MDA RESEARCHERS IDENTIFY SECOND GENE IN ALS

TUCSON, Ariz., Oct. 3, 2001 -- Two groups of scientists funded by the Muscular Dystrophy Association have found a new gene linked to amyotrophic lateral sclerosis (ALS) -- a discovery that identifies the second known cause of the fatal, poorly understood disease.

ALS, also known as Lou Gehrig's disease, kills muscle-controlling nerve cells (motor neurons) in the spinal cord and brain, eventually leading to paralysis and respiratory failure. Most of the time, ALS has no obvious cause, but it's genetic in about 10 percent of cases.

Until now, defects in the SOD1 gene on chromosome 21 were the only known cause of ALS. But today, two scientific teams report that defects in a previously unknown gene on chromosome 2 cause a rare form of ALS called ALS2. The finding may provide an important new clue to the ALS disease process.

"Knowing so little about what causes ALS has severely hindered the development of effective therapies. These two studies on ALS2 may lead to general insights about ALS and how to treat it," said Sharon Hesterlee, director of Research Development for MDA, which has the largest ALS research and services program of any voluntary health agency in the country.

Typically, ALS strikes during adulthood and leads to death three to five years after diagnosis. This "classic" form of ALS claimed the life of baseball legend Lou Gehrig, and currently affects about 30,000 people in the United States.

ALS2 -- also called autosomal recessive juvenile ALS type 3 -- affects a smaller number of people, mostly in Northern Africa and the Middle East. It manifests around 12 years of age and advances slowly over many years.

Despite those differences, classic ALS and ALS2 share many symptoms and may share a common disease process, according to the scientists who conducted the new studies.

The two teams present back-to-back articles in today's issue of Nature Genetics. The first team was led by Teepu Siddique, director of the MDA/ALS Center at Northwestern University in Chicago. The second team was led by Joh-E Ikeda of Tokai University in Japan, in collaboration with Michael Hayden of the University of British Columbia and Guy Rouleau of McGill University and Montreal General Hospital in Canada.

Siddique and Rouleau were part of the MDA-funded group that identified ALS-causing defects in the SOD1 gene in 1993.

"With the discovery of this new gene, we get a more complete view of ALS," Rouleau said. "It's another piece of the puzzle of how the disease kills motor neurons."

Surprisingly, the studies also implicate the gene in a juvenile form of primary lateral sclerosis (PLS). PLS destroys a subset of the motor neurons killed in ALS and ALS2, leading mostly to spasticity (a loss of fluid movement).

"Before, there were two views," said Afif Hentati, a neurogeneticist on Siddique's team. "People either thought PLS was the same disease as ALS or a separate condition. Our results favor the view that PLS and ALS are a single disease entity."

Defects in the new gene, which the teams have agreed to call ALS2, probably cause a loss of function of a protein that Siddique's group has dubbed "alsin."

The researchers have yet to determine how alsin deficiency leads to ALS, but they've identified the mouse version of the ALS2 gene, and plan to create and study mice in which the gene is deleted.

MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education.

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