Recessive amyotrophic lateral sclerosis families with the D90A SOD1 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, John F. Powell

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)2045-2050
Number of pages6
JournalHuman molecular genetics
Volume7
Issue number13
DOIs
StatePublished - Dec 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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