Human Molecular Genetics, Vol 7, 2045-2050, Copyright © 1998 by Oxford University Press
A Al-Chalabi, PM Andersen, B Chioza, C Shaw, PC Sham, W Robberecht, G Matthijs, W Camu, SL Marklund, L Forsgren, G Rouleau, NG Laing, PV Hurse, T Siddique, PN Leigh and JF Powell
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.
ARTICLES
Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor
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
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