansen
Valerie K
VK
van Vught
Paul W J
PW
Landers
John E
JE
Sapp
Peter
P
Van Den Bosch
Ludo
L
Knight
Joanne
J
Neale
Benjamin M
BM
Turner
Martin R
MR
Veldink
Jan H
JH
Ophoff
Roel A
RA
Tripathi
Vineeta B
VB
Beleza
Ana
A
Shah
Meera N
MN
Proitsi
Petroula
P
Van Hoecke
Annelies
A
Carmeliet
Peter
P
Horvitz
H Robert
HR
Leigh
P Nigel
PN
Shaw
Christopher E
CE
van den Berg
Leonard H
LH
Sham
Pak C
PC
Powell
John F
JF
Verstreken
Patrik
P
Brown
Robert H
RH
Robberecht
Wim
W
Al-Chalabi
Ammar
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D044465:White People / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
D009419:Nerve Tissue Proteins; C538730:ELP3 protein, Drosophila; C538729:ELP3 protein, human; C538731:ELP3 protein, zebrafish; D051548:Histone Acetyltransferases