Analysis of the 5' upstream sequence of the Huntington's disease (HD) gene shows six new rare alleles which are unrelated to the age at onset of HD

The CAG repeat number in the Huntington's disease (HD) gene accounts for about 50% of the variation seen in age at onset of HD. In order to determine whether promoter sequence variation can contribute to the residual variation in age at onset, we studied the conserved 303 bp region upstream of the +1 translation start site in the HD gene in a population of 56 control East Anglians, 30 Africans, 34 Japanese, and 208 English Huntington's disease patients. A surprisingly high degree of variation was found. Seven alleles were identified, comprising four polymorphisms: two single base pair substitutions, a 6 bp VNTR present as one or two copies, and a 20 bp VNTR with one to three copies of the tandem repeat. No correlation between polymorphisms and age at onset of symptoms was found in HD patients. The 6 bp and 20 bp stretches are present only in single copies in the chimpanzees and gorilla, suggesting that these VNTRs have evolved by duplication of the core sequences in the human lineage.