MSH2 is not required for either maintenance of DNA methylation or repeat contraction at the FMR1 locus in fragile X syndrome or the FXN locus in Friedreich’s ataxia

Our results suggest that there are mechanistic differences in the way that DNA methylation is maintained in the region upstream of expanded repeats among different REDs even though they share a similar mechanism of repeat expansion. The high frequency of transcription-induced MSH2-dependent and MSH2-independent contractions we have observed may contribute to the mosaicism that is frequently seen in carriers of FMR1 alleles with expanded CGG-repeat tracts. These contractions may reflect the underlying problems associated with transcription through the repeat. Given the recent interest in the therapeutic use of transcription-driven repeat contractions, our data may have interesting mechanistic, prognostic, and therapeutic implications.