SMN1 gene duplications are associated with sporadic ALS.
OBJECTIVE
To investigate the role of SMN1 and SMN2 copy number variation and point mutations in amyotrophic lateral sclerosis (ALS) pathogenesis in a large population.


METHODS
We conducted a genetic association study including 847 patients with ALS and 984 controls. We used multiplexed ligation-dependent probe amplification (MLPA) assays to determine SMN1 and SMN2 copy numbers and examined effects on disease susceptibility and disease course. Furthermore, we sequenced SMN genes to determine if SMN mutations were more prevalent in patients with ALS. A meta-analysis was performed with results from previous studies.


RESULTS
SMN1 duplications were associated with ALS susceptibility (odds ratio [OR] 2.07, 95% confidence interval [CI] 1.34-3.20, p = 0.001). A meta-analysis with previous data including 3,469 individuals showed a similar effect: OR 1.85, 95% CI 1.18-2.90, p = 0.008). SMN1 deletions and SMN2 copy number status were not associated with ALS. SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease. We found no enrichment of SMN point mutations in patients with ALS.


CONCLUSIONS
Our data provide firm evidence for a role of common SMN1 duplications in ALS, and raise new questions regarding the disease mechanisms involved.
Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
H M
HM
Blauw
C P
CP
Barnes
P W J
PW
van Vught
W
W
van Rheenen
M
M
Verheul
E
E
Cuppen
J H
JH
Veldink
L H
LH
van den Berg
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020440:Gene Duplication / Q000235:genetics* / Q000502:physiology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D009426:Netherlands / Q000453:epidemiology; D016017:Odds Ratio; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
D009419:Nerve Tissue Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein