Expansion of a tandem repeat tract is responsible for the Repeat Expansion 
diseases, a group of more than 20 human genetic disorders that includes those 
like Fragile X (FX) syndrome that result from repeat expansion in the FMR1 gene. 
We have previously shown that the ATM and Rad3-related (ATR) checkpoint kinase 
protects the genome against one type of repeat expansion in a FX premutation 
mouse model. By crossing the FX premutation mice to Ataxia 
Telangiectasia-Mutated (Atm) mutant mice, we show here that ATM also prevents 
repeat expansion. However, our data suggest that the ATM-sensitive mechanism is 
different from the ATR-sensitive one. Specifically, the effect of the ATM 
deficiency is more marked when the premutation allele is paternally transmitted 
and expansions occur more frequently in male offspring regardless of the Atm 
genotype of the offspring. The gender effect is most consistent with a repair 
event occurring in the early embryo that is more efficient in females, perhaps 
as a result of the action of an X-linked DNA repair gene. Our data thus support 
the hypothesis that two different mechanisms of FX repeat expansion exist, an 
ATR-sensitive mechanism seen on maternal transmission and an ATM-sensitive 
mechanism that shows a male expansion bias.