INCREASED INSTABILITY OF INTERMEDIATE ALLELES IN FAMILIES WITH SPORADIC HUNTINGTON DISEASE COMPARED TO SIMILAR SIZED INTERMEDIATE ALLELES IN THE GENERAL-POPULATION

We have directly compared intergenerational stability of intermediate alleles (IAs) derived from new mutation families (IA(NM)) for Huntington disease (HD) with IAs in the general population (IA(GP)) which Occur in similar to 1 in 50 persons. Analysis of meiotic events in blood and sperm reveals that IA(NM) are significantly more unstable than IA(GP) despite similar size. However, for both IA(NM) and IA(GP) CAG changes were small and risks for inheriting an expansion into the HD affected range were low. Sequence analysis reveals that the CAG tract is generally interrupted by a penultimate CAA in IA(GP) IA(NM) and alleles in the affected range. In one new mutation family, however, two A-->G mutations result in a pure CAG tract which is associated with very marked instability. These mutations alter the predicted DNA hairpin structure with a predicted increase in the likelihood of large expansion, supporting the model that hairpin loop formation plays an important role in trinucleotide instability.