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The Fragile X-related disorders (FXDs) are Repeat Expansion Diseases resulting from an expansion of a CGG-repeat tract at the 5’ end of the  FMR1  gene. The mechanism responsible for this unusual mutation is not fully understood. We have previously shown that mismatch repair (MMR) complexes, MSH2/MSH3 (MutSβ) and MSH2/MSH6 (MutSα), together with Polβ, a DNA polymerase important for base excision repair (BER), are important for expansions in a mouse model of these disorders. Here we show that MLH1/MLH3 (MutLγ), a protein complex that can act downstream of MutSβ in MMR, is also required for all germ line and somatic expansions. However, exonuclease I ( EXO1 ), which acts downstream of MutL proteins in MMR, is not required. In fact, a null mutation in  Exo1  results in more extensive germ line and somatic expansions than is seen in  Exo1   +/+   animals. Furthermore, mice homozygous for a point mutation (D173A) in  Exo1  that eliminates its nuclease activity but retains its native conformation, shows a level of expansion that is intermediate between  Exo1   +/+    and Exo1   -/-   animals. Thus, our data suggests that expansion of the FX repeat in this mouse model occurs via a MutLγ-dependent, EXO1-independent pathway, with EXO1 protecting against expansion both in a nuclease-dependent and a nuclease-independent manner. Our data thus have implications for the expansion mechanism and add to our understanding of the genetic factors that may be modifiers of expansion risk in humans.

MutLγ promotes repeat expansion in a Fragile X mouse model while EXO1 is protective