DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4)

• Published in: American journal of human genetics Vol. 74; no. 6; pp. 1128 - 1135
• Main Authors: Chen, Ying-Zhang, Bennett, Craig L., Huynh, Huy M., Blair, Ian P., Puls, Imke, Irobi, Joy, Dierick, Ines, Abel, Annette, Kennerson, Marina L., Rabin, Bruce A., Nicholson, Garth A., Auer-Grumbach, Michaela, Wagner, Klaus, De Jonghe, Peter, Griffin, John W., Fischbeck, Kenneth H., Timmerman, Vincent, Cornblath, David R., Chance, Phillip F.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.06.2004; University of Chicago Press; The American Society of Human Genetics
• Subjects: Adolescent; Adult; Age of Onset; Aged; Aged, 80 and over; Amino Acid Sequence; Amyotrophic Lateral Sclerosis - genetics; Animals; Autopsy; Base Sequence; Biological and medical sciences; Child; Chromosome Mapping; Chromosomes, Human, Pair 9 - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA - genetics; DNA Helicases; Female; Genes, Dominant; Genetic Linkage; Humans; Hybrid Cells; Male; Medical sciences; Mice; Molecular Sequence Data; Multifunctional Enzymes; Mutation, Missense - genetics; Neurology; Pedigree; RNA Helicases - genetics; Sequence Homology, Amino Acid; Nervous system diseases; Gene; RNA; DNA; Central nervous system disease; Amyotrophic lateral sclerosis; Degenerative disease; Mutation; Spinal cord disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/421054

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.