Genetic analysis of the GRIK2 modifier effect in Huntington's disease

We have tested this hypothesis by sequencing all GRIK2 exons, the exon-flanking sequences and 3'UTR in several individuals who were crucial to demonstrating the modifier effect, as they showed much earlier age at neurological onset than would be expected from the length of their HD CAG mutation. Though ten known SNPs were detected, no sequence variants were found in coding or adjacent sequence that could explain the modifier effect by linkage disequilibrium with the 16 TAA allele. Haplotype analysis using microsatellites, known SNPs and new variants discovered in the 3'UTR argues against a common ancestral origin for the 16 TAA repeat alleles in these individuals.These data suggest that the modifier effect is actually due to the TAA repeat itself, possibly via a functional consequence on the GRIK2 mRNA.Huntington disease (HD [MIM 143100]) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat that lengthens a polyglutamine tract near the amino terminus of the huntingtin protein [1]. The mutation involves a "gain-of-function" that leads to the selective loss of vulnerable neurons, most notably medium spiny neurons in the caudate nucleus, and results in characteristic progressive writhing movements, in addition to psychological changes and cognitive decline [2]. The age at onset of HD is variable, though the motor disturbance typically begins in mid-life, and is followed by an inexorable decline that ends in death after a course of 10–20 years. The length of the expanded CAG trinucleotide tract is the primary determinant of disease onset, although the mechanism whereby mutant huntingtin triggers the cascade of HD pathogenesis that eventually produces these symptoms is not yet clear [3,4]. Like several other polyglutamine neurodegenerative disorders, there is a strong inverse correlation between the length of the polyglutamine tract and the age at neurologic onset, with the longest mutations leading to juvenile HD. Indeed, the HD CAG repeat leng