title: Frameshift, nonsense and non amino acid altering mutations in SOD1 in familial ALS: report of a Japanese pedigree and literature review.
abstract: We demonstrated the clinical characteristics of each member of a family from Oki Island in western Japan, whose members have familial amyotrophic lateral sclerosis (FALS) with a 2-base pair (bp) deletion at codon 126 of Cu/Zn superoxide dismutase (SOD1) gene. Mean disease duration among the Oki family members was about 2 years. Long-term survivors with respiratory support presented disturbances in eye movement and urination toward the end stages of the disease. In addition, we focused on in-vitro instabilities in the frameshift and nonsense mutations, including the 2-bp deletion, as well as some deletional, insertional and intronic mutations. These mutations were all found within exon 4, exon 5 and intron 4. As for the durations of illness, there were no significant differences between FALS patients with these SOD1 mutations and those with point mutations, although the former cases were likely to have shorter disease durations. In cell culture experiments, SOD1 proteins with frameshift and nonsense mutations were extremely unstable and showed very short half-lives. We postulated that the in-vitro instability of the mutant SOD1 might be related to the pathogenesis of FALS, e.g. through the mechanism of copper release.
authors.affiliation: Division of Neurology, Institute of Neurological Sciences,  Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Watanabe
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: K
authors.initials: K
authors.lastname: Nakashima
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D018389:Codon, Nonsense; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D018389:Codon, Nonsense; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1