Get access

The Mismatch Repair Protein MSH2 is Rate Limiting for Repeat Expansion in a Fragile X Premutation Mouse Model

Authors

  • Rachel Adihe Lokanga,

    1. Section on Genomic Structure and Function, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Marland
    2. Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa
    Search for more papers by this author
  • Xiao-Nan Zhao,

    1. Section on Genomic Structure and Function, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Marland
    Search for more papers by this author
  • Karen Usdin

    Corresponding author
    1. Section on Genomic Structure and Function, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Marland
    • Correspondence to: Karen Usdin, Building 8, Room 2A19, National Institutes of Health, 8 CENTER DR MSC 0830, Bethesda, MD 20892-0830. E-mail: ku@helix.nih.gov

    Search for more papers by this author

  • Contract grant sponsor: Intramural Program of NIH (NIDDK) (DK057808-05).

  • Communicated by Finlay A. Macrae

ABSTRACT

Fragile X-associated tremor and ataxia syndrome, Fragile X-associated primary ovarian insufficiency, and Fragile X syndrome are Repeat Expansion Diseases caused by expansion of a CGG•CCG-repeat microsatellite in the 5′ UTR of the FMR1 gene. To help understand the expansion mechanism responsible for these disorders, we have crossed mice containing ∼147 CGG•CCG repeats in the endogenous murine Fmr1 gene with mice containing a null mutation in the gene encoding the mismatch repair protein MSH2. MSH2 mutations are associated with elevated levels of generalized microsatellite instability. However, we show here for the first time that in the FX mouse model, all maternally and paternally transmitted expansions require Msh2. Even the loss of one Msh2 allele reduced the intergenerational expansion frequency significantly. Msh2 is also required for all somatic expansions and loss of even one functional Msh2 allele reduced the extent of somatic expansion in some organs. Tissues with lower levels of MSH2 were more sensitive to the loss of a single Msh2 allele. This suggests that MSH2 is rate limiting for expansion in this mouse model and that MSH2 levels may be a key factor that accounts for tissue-specific differences in expansion risk.

Ancillary