The Fragile X-related disorders (FXDs) are members of the Repeat Expansion 
Diseases, a group of human genetic conditions resulting from expansion of a 
specific tandem repeat. The FXDs result from expansion of a CGG/CCG repeat tract 
in the 5' UTR of the FMR1 gene. While expansion in a FXD mouse model is known to 
require some mismatch repair (MMR) proteins, our previous work and work in mouse 
models of another Repeat Expansion Disease show that early events in the base 
excision repair (BER) pathway play a role in the expansion process. One model 
for repeat expansion proposes that a non-canonical MMR process makes use of the 
nicks generated early in BER to load the MMR machinery that then generates 
expansions. However, we show here that heterozygosity for a Y265C mutation in 
Polβ, a key polymerase in the BER pathway, is enough to significantly reduce 
both the number of expansions seen in paternal gametes and the extent of somatic 
expansion in some tissues of the FXD mouse. These data suggest that events in 
the BER pathway downstream of the generation of nicks are also important for 
repeat expansion. Somewhat surprisingly, while the number of expansions is 
smaller, the average size of the residual expansions is larger than that seen in 
WT animals. This may have interesting implications for the mechanism by which 
BER generates expansions.