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The Mismatch Repair Protein MSH 2 is Rate Limiting for Repeat Expansion in a Fragile X Premutation Mouse Model
Author(s) -
Lokanga Rachel Adihe,
Zhao XiaoNan,
Usdin Karen
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22464
Subject(s) - msh2 , biology , allele , trinucleotide repeat expansion , dna mismatch repair , fragile x syndrome , genetics , gene , mutation , dna repair
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 FMR 1 gene. To help understand the expansion mechanism responsible for these disorders, we have crossed mice containing ∼147 CGG • CCG repeats in the endogenous murine F mr1 gene with mice containing a null mutation in the gene encoding the mismatch repair protein MSH 2. MSH 2 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 MSH 2 were more sensitive to the loss of a single Msh2 allele. This suggests that MSH 2 is rate limiting for expansion in this mouse model and that MSH 2 levels may be a key factor that accounts for tissue‐specific differences in expansion risk.