Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes

Huntington's disease (HD) is an incurable neuropsychiatric disease associated 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 murine homolog...

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Bibliographic Details
Published in:Cell 1995-06, Vol.81 (5), p.811-823
Main Authors: Nasir, Jamal, Floresco, Stan B, O'Kusky, John R, Diewert, Virginia M, Richman, Joy M, Zeisler, Jutta, Borowski, Anita, Marth, Jamey D, Phillips, Anthony G, Hayden, Michael R
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Behavior, Animal
Brain - pathology
Chimera
Discrimination Learning
Embryo, Mammalian - pathology
Female
Genes, Lethal - genetics
Heterozygote
Huntington Disease - genetics
Huntington Disease - pathology
Huntington Disease - psychology
Male
Memory, Short-Term
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Motor Activity
Mutagenesis
Mutation
Nerve Tissue Proteins - genetics
Nuclear Proteins - genetics
Polymerase Chain Reaction
Recombination, Genetic
Selection, Genetic
Sequence Deletion
Spatial Behavior
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Summary:Huntington's disease (HD) is an incurable neuropsychiatric disease associated 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 murine homolog of the HD gene. Homozygotes die before embryonic day 8.5, initiate gastrulation, but do not proceed to the formation of somites or to organogenesis. Mice heterozygous for the Hdh ex5 mutation display increased motor activity and cognitive deficits. Neuropathological assessment of two heterozygous mice shows significant neuronal loss in the subthalamic nucleus. These studies show that the HD gene is essential for postimplantation development and that it may play an important role in normal functioning of the basal ganglia.
ISSN:0092-8674
1097-4172
DOI:10.1016/0092-8674(95)90542-1