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

@article{Nasir1995TargetedDO,
  title={Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes},
  author={Jamal Nasir and Stan B. Floresco and John R. O’Kusky and Virginia M. Diewert and Joy Richman and Jutta Zeisler and Anita H. Borowski and Jamey D Marth and Anthony G Phillips and Michael R. Hayden},
  journal={Cell},
  year={1995},
  volume={81},
  pages={811-823}
}
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 (Hdhex5), 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 Hdhex5 mutation display… Expand
Inactivation of the mouse Huntington's disease gene homolog Hdh.
TLDR
That Hdh inactivation does not mimic adult HD neuropathology suggests that the human disease involves a gain of function, and that huntingtin is critical early in embryonic development, before the emergence of the nervous system. Expand
Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue
TLDR
This work proposes that huntingtin is involved in processes counterbalancing the operation of an apoptotic pathway, and shows that this protein is functionally indispensable for nullizygous embryos become developmentally retarded and disorganized, and die between days 8.5 and 10.5 of gestation. Expand
A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice.
TLDR
Analysis of the mutation introduced into the endogenous mouse Hdh gene reveals significant levels of germline instability, which implies that effective treatment of HD may require an understanding and amelioration of these dysfunctional processes, rather than simply preventing the premature death of neurons in the brain. Expand
Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion
TLDR
The HD defect in man does not mimic complete or partial Hdh inactivation and appears to cause neurodegenerative disease by a gain-of-function mechanism. Expand
Use of Genetically Engineered Mice to Study the Biology of Huntingtin
TLDR
Understanding the normal function of hungtingtin not only provides insight into HD pathology but also offers guidance for the development of more efficient therapeutic strategies. Expand
Lessons from animal models of Huntington's disease.
TLDR
There is now a wide range of mouse models for HD, providing important insights into processes associated with disease pathogenesis, and studies in mouse models and human suggest that the mutation is associated with a deleterious gain of function. Expand
Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation
TLDR
It is observed that mice transgenic for exon 1 of the human HD gene carrying CAG115 to (CAG)156 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype. Expand
Transgenic models of Huntington's disease.
  • K. Sathasivam, C. Hobbs, +5 authors G. Bates
  • Biology, Medicine
  • Philosophical transactions of the Royal Society of London. Series B, Biological sciences
  • 1999
TLDR
An investigation into the skeletal muscle atrophy that occurs in the R6 lines is conducted to provide possible insights into the muscle bulk loss observed in HD patients and to conduct a parallel analysis into the consequence of inclusion formation to that being performed in brain. Expand
Hypomorphic mutation of the mouse Huntington’s disease gene orthologue
TLDR
It is shown that Htt is required both pre- and post-gastrulation to support normal development, and gene network dysregulation associated with organ development that nominate polycomb repressive complexes and miRNAs as molecular mediators are revealed. Expand
Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice
TLDR
It is proposed that huntingtin is required for neuronal function and survival in the brain and that a loss-of-function mechanism may contribute to HD pathogenesis. Expand
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TLDR
Observations suggest that the dominant HD mutation either confers a new property on the mRNA or alters an interaction at the protein level, suggesting the operation of interacting factors in determining specificity of cell loss. Expand
Huntington's disease gene (IT15) is widely expressed in human and rat tissues
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TLDR
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TLDR
The sequencing of cDNA clones spanning 9,992 nucleotides encoding the murine HD homologue (hd), which exhibits 90% peptide sequence identity, including conservation of the CAG and adjacent CCG repeats, is reported. Expand
Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice
TLDR
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TLDR
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TLDR
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TLDR
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