DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).
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.
Chen
Ying-Zhang
YZ
Division of Genetics and Developmental Medicine, University of Washington, Seattle, WA 98195, USA.
Bennett
Craig L
CL
Huynh
Huy M
HM
Blair
Ian P
IP
Puls
Imke
I
Irobi
Joy
J
Dierick
Ines
I
Abel
Annette
A
Kennerson
Marina L
ML
Rabin
Bruce A
BA
Nicholson
Garth A
GA
Auer-Grumbach
Michaela
M
Wagner
Klaus
K
De Jonghe
Peter
P
Griffin
John W
JW
Fischbeck
Kenneth H
KH
Timmerman
Vincent
V
Cornblath
David R
DR
Chance
Phillip F
PF
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001344:Autopsy; D001483:Base Sequence; D002648:Child; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004265:DNA Helicases; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D006822:Hybrid Cells; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D064251:Multifunctional Enzymes; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D020365:RNA Helicases / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D064251:Multifunctional Enzymes; D004247:DNA; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases