Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease

Abstract

Huntington disease (HD) is associated with abnormal expansions of a CAG 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 logarithm of age of onset to a function of CAG repeat number. Since other familial factors have been proposed to inf luence the age of onset of HD, we have examined a number of candidate loci. The CAG repeat number on normal chromosomes, the ⌬2642 polymorphism in the HD gene, and apolipoprotein E genotypes did not affect the age of onset of HD. Although mitochondrial energy production defects in HD have led to suggestions that variants in the mitochondrial genome may be associated with clinical variability in HD, this suggestion was not supported by our preliminary experiments that examined the DdeI mitochondrial restriction fragment length polymorphism at position 10,394. Excitotoxicity has been a favored mechanism to explain the cell death in HD, particularly since intrastriatal injection of excitatory amino acids in animals creates HD-like pathology. Accordingly, we investigated the GluR6 kainate receptor. Of the variance in the age of onset of HD that was not accounted for by the CAG repeats, 13% could be attributed to GluR6 genotype 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.

Linkage and association of the glutamate receptor 6 gene with autism

“…57 Finally, two independent studies have suggested that the age of onset of Huntington disease is associated with GluR6 genotype variation. 58 In conclusion, we observed an excess of allele sharing, LD, and association between GluR6 and autism. These results apparently contrast with other studies using whole genome scans, which have not found significant MLS for chromosome 6q16-23.…”

Subcellular and Subsynaptic Localization of Presynaptic and Postsynaptic Kainate Receptor Subunits in the Monkey Striatum

“…In Ͼ60% of HD patients, increasing length of CAG repeats correlates highly with a decrease in the age of onset of the disease or the extent of striatal degeneration (Persichetti et al, 1994;Aronin et al, 1995;Penney et al, 1997). However, recent findings have reported that the variance in the age of onset of HD could also be attributed to mutations in the gene encoding the GluR6 KAR subunit (Rubinsztein et al, 1997;MacDonald et al, 1999). Injections of kainic acid into the striatum have, indeed, been known to cause cell death in striatal projection neurons, but to have no such effect on axons crossing or terminating in the area (Coyle and Schwarcz, 1976;McGeer and McGeer, 1976).…”

“…In this study we tested the hypothesis that the relative abundance of K AR-containing terminals was greater in areas that are more sensitive to neurodegeneration in H D. It has, indeed, been shown that variation of the GluR6 subunit genotype is correlated with the age on onset of H D that cannot be accounted for by the number of CAG repeats (Rubinsztein et al, 1997;MacDonald et al, 1999). These observations, combined with the fact that some striatal regions are more sensitive than others to neurodegeneration, led us to consider the possibility that this particular pattern of neuronal death might be attributable to a differential distribution of K AR-containing terminals throughout the striatum.…”

Predicting clinical diagnosis in Huntington's disease: An imaging polymarker

“…Furthermore, HD is a slow progressing disease with a large variance in age of onset, especially for individuals with smaller CAG repeat lengths 4, 5. Currently, proximity to clinical diagnosis is estimated using statistical models based upon CAG repeat length and age 4, 6. However, the CAG repeat length only accounts for between 50% and 69% of the variance observed in age at diagnosis 6, 7, 8.…”

“…Currently, proximity to clinical diagnosis is estimated using statistical models based upon CAG repeat length and age 4, 6. However, the CAG repeat length only accounts for between 50% and 69% of the variance observed in age at diagnosis 6, 7, 8. Consequently, the statistical estimations of proximity to diagnosis are unreliable at the level of the individual,5 resulting in the need for increased sample sizes to adequately power premanifest clinical trials.…”