Dc. Rubinsztein et al., GENOTYPES AT THE GLUR6 KAINATE RECEPTOR LOCUS ARE ASSOCIATED WITH VARIATION IN THE AGE-OF-ONSET OF HUNTINGTON-DISEASE, Proceedings of the National Academy of Sciences of the United Statesof America, 94(8), 1997, pp. 3872-3876
Huntington disease (HD) is associated with abnormal expansions of a CA
G repeat close to the 5' end of the IT15 gene. We have assembled a set
of 293 HD subjects whose ages of onset were known and sized their HD
CAG repeats. These repeats accounted for 69% of the variance of age of
onset when we used the most parsimonious model, which relates the log
arithm of age of onset to a function of CAG repeat number. Since other
familial factors have been proposed to influence the age of onset of
HD, we have examined a number of candidate loci. The CAG repeat number
on normal chromosomes, the Delta 2642 polymorphism in the HD gene, an
d apolipoprotein E genotypes did not affect the age of onset of HD. Al
though mitochondrial energy production defects in HD have led to sugge
stions that variants in the mitochondrial genome mag be associated wit
h clinical variability in HD, this suggestion was not supported by our
preliminary experiments that examined the DdeI mitochondrial restrict
ion fragment length polymorphism at position 10,394. Excitotoxicity ha
s been a favored mechanism to explain the cell death in HD, particular
ly since intrastriatal injection of excitatory amino acids in animals
creates HD-like pathology. Accordingly, we investigated the GluR6 kain
ate receptor. Of the variance in the age of onset of HD that was not a
ccounted for by the CAG repeats, 13% could be attributed to GluR6 geno
type variation. These data implicate GluR6-mediated excitotoxicity in
the pathogenesis of HD and highlight the potential importance of this
process in other polyglutamine repeat expansion diseases.