PMS2 has both pro-mutagenic and anti-mutagenic effects on repeat instability in the Repeat Expansion Diseases

Authors

• A Walker
• DA Jimenez
• K Usdin
• X Zhao

Abstract

Repeat Expansion Diseases (REDs) are a group of disorders caused by expansion of a short tandem repeat tract. They include the Fragile X-related disorders (FXDs), which are caused by expansion of a CGG-repeat in the Fmr1 gene, and Huntington’s disease (HD), which is caused by expansion of a CAG-repeat in the Htt gene. Genome Wide Association studies have implicated PMS2 as a modifier of somatic expansion in HD. PMS2 is a subunit of the MutL complex, a major component of the mismatch repair (MMR) system. In some cell and mouse models PMS2 protects against expansion, while it promotes expansion in others. To address the nature of these differences, we have examined the effect of the loss of PMS2 in different tissues of HD and FXD mouse models, matched for age and repeat size. We found that PMS2 plays a similar but complex role in repeat instability at both loci. Mice heterozygous for Pms2 show increased expansions in most tissues. While the extent of expansions increased in some tissues of Pms2 null mice, consistent with a continued protective role of PMS2, expansions decreased in others, suggesting a pro-mutagenic effect. Thus, previously reported differences in PMS2’s effect in different model systems, do not reflect fundamentally different roles played by PMS2 in different REDs, but rather the paradoxical effects of PMS2 in different cells. These findings have implications for the mechanism of expansion and for development of therapeutic approaches to reduce the pathology generated by repeat expansion.

Scientific Focus Area: Molecular Biology and Biochemistry

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