title: Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegeneration resulting in paralysis and death from respiratory failure within 3-5 years. About 20% of familial cases are associated with mutations in the gene for copper/zinc superoxide dismutase ( SOD1 ), which catalyses the dismutation of the superoxide radical to hydrogen peroxide and oxygen. Experimental evidence suggests mutations act by a toxic gain of function but the mechanism is unknown. There are >60 known SOD1 mutations associated with ALS and all are dominant except for one in exon 4, a D90A substitution which is recessive. D90A pedigrees with dominant inheritance have now been reported and this apparent contradiction needs to be explained. We performed a worldwide haplotype study on 28 D90A pedigrees using six highly polymorphic microsatellite markers. We now show that all 20 recessive families share the same founder (alpha = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (alpha = 0.385). This finding confirms that D90A can act in a dominant fashion in keeping with all other SOD1 mutations, but that on one occasion, a new instance of this mutation has been recessive. We propose a tightly linked protective factor which modifies the toxic effect of mutant SOD1 in recessive families.
authors.affiliation: Departments of Neuroscience and Clinical Neurosciences, Institute of Psychiatry and King's College School of Medicine and Dentistry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. ammar@iop.bpmf.ac.uk
authors.forename: A
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: P M
authors.initials: PM
authors.lastname: Andersen
authors.forename: B
authors.initials: B
authors.lastname: Chioza
authors.forename: C
authors.initials: C
authors.lastname: Shaw
authors.forename: P C
authors.initials: PC
authors.lastname: Sham
authors.forename: W
authors.initials: W
authors.lastname: Robberecht
authors.forename: G
authors.initials: G
authors.lastname: Matthijs
authors.forename: W
authors.initials: W
authors.lastname: Camu
authors.forename: S L
authors.initials: SL
authors.lastname: Marklund
authors.forename: L
authors.initials: L
authors.lastname: Forsgren
authors.forename: G
authors.initials: G
authors.lastname: Rouleau
authors.forename: N G
authors.initials: NG
authors.lastname: Laing
authors.forename: P V
authors.initials: PV
authors.lastname: Hurse
authors.forename: T
authors.initials: T
authors.lastname: Siddique
authors.forename: P N
authors.initials: PN
authors.lastname: Leigh
authors.forename: J F
authors.initials: JF
authors.lastname: Powell
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D005190:Family; D005192:Family Health; D005260:Female; D018703:Founder Effect; D005808:Genes, Recessive; D008040:Genetic Linkage; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1