Abstract
The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease HdhQ111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.HdhQ111) than on a 129 background (129.HdhQ111). Linkage mapping in (B6x129).HdhQ111 F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.HdhQ111 mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. HdhQ111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1–MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2–MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions.
Highlights
Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disease, which is caused by the expansion of a CAG repeat within exon 1 of the HTT gene, resulting in an extended glutamine tract in the huntingtin protein (HTT) [1]
We are using mouse models of HD to identify the factors that modify the somatic expansion of the HD CAG repeat, as these may provide novel targets for therapeutic intervention
Our results demonstrate that: 1) Mlh1 and Mlh3 genes, encoding components of the DNA mismatch repair pathway, are critical for somatic CAG expansion; 2) in the absence of somatic expansion the pathogenic process in the mouse is slowed; 3) MLH1 protein levels are likely to be a driver of the efficiency of somatic expansion
Summary
Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disease, which is caused by the expansion of a CAG repeat within exon 1 of the HTT gene, resulting in an extended glutamine tract in the huntingtin protein (HTT) [1]. Precise disease expression and timing are clearly modifiable by other factors, with strong evidence supporting the contribution of genetic factors [3,4]. The identification of such factors could lead to the development of novel therapeutic interventions that modify the nature and/or pace of the HD-associated pathogenic process, and is being pursued via a number of candidate and global genetic approaches [5]. Given the strong CAG length-dependence of disease onset and severity, somatic expansion is predicted to accelerate the disease process. Whether somatic expansion beyond a typically inherited repeat length of 40–50 CAGs is required for disease onset is unclear
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