Identification of New Gene Boosts ALS Research

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
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.

Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001 Oct;29(2):166-73. Abstract

Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T. 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. Abstract

Shaw PJ. Genetic inroads in familial ALS. Nat Genet 2001 Oct;29(2):103-4. Abstract

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