title: Clinical and functional investigation of 10 missense mutations and a novel frameshift insertion mutation of the gene for copper-zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis.
abstract: Mutations of the gene SOD-1, which encodes the enzyme copper-zinc superoxide dismutase, occur in patients with a familial form of amyotrophic lateral sclerosis (ALS). We investigated 71 families with more than one individual affected by ALS for clinical features and SOD-1 mutations. Mutations were identified in 14 families, indicating the presence of SOD-1 mutations in around 20% of this population. There were 10 different heterozygote missense point mutations in eight different codons, and a novel two-base frameshift insertion (132insTT), which leads to substitution of aspartic acid for glutamic acid at codon 132, and a premature stop codon at 133, with predicted truncation of the protein. SOD enzyme activity was reduced to around 50% of normal in individuals with SOD-1 mutations, and may be a useful predictor for the presence of these mutations. A predilection for disease onset in the lower limbs appears to be a distinguishing feature of familial ALS with SOD-1 mutations, and accords with findings in transgenic mouse models. In general, the finding of an SOD-1 mutation does not accurately predict a prognosis or disease severity.
authors.affiliation: Department of Biochemistry, Charing Cross and Westminster Medical School, London, England.
authors.forename: R W
authors.initials: RW
authors.lastname: Orrell
authors.forename: J J
authors.initials: JJ
authors.lastname: Habgood
authors.forename: I
authors.initials: I
authors.lastname: Gardiner
authors.forename: A W
authors.initials: AW
authors.lastname: King
authors.forename: F A
authors.initials: FA
authors.lastname: Bowe
authors.forename: R A
authors.initials: RA
authors.lastname: Hallewell
authors.forename: S L
authors.initials: SL
authors.lastname: Marklund
authors.forename: J
authors.initials: J
authors.lastname: Greenwood
authors.forename: R J
authors.initials: RJ
authors.lastname: Lane
authors.forename: J
authors.initials: J
authors.lastname: deBelleroche
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics*; D001483:Base Sequence; D003300:Copper / Q000378:metabolism*; D016368:Frameshift Mutation; D006801:Humans; D008875:Middle Aged; D017354:Point Mutation; D013482:Superoxide Dismutase / Q000235:genetics*; D015032:Zinc / Q000378:metabolism*
chemical_list: D003300:Copper; D013482:Superoxide Dismutase; D015032:Zinc