Journal Article

Recessive Amyotrophic Lateral Sclerosis Families with the D90A <i>SOD1</i> Mutation Share a Common Founder: Evidence for a Linked Protective Factor

Ammar Al-Chalabi, Peter M. Andersen, Barry Chioza, Christopher Shaw, Pak C. Sham, Wim Robberecht, Gert Matthijs, William Camu, Stefan L. Marklund, Lars Forsgren, Guy Rouleau, Nigel G. Laing, P. V. Hurse, Teepu Siddique, P. Nigel Leigh and John F. Powell

in Human Molecular Genetics

Volume 7, issue 13, pages 2045-2050
Published in print December 1998 | ISSN: 0964-6906
Published online December 1998 | e-ISSN: 1460-2083 | DOI:
Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor

Show Summary Details


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 (α = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (α = 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.

Journal Article.  3748 words.  Illustrated.

Subjects: Genetics and Genomics

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