The C57BL/6J-congenic, HD-repeat knock-in line Hdh4/Q80 (B6J.HdhQ80) has the mouse Htt with an expanded tract of ~86 CAG repeats. These B6J.HdhQ80 knock-in mice may be useful for studying Huntington's disease, specifically to investigate the influence of CAG size on the desired outcome measures.
Peggy F Shelbourne, University of Glasgow
Dr. David Howland, CHDI Foundation
Stock No. 027412 was formerly associated with CHDI Foundation colony Stock No. 370506 [CHDI-81003007].
Huntington's disease (HD) is an autosomally dominant, fatal neurodegenerative disorder characterized by uncontrolled movements, psychiatric disturbances and cognitive impairment. HD is caused by an unstable trinucleotide (polyglutamine) repeat expansion in the huntingtin gene (HTT; HD or Hdh).
The HD-repeat knock-in allele Hdh4/Q80 (HdhQ80 or HdhQ80) expresses a mutant mouse huntingtin protein with an expanded tract of ~86 CAG repeats. The CAG repeat number is subject to germline and somatic instability, and may expand or contract (see note on CAG instability below). On a C57BL/6J background or a mixed C57BL/6;129 genetic background, heterozygous mice are viable and fertile with normal lifespan. On a mixed C57BL/6;129 genetic background, heterozygotes display chronic aggressive behavior from ~3 months of age.
This Huntington's disease mouse model is available by way of a collaborative effort between CHDI Foundation, Dr. Marcy E. MacDonald (Massachusetts General Hospital) and The Jackson Laboratory.
Expanded CAG sequences in huntingtin exon 1 may be subject to germline or somatic instability, and may expand or contract. The CAG repeat number in the HdhQ80 knock-in allele is reported to have intermediate levels of instability. When using lines with unstable CAG repeat length, it is strongly recommended the CAG repeat number be quantified in all the experimental animals; all animals in all experimental groups should carry comparable CAG repeat sizes. CAG repeat sizing of HD mice should be done using high-resolution methods as assays based on agarose gel electrophoresis typically do not provide sufficient resolution to accurately measure CAG repeat numbers. If labs do not have access to the appropriate equipment for determining CAG repeat length, CAG repeats can be evaluated on a fee-for-service basis by Laragen, Inc.
The HD-repeat knock-in allele Hdh4/Q80 (HdhQ80 or HdhQ80) was designed by Dr. Peggy F. Shelbourne (University of Glasgow) to have the polyglutamine-encoding stretch [(CAG)2CAA(CAG)4] of the first exon of the endogenous mouse huntingtin (Htt; HD or Hdh) gene replaced by an expanded tract of 80 perfect CAG repeat units isolated from a human HTT sequence. The targeting vector was microinjected into 129S4/SvJae-derived RF8 embryonic stem (ES) cells. A floxed neomycin resistance cassette inserted into intron 1 was removed in ES cells by transient transfection with a Cre recombinase-expressing plasmid.
The HdhQ80 knock-in mice were backcrossed with C57BL/6J inbred mice for 5-10 generations, sent to the CHDI Foundation, and then backcrossed an additional nine generations with C57BL/6J inbred mice (Stock No. 000664) to create the C57BL/6J-congenic colony (B6J.HdhQ80 or B6J.HdhQ80), called CHDI Foundation colony Stock No. 370506 [CHDI-81003007]. In 2015, heterozygous animals with ~86 CAG repeat length were sent from the CHDI Foundation colony to The Jackson Laboratory Repository, from which B6J.HdhQ80 heterozygotes are available as Stock No. 027412.
|Allele Name||targeted mutation 1.1, Peggy F Shelbourne|
|Gene Symbol and Name||Htt, huntingtin|
|Strain of Origin||129S4/SvJae|
|Molecular Note||This allele carries 80 CAG repeat units in the first exon of the endogenous gene. A loxP flanked neomycin selection cassette in the first intron was removed by Cre mediated recombination in the final allele.|
Homozygous and heterozygous mice are viable and fertile with normal lifespans. When maintaining our live colony, C57BL/6J inbred females (Stock No. 000664) or wildtype females from the colony are bred to heterozygous males. Breeding heterozygous mice to wildtype animals from the colony or to C57BL/6J inbred mice may also be possible regardless of specific sex.
When using the B6J.HdhQ80 ; HttQ80 ; CHDI-81003007 mouse strain in a publication, please cite the originating article(s) and include JAX stock #027412 in your Materials and Methods section.