Huntington's disease (HD) is a neurodegenerative disorder characterized by the 
expansion of CAG repeats in exon 1 of the HD gene. To clarify the instability of 
expanded CAG repeats in HD patients, an HD model mouse has been generated by 
gene replacement with human exon 1 of the HD gene with expansion to 77 CAG 
repeats. Chimeric proteins composed of human mutated exon 1 and mouse huntingtin 
are expressed ubiquitously in brain and peripheral tissues. One or two CAG 
repeat expansion was found in litters from paternal transmission, whereas 
contraction of CAG repeat in litters was observed through maternal transmission. 
Elderly mice show greater CAG repeat instability than younger mice, and a unique 
case was observed of an expanded 97 CAG repeat mouse. Somatic CAG repeat 
instability is particularly pronounced in the liver, kidney, stomach, and brain 
but not in the cerebellum of 100-week-old mice. The same results of expanded CAG 
repeat instability as observed in this HD model mouse were confirmed in the 
human brain of HD patients. Glial fibrillary acidic protein (GFAP)-positive 
cells have been found to be increased in the substantia nigra (SN), globus 
pallidus (GP), and striatum (St) in the brains of 40-week-old affected mice, 
although without neuronal cell death. The CAG repeat instability and increase in 
GFAP-positive cells in this mouse model appear to mirror the abnormalities in HD 
patients. The HD model mouse may therefore have advantages for investigations of 
molecular mechanisms underlying instability of CAG repeats.