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New gene identified for inherited form of ALS
Edward R. Winstead

Two teams of researchers have identified the gene whose mutation causes an inherited form of the neurodegenerative disorder ALS, or amyotrophic lateral sclerosis. They discovered the gene, called ALS2, by analyzing DNA from families in Saudi Arabia, Tunisia, and Kuwait, where this very rare form of the disorder occurs.

The first gene for an inherited form of ALS was identified in 1993. Mutant forms of this gene, SOD1, account for only 20 percent of inherited ALS cases.

"The field has been keenly awaiting a 'new' ALS gene, with all the attendant opportunities for elucidating key pathways for motor neuron injury," writes Pamela J. Shaw, of the University of Sheffield, U.K., in a News and Views article that accompanies the findings in Nature Genetics. "We now have two genes that are expressed in many cell types and yet cause a highly selective clinical syndrome of motor system failure."

The ALS2 gene is expressed in neurons throughout the brain and spinal cord, making it a strong candidate to play a role in ALS. The research team led by Joh-E Ikeda, of Tokai University School of Medicine, in Japan, has isolated the mouse counterpart to ALS2. The next step is to disrupt the gene in mice in order to study its biological function. Genetic 'knockout' studies in animals have not been possible with SOD1, because mutations in that gene cause more activity in the cell rather than less.

Mutations in ALS2 cause juvenile ALS, which starts before age 25 and tends to progress more slowly than classical ALS—a disease of middle and later life. ALS causes the progressive loss of motor control over limbs and facial muscles, and is usually fatal within several years of the onset of symptoms. Most cases of ALS, like the one that killed the baseball player Lou Gehrig, develop 'spontaneously' and do not run in families.

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Hadano, S. et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 29, 166-173 (October 2001).
Shaw, P.J. Genetic inroads in familial ALS. Nat Genet 29, 103-104 (October 2001).
Yang, Y. et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 29, 160-165 (October 2001).

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