TARGETED DISRUPTION OF THE HUNTINGTONS-DISEASE GENE RESULTS IN EMBRYONIC LETHALITY AND BEHAVIORAL AND MORPHOLOGICAL-CHANGES IN HETEROZYGOTES

Huntington's disease (HD) is an incurable neuropsychiatric disease ass ociated with CAG repeat expansion within a widely expressed gene that causes selective neuronal death. To understand its normal function, we have created a targeted disruption in exon 5 of Hdh (Hdh(ex5)), the m urine homolog of the HD gene. Homozygotes die before embryonic day 8.5 , initiate gastrulation, but do not proceed to the formation of somite s or to organogenesis, Mice heterozygous for the Hdh(ex5) mutation dis play increased motor activity and cognitive deficits. Neuropathologica l assessment of two heterozygous mice shows significant neuronal loss in the subthalamic nucleus. These studies show that the HD gene is ess ential for postimplantation development and that it may play an import ant role in normal functioning of the basal ganglia.