RESEARCH: Gene for juvenile onset ALS discovered

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DNA/RNA Helicase Gene Mutations in a Form of Juvenile

Amyotrophic Lateral Sclerosis (ALS4).

Chen YZ, CL, Huynh HM, Blair IP, Puls I, Irobi

J, Dierick I, Abel A, Kennerson ML, Rabin BA,

Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P,

JW, Fischbeck KH, Timmerman V, Cornblath DR,

Chance PF.

Division of Genetics and Developmental Medicine,

Department of Pediatrics, University of Washington,

Seattle, WA, 98195, USA.

Juvenile amyotrophic lateral sclerosis (ALS4) is a

rare autosomal dominant form of juvenile amyotrophic

lateral sclerosis (ALS) characterized by distal muscle

weakness and atrophy, normal sensation, and pyramidal

signs. Individuals affected with ALS4 usually have an

onset of symptoms at age <25 years, a slow rate of

progression, and a normal life span. The ALS4 locus

maps to a 1.7-Mb interval on chromosome 9q34 flanked

by D9S64 and D9S1198. To identify the molecular basis

of ALS4, we tested 19 genes within the ALS4 interval

and detected missense mutations (T3I, L389S, and

R2136H) in the Senataxin gene (SETX). The SETX gene

encodes a novel 302.8-kD protein. Although its

function remains unknown, SETX contains a DNA/RNA

helicase domain with strong homology to human RENT1

and IGHMBP2, two genes encoding proteins known to have

roles in RNA processing. These observations of ALS4

suggest that mutations in SETX may cause neuronal

degeneration through dysfunction of the helicase

activity or other steps in RNA processing.

SOURCE: Am J Hum Genet. 2004 Apr 21;74(6). [Epub

ahead of print]

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