INSTABILITY OF HIGHLY EXPANDED CAG REPEATS IN MICE TRANSGENIC FOR THEHUNTINGTONS-DISEASE MUTATION

Six inherited neurodegenerative diseases are caused by a CAG/polygluta mine 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 di sease (MJD or SCA3)(6) and SCA2(7-9). Normal and expanded HD allele si zes of 6-39 and 35-121 repeats have been reported(10-13), and the alle le distributions for the other diseases are comparable. Intergeneratio nal instability has been described in all cases, and repeats tend to b e more unstable on paternal transmission. This may present as larger i ncreases on paternal inheritance as in HD14, or as a tendency to incre ase on male and decrease on female transmission as in SCA1 (ref.15). S tomatic repeat instability is also appears most pronounced in the CNS1 6,17. The major exception is the cerebellum, which in HD, DRPLA, SCA1 and MJD has a smaller repeat relative to the other brain regions teste d(16-21). Of non-CNS tissues, instability was observed in blood, liver , kidney and colon(16,20,21). A mouse model of CAG repeat instability would be helpful in unravelling its molecular basis although an absenc e of CAG repeat instability in transgenic mice has so far been reporte d. These studies include (CAG)(45) in the androgen receptor cDNA(22), (CAG)(44), in the HD cDNA(23), (CAG)(82) in the SCA1 cDNA(24), (CAG)(7 9) in the SCA3 cDNA and as an isolated (CAC)(79) tract(25).