Duplications (extra copies) of the SMN1 gene are a "major" risk factor for developing sporadic (noninherited) ALS (amyotrophic lateral sclerosis), a team of scientists based in the Netherlands and United Kingdom has reported.
The SMN1 gene also is implicated in the motor neuron disease spinal muscular atrophy (SMA). Deletions or mutations in the SMN1 gene (SMN stands for "survival of motor neurons") lead to a deficiency of SMN protein and are the underlying cause of SMA.
ALS and SMA both are diseases in which muscle-controlling nerve cells called motor neurons degenerate and die, leading to profound muscle weakness and, eventually, paralysis.
The research team, including corresponding author L.H. van den Berg at the University Medical Center Utrecht in Utrecht, the Netherlands, described its findings online Feb. 8, 2012, in Neurology. (See SMN1 gene duplications are associated with sporadic ALS.)
Further research is needed to determine how SMN1 gene duplications raise the risk of developing ALS, and any potential for SMN1-based ALS biological markers (biomarkers) or therapies.
Researchers examined copy numbers of SMN1 and the similar SMA-associated gene SMN2 in 847 people with confirmed sporadic ALS and in 984 people without the disease. They found that the risk of developing ALS in those with SMN1 duplications (three copies) was approximately double that of people without the duplications. (The odds of developing ALS over a lifetime are 1 in 350 for men, and 1 in 450 for women.)
There was no effect on disease susceptibility for those with only one copy of the SMN1 gene, and no correlation between SMN2 copy number and ALS risk.
The investigators also studied 814 people from the original group with confirmed ALS to determine whether SMN1 or SMN2 copy number has an effect on disease onset or progression. Results showed that neither deletions nor duplications of SMN1 or SMN2 had any effect on survival time or age at onset in sporadic ALS.
The mechanism by which SMN1 duplications increase the risk of sporadic ALS currently is unknown, but the study team proposed a number of possible explanations, including:
For more on the mechanism by which SMN1 duplications might cause susceptibility to ALS, read More can be less: SMN1 gene duplications are associated with sporadic ALS, also published Feb. 8, in Neurology (fee required).
Further study is needed to determine how extra copies of SMN1 increase the risk of developing sporadic ALS. In the meantime, the identification of the risk factor provides the opportunity for genetic testing to determine ALS risk or help speed diagnosis.
The new findings also provide scientists with potential targets and additional avenues to pursue in the development of ALS therapies.