Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation

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Abstract
Six inherited neurodegenerative diseases are caused by a CAG/polyglutamine expansion, including spinal and bulbar muscular atrophy (SBMA)1, Huntington's disease (HD)2, spinocerebellar ataxia type 1 (SCA1)3, dentatorubral pallidoluysian atrophy (DRPLA)4,5 Machado-Joseph disease (MJD or SCAB)6 and SCA27–9. Normal and expanded HD allele sizes of 6–39 and 35–121 repeats have been reported10–13, and the allele distributions for the other diseases are comparable. Intergenerational instability has been described in all cases, and repeats tend to be more unstable on paternal transmission. This may present as larger increases on paternal inheritance as in HD14, or as a tendency to increase on male and decrease on female transmission as in SCA1 (ref. 15). Somatic repeat instability is also apparent and appears most pronounced in the CNS16,17. The major exception is the cerebellum, which in HD, DRPLA, SCA1 and MJD has a smaller repeat relative to the other brain regions tested16–21. Of non-CNS tissues, instability was observed in blood, liver, kidney and colon16,20,21. A mouse model of CAG repeat instability would be helpful in unravelling its molecular basis although an absence of CAG repeat instability in transgenic mice has so far been reported. These studies include (CAG)45 in the androgen receptor cDNA22, (CAG)44 in the HD cDNA23, (CAG)82 in the SCA1 cDNA24, (CAG)79 in the SCA3 cDNA andas an isolated (CAG)79 tract25.