Expansion of a CGG-repeat tract in the 5' untranslated region of the FMR1 gene 
causes the fragile X-related disorders (FXDs; aka the FMR1 disorders). The 
expansion mechanism is likely shared by the 35+ other diseases resulting from 
expansion of a disease-specific microsatellite, but many steps in this process 
are unknown. We have shown previously that expansion is dependent upon 
functional mismatch repair proteins, including an absolute requirement for 
MutLγ, one of the three MutL heterodimeric complexes found in mammalian cells. 
We demonstrate here that both MutLα and MutLβ, the two other MutL complexes 
present in mammalian cells, are also required for most, if not all, expansions 
in a mouse embryonic stem cell model of the FXDs. A role for MutLα and MutLβ is 
consistent with human GWA studies implicating these complexes as modifiers of 
expansion risk in other Repeat Expansion Diseases. The requirement for all three 
complexes suggests a novel model in which these complexes co-operate to generate 
expansions. It also suggests that the PMS1 subunit of MutLβ may be a reasonable 
therapeutic target in those diseases in which somatic expansion is an important 
disease modifier.