This human FXN YAC transgenic mouse model has the mouse frataxin knockout allele (Fxn-) and the YG8 small repeat human FXN YAC transgene (YG8s). The YG8s transgene has a contraction of the original YG8 transgene integration to a single copy. Like other GAA repeat mouse models, the YG8s transgene exhibits somatic GAA repeat instability. Upon arrival at The Jackson Laboratory in 2014, the transgene contained ~200 GAA repeats. Repeats are now in the 250-300 range (Jan 2017).
Compared to other human FXN YAC transgenic rescue mouse models, the YG8sR model expresses a contracted human frataxin, resulting in much greater FXN deficiency. As such, the donating investigator concludes that YG8sR can be considered the most suitable YAC transgenic GAA repeat-based mouse model for the investigation of potential therapies for Friedreich's Ataxia (FRDA).
Mice that are heterozygous for Fxn- and hemizygous for the YG8s transgene are viable and fertile with normal lifespan. When singly homozygous for the frataxin knockout allele, mice are embryonic lethal. Mice homozygous for the knockout (Fxn-/-) and hemizygous for the YG8s transgene, called YG8 small repeat human FXN YAC transgenic rescue mice (or YG8sR mice), exhibit an age-dependent GAA repeat expansion accumulation in the CNS (particularly cerebellum), progressive decrease in motor coordination and significant functional locomotor deficits; all similar to the human pathology of FRDA. YG8sR mice also exhibit glucose intolerance and insulin hypersensitivity. Of note, YG8sR mice have a progressive gain in weight compared to C57BL6/J mice (which may affect rotarod performance).
It should be noted that the YAC transgenic FRDA mouse models available from The Jackson Laboratory (YG22R, YG8R and YG8sR) may have different GAA repeat sizes than the animals used in the publications described below.
Publications from Dr. Mark A. Pook (Brunel University London) in 2014-2015 examine the correlation between the FRDA-like pathological phenotype and frataxin-deficiency in the YAC transgenic FRDA mouse models YG22R (two copies of the FRDA transgene; 190 GAA repeats expanded to ~170-260), YG8R (two copies of the FRDA transgene; 90-190 GAA repeats expanded to ~120-220) and YG8sR (a contraction of the transgene to a single copy; ~120-150 GAA repeats) compared to Y47R control mice (one copy of the FRDA transgene with a stable 9 GAA repeat) and C57BL6/J wildtype mice. The results described below are all in comparison to control mice.
The three YAC transgenic FRDA mouse models (YG8R, YG22R and YG8sR) had a progressive decrease in motor coordination; the degree of impairment was most significant in YG8R mice. All three models exhibited GAA repeat somatic instability in the brain, cerebellum and liver, as well as exhibited glucose intolerance and insulin hypersensitivity. The greatest FXN deficiency of the three models tested was in YG8sR. Expression levels of the transgenes in various tissues are reported in the Pook publications.
