Mice have been generated that are transgenic for the 5' end of the human HD gene carrying approximately 100 CAG repeat expansions. In this founder line (61Gpb), the transgene is ubiquitously expressed. Transgenic mice exhibit a progressive neurological phenotype that mimics many of the features of HD, including choreiform-like movements, involuntary stereotypic movements, tremor, and epileptic seizures, as well as nonmovement disorder components, including unusual vocalization. They urinate frequently and exhibit loss of body weight and muscle bulk through the course of the disease. Neurologically they develop Neuronal Intranuclear Inclusions (NII) which contain both the huntingtin and ubiquitin proteins. These NII have also been identified in human HD patients. The age of onset of HD symptoms is reported to occur between 15 and 21 weeks for this 61Gpb line. On the BALB/cByJ genetic background, the CAG tract remains somatically stable throughout the life span of the mouse but may contract over generations (even with male transmission). These HDexon1 mice may be useful in Huntington's Disease research.
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. Mice with this mutation were originally published on a mixed CBA x C57BL6 genetic background. It should be noted that the phenotype could vary from that originally described. We will modify the strain description as published results become available.
This 1.9 kb transgene was isolated from a phage genomic clone derived from an Huntington's Disease (HD) patient and contained the 5' end of the human huntingtin (Huntington disease) gene. It was composed of approximately 1 kb of 5' UTR sequences, exon 1 (carrying expanded CAG repeats of varying size but of the order of 130 units) and the first 262 bp of intron 1. This construct was microinjected into single cell CBAxC57BL/6 embryos. Male founder R6 was bred to CBA x C57BL/6 females, producing several founder lines. Mice from founder line R6/1 have the transgene integrated as a single intact copy and were originally found to have 116 CAG repeats. At some point, these mice were backcrossed to BALB/cBy mice for at least 25 generations by Dr. Anne Messer at the Wadsworth Center (Univ. of Albany). As of 2007, the donating investigator reports that these mice carry approximately 100 CAG repeats.
|Expressed Gene||HTT, huntingtin, human|
|Site of Expression|
|Allele Name||transgene insertion 61, Gillian Bates|
|Allele Type||Transgenic (Inserted expressed sequence, Humanized sequence)|
|Allele Synonym(s)||HD R6/1; httm; R6/1|
|Gene Symbol and Name||Tg(HDexon1)61Gpb, transgene insertion 61, Gillian Bates|
|Promoter||HTT, huntingtin, human|
|Expressed Gene||HTT, huntingtin, human|
|Strain of Origin||CBA x C57BL/6|
|General Note||The transgene is ubiquitously expressed. |
Transgenic mice on a background that involves C57BL/6 and CBA display a progressive neurological phenotype that mimics many of the features of Huntington Disease in humans, including choreiform-like movements, involuntary stereotypic movements, tremor, and epileptic seizures, as well as nonmovement disorder components, including unusual vocalization.Frequent urination and loss of body weight and muscle bulk occurs through the course of the disease. Neurological developments include Neuronal Intranuclear Inclusions (NII), which contain both the huntingtin and ubiquitin proteins (NII have subsequently been identified in human HD patients). Onset of HD symptoms occurs between 15 and 21 weeks of age.
|Molecular Note||A human HD fragment containing a polyglutamine-repeat expansion was isolated from a clone derived from a patient with Huntington's disease. The transgene contained approximately 1 kb of 5' UTR region, exon 1 which initially contained 113 CAG repeats, and 262 bp of intron 1 followed by a neomycin cassette. Subsequent analysis showed that the number of CAG repeats was prone to increase due to instability in the germline, and a range of 109.5 to 121 was observed.|
|Mutations Made By|| |
Gillian Bates, University College London, Institute of Neurology
When maintaining a live colony, hemizygous mice are bred to BALB/cByJ inbred mice or to wildtype siblings.
When using the BALB R6/1 mouse strain in a publication, please cite the originating article(s) and include JAX stock #007578 in your Materials and Methods section.