Most cases of amyotrophic lateral sclerosis (ALS) have no familial history that could help researchers home in on genetic causes. About 10 percent of cases are inherited, from which five potential ALS genes have been mapped to independent chromosome regions. However, only one ALS gene, encoding a Cu-Zn superoxide dismutase (SOD1), has been identified to date, and since its discovery in 1993 (Rosen et al) progress in understanding its role in the disease has been slow.

Now a new gene has burst on the scene. Two international collaborations-one comprising scientists from the U.S., Saudi Arabia and Tunisia and led by Teepu Siddique, Northwestern University, and the other led by Joh-E Ikeda, Tokai University, Japan-report in this month's Nature Genetics that they have independently identified the gene responsible for ALS2, a juvenile-onset, familial form of the disease.

Both groups have localized the gene on chromosome 2. They show that it undergoes alternative splicing, resulting in a short and a long transcript, both widely expressed. The function of the protein is unknown, though it contains several guanine-nucleotide exchange factor domains, and regions that may be involved in membrane attachment and phosphatidylinositol signaling.

The disease phenotypes result from single or double-base pair deletion mutations, which cause truncating frameshifts. The papers report different single base-pair deletions in exon three of the gene, which reduce the protein to 49 amino acids. Ikeda's group located a double base-pair deletion in exon five, shortening the protein to 545 amino acids, and Siddique's group found a two base-pair deletion in exon nine, causing premature termination after 645 amino acids. This latter mutation occurs in families affected with juvenile primary lateral sclerosis (JPLS), providing the first molecular link between this disease, which affects only upper motor neurons, and ALS.

"This is an important advance for the field of ALS research," states Pamela Shaw of the University of Sheffield in an accompanying News & Views article. The loss of function associated with these mutations should be more amenable to study than the gain of function associated with the SOD1 mutations. "The field of ALS research is therefore at the start of a new endeavor," Shaw adds.—Tom Fagan


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Further Reading


  1. . Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4;362(6415):59-62. PubMed.

Primary Papers

  1. . A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001 Oct;29(2):166-73. PubMed.
  2. . 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. 2001 Oct;29(2):160-5. PubMed.
  3. . Genetic inroads in familial ALS. Nat Genet. 2001 Oct;29(2):103-4. PubMed.