Expansion of an unstable CGG-repeat tract in the 5′UTR of the FMR1 gene, which is unstable when intergenerationally transmitted, is associated with the Fragile X-related disorders. These disorders include Fragile X-associated tremor and ataxia syndrome (FXTAS), a late onset neurodegenerative disorder, Fragile X-associated primary ovarian insufficiency (FXPOI), a disorder of ovarian dysfunction and Fragile X syndrome, a neurodevelopmental disorder.
The mechanism(s) that leads to the CGG expansion is not known; however, in this issue, Lokanga et al. (Hum Mutat 35:129–136, 2014) have shown that the mismatch repair protein MSH2 is required for all germ-line and somatic expansions in a FMR1 premutation mouse model. However, MSH2 is not required for contractions, which are also observed in CGG alleles and likely occur by a different mechanism.
The involvement of MSH2, which has also been reported in mouse models of other repeat expansion disorders like myotonic dystrophy, suggests that a similar mechanism may be responsible for all of these disorders. It would also be consistent with the idea that such tandem repeats are prone to expand because they form DNA secondary structures, perhaps during transcription or replication, that contain non-Watson-Crick base pairs that are recognized by components of the mismatch repair machinery.
The work presented by Lokanga et al. emphasizes the complexity and the challenges of the instability process. Expansion occurs both in germ-line and in specific somatic tissue and their findings suggest that a number of additional factors, including environmental triggers and trans acting factors, may act as modulators of the expansion process that may explain the broad variation of somatic instability that is seen in human carriers of expansion-prone alleles. This paper represents a further step in our understanding of the mechanism(s) involved in the CGG trinucleotide repeat expansion and perhaps of repeat expansion in other disease models.