All three mammalian MutL complexes are required for repeat expansion in a mouse cell model of the Fragile X-related disorders
Autoři:
Carson J. Miller aff001; Geum-Yi Kim aff001; Xiaonan Zhao aff001; Karen Usdin aff001
Působiště autorů:
Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
aff001
Vyšlo v časopise:
All three mammalian MutL complexes are required for repeat expansion in a mouse cell model of the Fragile X-related disorders. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008902
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008902
Souhrn
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.
Klíčová slova:
Genome-wide association studies – Guide RNA – Mouse models – Mutation – Nucleases – Oligonucleotides – Point mutation – Polymerase chain reaction
Zdroje
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