Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches

摘要: The Huntington’s disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of may therefore provide routes for therapies targeting the underlying mutation, an approach is likely applicable to other trinucleotide diseases. Hdh Q111 mice exhibit higher levels HTT on a C57BL/6 genetic background (B6.Hdh ) than 129 (129.Hdh ). Linkage mapping in (B6x129).Hdh F2 intercross animals identified single quantitative trait locus strainspecific difference striatum, implicating mismatch repair (MMR) Mlh1 as most candidate modifier. Crossing B6.Hdh onto null demonstrated essential expansions and it enhancer nuclear huntingtin accumulation striatal neurons. was also abolished deficient Mlh3 gene, MutLc (MLH1–MLH3) complex key driver expansion. Strikingly, genes encoding MMR effector proteins were critical Msh2 Msh3 DNA recognition MutSb (MSH2–MSH3). highly polymorphic between B6 strains. While we unable detect any base-base or short slipped-repeat activity MLH1 variants, efficiency dose-dependent. mRNA protein significantly decreased compared mice, consistent dose-sensitive MLH1-dependent mechanism these Together, data identify novel modifiers instability, point variation source instability strains suggest play important role driving expansions.