Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor

Al-Chalabi, A.; Andersen, P.M.; Chioza, B.; Shaw, C.; Sham, P.C.; Robberecht, W.; Matthijs, G.; Camu, W.; Marklund, S.L.; Forsgren, L.; Rouleau, G.; Laing, N.G.; Hurse, P.V.; Siddique, T.; Leigh, P.N.; Powell, J.F.

Human Molecular Genetics 7(13): 2045-2050


ISSN/ISBN: 0964-6906
PMID: 9817920
DOI: 10.1093/hmg/7.13.2045
Accession: 011253457

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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.