THURSDAY, Oct. 4, 2001 (HealthDayNews) -- A rare form of Lou Gehrig's disease that only strikes young people has been linked to a specific gene that clips a certain protein's vital areas, effectively deactivating it, scientists say.
Two international teams of researchers working independently discovered the second gene, now known to be related to amyotrophic lateral sclerosis. ALS is a progressive neurodegenerative disease that causes muscle weakness, impaired movement and, ultimately, paralysis and death. The studies appear in the October issue of the journal Nature Genetics.
The new gene, called ALS2CR6, is linked to a form of the disease called autosomal recessive juvenile ALS2. Like the more common form of ALS, this variant also damages nerve cells that control movement. Understanding this gene could lead researchers to a common pathway that causes nerve cell death in other forms of ALS.
In 1993, researchers identified the SOD1 gene as the cause for about 20 percent of all cases of the disease. ALS, which affects about 20,000 Americans, is also known as Lou Gehrig's disease, named for the legendary New York Yankees player who died of the disorder in 1941.
As the disease runs its course, nerve cells that control muscles die and the muscles waste away until the person can no longer speak, swallow or breathe, yet remains mentally sharp.
In most cases, patients survive for three to five years after diagnosis, although some can live as long as 10 years. The average age at which people develop ALS is 55.
But in ALS2, the disorder generally surfaces around the age of 12 and before the age of 25. This variant is most commonly found in North African and Middle Eastern populations.
A mutation that turns off the ALS2CR6 gene, which is found in nerve cells throughout the brain and spinal cord, is probably linked to this form of ALS.
The first paper, by Japanese, Canadian, Israeli, American and British authors, identified the gene in a Tunisian family and a Kuwaiti family. According to co-investigator Dr. Guy Rouleau, the ALS2CR6 gene normally produces a protein, which is tentatively being called "alsin." The mutation appears to shorten the protein, removing regions that are crucial to how it works.
"The gene is inactivated," says Rouleau, a professor at the Centre for Research in Neuroscience at McGill University in Montreal, Quebec. "The mutation is a very early, severe mutation that we can [speculate] prevents the resultant protein from having any of its normal function."
"The disease is familial, and it's recessive," he notes. In other words, in order to develop ALS2, a person must inherit an inactive copy of the gene from both parents.
The second paper, by American, Saudi Arabian and Tunisian researchers, looked at mutations in the same gene in two unrelated Saudi Arabian families.
Lucie Bruijn, the science director of the ALS Association, says that this is another crucial piece of the ALS puzzle. "The discovery of a second gene is so important because we might be able to start to put all the pieces together to really understand the disease mechanism," she says.
The researchers can't yet say for certain exactly how the gene plays a role in ALS2. But they speculate that if the gene doesn't work, that interferes with the regulation or activation of other proteins that control the structure and transport mechanisms inside cells.
"That's very important, because a lot of the evidence has pointed to abnormalities in the [cell's outer structure] as being involved in this disease," says Rouleau.
Bruijn says that, although more information is needed, "we know that all these functions are extremely important in the maintenance of a motor neuron."
She adds that the next step will be the creation of a genetically engineered mouse in which the ALS2CR6 gene can be deactivated in certain cells, which would show researchers exactly what the alsin protein does.
Although juvenile ALS2 is extremely rare, the research teams hope that discovering the exact function of alsin could shed light on the mechanisms that lead to the inherited and sporadic forms of ALS. Ultimately, says Rouleau, those discoveries could lead to new therapies for the many variants of this disease.
What To Do
Unfortunately, says Bruijn, the findings don't mean much in a practical sense right now. "[But] the note of hope for patients is that we are that much further to whole new avenues of ALS research," she says. "There will be a lot of groups working just to understand how this works, and it may then become a target for therapy."
For information about ALS, visit the ALS Survival Guide or the Web sites for the ALS Association or the National Institute of Neurological Disorders and Stroke.
